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Franz, Katherine J.

Overview:

Research in the Franz group is involved in elucidating the structural and functional consequences of metal ion coordination in biological systems. We are particularly interested in understanding the coordination chemistry utilized by biology to manage essential yet toxic species like copper and iron. Understanding these principles further guides our development of new chemical tools to manipulate biological metal ion location, speciation, and reactivity for potential therapeutic benefit. We use a combination of synthesis, spectroscopy, and biochemistry in our work. Please visit our group website to learn more about our research.

Positions:

Professor in the Department of Chemistry

Chemistry
Trinity College of Arts & Sciences

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Alexander F. Hehmeyer Professor of Chemistry

Chemistry
Trinity College of Arts & Sciences

Education:

B.A. 1995

B.A. — Wellesley College

Ph.D. 2000

Ph.D. — Massachusetts Institute of Technology

News:

Grants:

Duke University Program in Environmental Health

Administered By
Environmental Sciences and Policy
AwardedBy
National Institute of Environmental Health Sciences
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2018

Development of Chemical Tools to Manipulate Copper at the Host/Pathogen Interface

Administered By
Chemistry
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
June 01, 2008
End Date
May 31, 2017

Stimulus-Responsive Agents For Manipulating Cellular Copper

Administered By
Chemistry
AwardedBy
National Science Foundation
Role
Principal Investigator
Start Date
September 01, 2012
End Date
March 31, 2016

REU Site: Chemistry and Applications of Smart Molecules and Materials at Duke University

Administered By
Chemistry
AwardedBy
National Science Foundation
Role
Co-Principal Investigator
Start Date
April 15, 2011
End Date
March 31, 2016

BioMetals 2014 Conference at Duke University

Administered By
Chemistry
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 2014
End Date
June 30, 2015

High sensitivity multi-purpose electron paramagnetic resonance spectroscopy for biotechnological and biomedical research

Administered By
Biochemistry
AwardedBy
North Carolina Biotechnology Center
Role
Collaborating Investigator
Start Date
May 01, 2014
End Date
April 30, 2015

Purchase of a Q-TOF LC/MS System

Administered By
Chemistry
AwardedBy
National Institutes of Health
Role
Major User
Start Date
August 09, 2010
End Date
August 08, 2011

Metal-Binding Studies of Phosporylated alpha-Synuclein Peptides

Administered By
Chemistry
AwardedBy
National Science Foundation
Role
Principal Investigator
Start Date
September 01, 2005
End Date
August 31, 2010
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Awards:

Sloan Research Fellowship-Chemistry. Alfred P. Sloan Foundation.

Type
National
Awarded By
Alfred P. Sloan Foundation
Date
January 01, 2008

Publications:

Chemical and functional properties of metal chelators that mobilize copper to elicit fungal killing of Cryptococcus neoformans.

A panel of iron (Fe) and copper (Cu) chelators was screened for growth inhibitory activity against the fungal pathogen Cryptococcus neoformans. Select bidentate metal-binding ligands containing mixed O,S or O,N donor atoms were identified as agents that induce cell killing in a Cu-dependent manner. Conversely, structurally similar ligands with O,O donor atoms did not inhibit C. neoformans growth regardless of Cu status. Studies of Cu(ii) and Cu(i) binding affinity, lipophilicity, and growth recovery assays of Cu-import deficient cells identified lipophilicity of thermodynamically stable CuIIL2 complexes as the best predictor of antifungal activity. These same complexes induce cellular hyperaccumulation of Zn and Fe in addition to Cu. The results described here present the utility of appropriate metal-binding ligands as potential antifungal agents that manipulate cellular metal balance as an antimicrobial strategy.

Authors
Helsel, ME; White, EJ; Razvi, SZA; Alies, B; Franz, KJ
MLA Citation
Helsel, ME, White, EJ, Razvi, SZA, Alies, B, and Franz, KJ. "Chemical and functional properties of metal chelators that mobilize copper to elicit fungal killing of Cryptococcus neoformans." Metallomics : integrated biometal science 9.1 (January 2017): 69-81.
PMID
27853789
Source
epmc
Published In
Metallomics
Volume
9
Issue
1
Publish Date
2017
Start Page
69
End Page
81
DOI
10.1039/c6mt00172f

Stimulus-Responsive Prochelators for Manipulating Cellular Metals.

Metal ions are essential for a wide range of physiological processes, but they can also be toxic if not appropriately regulated by a complex network of metal trafficking proteins. Intervention in cellular metal distribution with small-molecule or peptide chelating agents has promising therapeutic potential to harness metals to fight disease. Molecular outcomes associated with forming metal-chelate interactions in situ include altering the concentration and subcellular metal distribution, inhibiting metalloenzymes, enhancing the reactivity of a metal species to elicit a favorable biological response, or passivating the reactivity of a metal species to prevent deleterious reactivity. The systemic administration of metal chelating agents, however, raises safety concerns due to the potential risks of indiscriminate extraction of metals from critical metalloproteins and inhibition of metalloenzymes. One can estimate that chelators capable of complexing metal ions with dissociation constants in the submicromolar range are thermodynamically capable of extracting metal ions from some metalloproteins and disrupting regular function. Such dissociation constants are easily attainable for multidentate chelators interacting with first-row d-block metal cations in relevant +1, + 2, and +3 oxidation states. To overcome this challenge of indiscriminate metal chelation, we have pursued a prodrug strategy for chelating agents in which the resulting "prochelator" has negligible metal binding affinity until a specific stimulus generates a favorable metal binding site. The prochelator strategy enables conditional metal chelation to occur preferentially in locations affected by disease- or therapy-associated stimuli, thereby minimizing off-target metal chelation. Our design of responsive prochelators encompasses three general approaches of activation: the "removal" approach operates by eliminating a masking group that blocks a potential metal chelation site to reveal the complete binding site under the desired conditions; the molecular "switch" approach involves a reversible conformational change between inactive and active forms of a chelator with differential metal binding affinity under specific conditions; and the "addition" approach adds a new ligand donor arm to the prochelator to constitute a complete metal chelation site. Adopting these approaches, we have created four categories of triggerable prochelators that respond to (1) reactive oxygen species, (2) light, (3) specific enzymes, and (4) biological regulatory events. This Account highlights progress from our group on building prochelators that showcase these four categories of responsive metal chelating agents for manipulating cellular metals. The creation and chemical understanding of such stimulus-responsive prochelators enables exciting applications for understanding the cell biology of metals and for developing therapies based on metal-dependent processes in a variety of diseases.

Authors
Wang, Q; Franz, KJ
MLA Citation
Wang, Q, and Franz, KJ. "Stimulus-Responsive Prochelators for Manipulating Cellular Metals." Accounts of chemical research 49.11 (November 2016): 2468-2477.
PMID
27749047
Source
epmc
Published In
Accounts of Chemical Research
Volume
49
Issue
11
Publish Date
2016
Start Page
2468
End Page
2477

Novel aminoalkyl tris-cyclometalated iridium complexes as cellular stains.

Herein we report the synthesis and investigation of the properties of two tris-cyclometalated luminescent iridium complexes. These complexes are the simple derivatives of fac-[Ir(ppy)3] bearing amino alkyl groups on one of the phenylpyridine rings. The complexes are highly emissive and exhibit structured emission peaks in aqueous solution while having only broad unstructured emission in organic solvents. The complexes have been shown to be taken up by NIH-3T3 and PC3 cells, where they localize in the lysosomes and remain emissive with lifetimes in the microsecond domain.

Authors
Sansee, A; Meksawangwong, S; Chainok, K; Franz, KJ; Gál, M; Pålsson, L-O; Puniyan, W; Traiphol, R; Pal, R; Kielar, F
MLA Citation
Sansee, A, Meksawangwong, S, Chainok, K, Franz, KJ, Gál, M, Pålsson, L-O, Puniyan, W, Traiphol, R, Pal, R, and Kielar, F. "Novel aminoalkyl tris-cyclometalated iridium complexes as cellular stains." Dalton transactions (Cambridge, England : 2003) 45.43 (November 2016): 17420-17430.
PMID
27734036
Source
epmc
Published In
Dalton Transactions
Volume
45
Issue
43
Publish Date
2016
Start Page
17420
End Page
17430
DOI
10.1039/c6dt02776h

Cardioprotective effects of iron chelator HAPI and ROS-activated boronate prochelator BHAPI against catecholamine-induced oxidative cellular injury.

Catecholamines may undergo iron-promoted oxidation resulting in formation of reactive intermediates (aminochromes) capable of redox cycling and reactive oxygen species (ROS) formation. Both of them induce oxidative stress resulting in cellular damage and death. Iron chelation has been recently shown as a suitable tool of cardioprotection with considerable potential to protect cardiac cells against catecholamine-induced cardiotoxicity. However, prolonged exposure of cells to classical chelators may interfere with physiological iron homeostasis. Prochelators represent a more advanced approach to decrease oxidative injury by forming a chelating agent only under the disease-specific conditions associated with oxidative stress. Novel prochelator (lacking any iron chelating properties) BHAPI [(E)-Ń-(1-(2-((4-(4,4,5,5-tetramethyl-1,2,3-dioxoborolan-2-yl)benzyl)oxy)phenyl)ethylidene) isonicotinohydrazide] is converted by ROS to active chelator HAPI with strong iron binding capacity that efficiently inhibits iron-catalyzed hydroxyl radical generation. Our results confirmed redox activity of oxidation products of catecholamines isoprenaline and epinephrine, that were able to activate BHAPI to HAPI that chelates iron ions inside H9c2 cardiomyoblasts. Both HAPI and BHAPI were able to efficiently protect the cells against intracellular ROS formation, depletion of reduced glutathione and toxicity induced by catecholamines and their oxidation products. Hence, both HAPI and BHAPI have shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity.

Authors
Hašková, P; Jansová, H; Bureš, J; Macháček, M; Jirkovská, A; Franz, KJ; Kovaříková, P; Šimůnek, T
MLA Citation
Hašková, P, Jansová, H, Bureš, J, Macháček, M, Jirkovská, A, Franz, KJ, Kovaříková, P, and Šimůnek, T. "Cardioprotective effects of iron chelator HAPI and ROS-activated boronate prochelator BHAPI against catecholamine-induced oxidative cellular injury." Toxicology 371 (September 2016): 17-28.
PMID
27744045
Source
epmc
Published In
TOXICOLOGY
Volume
371
Publish Date
2016
Start Page
17
End Page
28
DOI
10.1016/j.tox.2016.10.004

Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products.

Free cellular iron catalyzes the formation of toxic hydroxyl radicals and therefore chelation of iron could be a promising therapeutic approach in pathological states associated with oxidative stress. Salicylaldehyde isonicotinoyl hydrazone (SIH) is a strong intracellular iron chelator with well documented potential to protect against oxidative damage both in vitro and in vivo. Due to the short biological half-life of SIH and risk of toxicity due to iron depletion, boronate prochelator BSIH has been designed. BSIH cannot bind iron until it is activated by certain reactive oxygen species to active chelator SIH. The aim of this study was to examine the toxicity and cytoprotective potential of BSIH, SIH, and their decomposition products against hydrogen peroxide-induced injury of H9c2 cardiomyoblast cells. Using HPLC, we observed that salicylaldehyde was the main decomposition products of SIH and BSIH, although a small amount of salicylic acid was also detected. In the case of BSIH, the concentration of formed salicylaldehyde consistently exceeded that of SIH. Isoniazid and salicylic acid were not toxic nor did they provide any antioxidant protective effect in H9c2 cells. In contrast, salicylaldehyde was able to chelate intracellular iron and significantly preserve cellular viability and mitochondrial inner membrane potential induced by hydrogen peroxide. However it was consistently less effective than SIH. The inherent toxicities of salicylaldehyde and SIH were similar. Hence, although SIH - the active chelating agent formed following the BSIH activation - undergoes rapid hydrolysis, its principal decomposition product salicylaldehyde accounts markedly for both cytoprotective and toxic properties.

Authors
Jansová, H; Bureš, J; Macháček, M; Hašková, P; Jirkovská, A; Roh, J; Wang, Q; Franz, KJ; Kovaříková, P; Šimůnek, T
MLA Citation
Jansová, H, Bureš, J, Macháček, M, Hašková, P, Jirkovská, A, Roh, J, Wang, Q, Franz, KJ, Kovaříková, P, and Šimůnek, T. "Characterization of cytoprotective and toxic properties of iron chelator SIH, prochelator BSIH and their degradation products." Toxicology 350-352 (March 2016): 15-24.
PMID
27046792
Source
epmc
Published In
TOXICOLOGY
Volume
350-352
Publish Date
2016
Start Page
15
End Page
24
DOI
10.1016/j.tox.2016.03.004

A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress.

UVA radiation can damage cells and tissues by direct photodamage of biomolecules as well as by initiating metal-catalyzed oxidative stress. In order to alleviate both concerns simultaneously, we synthesized a multifunctional prochelator PC-HAPI (2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (trans)-3-(2,4-dihydroxyphenyl)acrylate) that contains a trans-(o-hydroxy)cinnamate ester photocleavable protecting group that is cleaved upon UVA exposure to release a coumarin, umbelliferone, and an aroylhydrazone metal chelator, HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide). While the prochelator PC-HAPI exhibits negligible affinity for iron, it responds rapidly to UVA irradiation and converts to an iron-binding chelator that inhibits iron-catalyzed formation of reactive oxygen species and protects cells from UVA damage.

Authors
Franks, AT; Wang, Q; Franz, KJ
MLA Citation
Franks, AT, Wang, Q, and Franz, KJ. "A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress." Bioorganic & medicinal chemistry letters 25.21 (November 2015): 4843-4847.
PMID
26152427
Source
epmc
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
25
Issue
21
Publish Date
2015
Start Page
4843
End Page
4847
DOI
10.1016/j.bmcl.2015.06.048

Model Peptide Studies Reveal a Mixed Histidine-Methionine Cu(I) Binding Site at the N-Terminus of Human Copper Transporter 1.

Copper is a vital metal cofactor in enzymes that are essential to myriad biological processes. Cellular acquisition of copper is primarily accomplished through the Ctr family of plasma membrane copper transport proteins. Model peptide studies indicate that the human Ctr1 N-terminus binds to Cu(II) with high affinity through an amino terminal Cu(II), Ni(II) (ATCUN) binding site. Unlike typical ATCUN-type peptides, the Ctr1 peptide facilitates the ascorbate-dependent reduction of Cu(II) bound in its ATCUN site by virtue of an adjacent HH (bis-His) sequence in the peptide. It is likely that the Cu(I) coordination environment influences the redox behavior of Cu bound to this peptide; however, the identity and coordination geometry of the Cu(I) site has not been elucidated from previous work. Here, we show data from NMR, XAS, and structural modeling that sheds light on the identity of the Cu(I) binding site of a Ctr1 model peptide. The Cu(I) site includes the same bis-His site identified in previous work to facilitate ascorbate-dependent Cu(II) reduction. The data presented here are consistent with a rational mechanism by which Ctr1 provides coordination environments that facilitate Cu(II) reduction prior to Cu(I) transport.

Authors
Pushie, MJ; Shaw, K; Franz, KJ; Shearer, J; Haas, KL
MLA Citation
Pushie, MJ, Shaw, K, Franz, KJ, Shearer, J, and Haas, KL. "Model Peptide Studies Reveal a Mixed Histidine-Methionine Cu(I) Binding Site at the N-Terminus of Human Copper Transporter 1." Inorganic chemistry 54.17 (September 2015): 8544-8551.
PMID
26258435
Source
epmc
Published In
Inorganic Chemistry
Volume
54
Issue
17
Publish Date
2015
Start Page
8544
End Page
8551
DOI
10.1021/acs.inorgchem.5b01162

Preface

Authors
Crumbliss, AL; Franz, KJ; Thiele, DJ
MLA Citation
Crumbliss, AL, Franz, KJ, and Thiele, DJ. "Preface." BioMetals 28.3 (June 2015): 431-431.
Source
crossref
Published In
BioMetals
Volume
28
Issue
3
Publish Date
2015
Start Page
431
End Page
431
DOI
10.1007/s10534-015-9854-8

Preface. Biometals 2014--Proceedings of the 9th International Symposium Biometals 2014 at Duke University, Durham, NC, USA.

Authors
Crumbliss, AL; Franz, KJ; Thiele, DJ
MLA Citation
Crumbliss, AL, Franz, KJ, and Thiele, DJ. "Preface. Biometals 2014--Proceedings of the 9th International Symposium Biometals 2014 at Duke University, Durham, NC, USA." Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 28.3 (June 2015): 431-.
PMID
25929460
Source
epmc
Published In
BioMetals
Volume
28
Issue
3
Publish Date
2015
Start Page
431
DOI
10.1007/s10534-015-9854-8

Pharmacological activity of metal binding agents that alter copper bioavailability.

Iron, copper and zinc are required nutrients for many organisms but also potent toxins if misappropriated. An overload of any of these metals can be cytotoxic and ultimately lead to organ failure, whereas deficiencies can result in anemia, weakened immune system function, and other medical conditions. Cellular metal imbalances have been implicated in neurodegenerative diseases, cancer and infection. It is therefore critical for living organisms to maintain careful control of both the total levels and subcellular distributions of these metals to maintain healthy function. This perspective explores several strategies envisioned to alter the bioavailability of metal ions by using synthetic metal-binding agents targeted for diseases where misappropriated metal ions are suspected of exacerbating cellular damage. Specifically, we discuss chemical properties that influence the pharmacological outcome of a subset of metal-binding agents known as ionophores, and review several examples that have shown multiple pharmacological activities in metal-related diseases, with a specific focus on copper.

Authors
Helsel, ME; Franz, KJ
MLA Citation
Helsel, ME, and Franz, KJ. "Pharmacological activity of metal binding agents that alter copper bioavailability." Dalton transactions (Cambridge, England : 2003) 44.19 (May 2015): 8760-8770.
PMID
25797044
Source
epmc
Published In
Dalton Transactions
Volume
44
Issue
19
Publish Date
2015
Start Page
8760
End Page
8770
DOI
10.1039/c5dt00634a

LC-UV/MS methods for the analysis of prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH) and its active chelator salicylaldehyde isonicotinoyl hydrazone (SIH).

Salicylaldehyde isonicotinoyl hydrazone (SIH) is an intracellular iron chelator with well documented potential to protect against oxidative injury both in vitro and in vivo. However, it suffers from short biological half-life caused by fast hydrolysis of the hydrazone bond. Recently, a concept of boronate prochelators has been introduced as a strategy that might overcome these limitations. This study presents two complementary analytical methods for detecting the prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone-BSIH along with its active metal-binding chelator SIH in different solution matrices and concentration ranges. An LC-UV method for determination of BSIH and SIH in buffer and cell culture medium was validated over concentrations of 7-115 and 4-115 μM, respectively, and applied to BSIH activation experiments in vitro. An LC-MS assay was validated for quantification of BSIH and SIH in plasma over the concentration range of 0.06-23 and 0.24-23 μM, respectively, and applied to stability studies in plasma in vitro as well as analysis of plasma taken after i.v. administration of BSIH to rats. A Zorbax-RP bonus column and mobile phases containing either phosphate buffer with EDTA or ammonium formate and methanol/acetonitrile mixture provided suitable conditions for the LC-UV and LC-MS analysis, respectively. Samples were diluted or precipitated with methanol prior to analysis. These separative analytical techniques establish the first validated protocols to investigate BSIH activation by hydrogen peroxide in multiple matrices, directly compare the stabilities of the prochelator and its chelator in plasma, and provide the first basic pharmacokinetic data of this prochelator. Experiments reveal that BSIH is stable in all media tested and is partially converted to SIH by H2O2. The observed integrity of BSIH in plasma samples from the in vivo study suggests that the concept of prochelation might be a promising strategy for further development of aroylhydrazone cytoprotective agents.

Authors
Bureš, J; Jansová, H; Stariat, J; Filipský, T; Mladěnka, P; Šimůnek, T; Kučera, R; Klimeš, J; Wang, Q; Franz, KJ; Kovaříková, P
MLA Citation
Bureš, J, Jansová, H, Stariat, J, Filipský, T, Mladěnka, P, Šimůnek, T, Kučera, R, Klimeš, J, Wang, Q, Franz, KJ, and Kovaříková, P. "LC-UV/MS methods for the analysis of prochelator-boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH) and its active chelator salicylaldehyde isonicotinoyl hydrazone (SIH)." Journal of pharmaceutical and biomedical analysis 105 (February 2015): 55-63.
PMID
25527982
Source
epmc
Published In
Journal of Pharmaceutical and Biomedical Analysis
Volume
105
Publish Date
2015
Start Page
55
End Page
63
DOI
10.1016/j.jpba.2014.11.044

A prochelator peptide designed to use heterometallic cooperativity to enhance metal ion affinity

Authors
Alies, B; Wiener, JD; Franz, KJ
MLA Citation
Alies, B, Wiener, JD, and Franz, KJ. "A prochelator peptide designed to use heterometallic cooperativity to enhance metal ion affinity." Chem. Sci. 6.6 (2015): 3606-3610.
Source
crossref
Published In
Chemical Science
Volume
6
Issue
6
Publish Date
2015
Start Page
3606
End Page
3610
DOI
10.1039/C5SC00602C

A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress

© 2015 Elsevier Ltd. All rights reserved.UVA radiation can damage cells and tissues by direct photodamage of biomolecules as well as by initiating metal-catalyzed oxidative stress. In order to alleviate both concerns simultaneously, we synthesized a multifunctional prochelator PC-HAPI (2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (trans)-3-(2,4-dihydroxyphenyl)acrylate) that contains a trans-(o-hydroxy)cinnamate ester photocleavable protecting group that is cleaved upon UVA exposure to release a coumarin, umbelliferone, and an aroylhydrazone metal chelator, HAPI (N′-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide). While the prochelator PC-HAPI exhibits negligible affinity for iron, it responds rapidly to UVA irradiation and converts to an iron-binding chelator that inhibits iron-catalyzed formation of reactive oxygen species and protects cells from UVA damage.

Authors
Franks, AT; Wang, Q; Franz, KJ
MLA Citation
Franks, AT, Wang, Q, and Franz, KJ. "A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress." Bioorganic and Medicinal Chemistry Letters 25.21 (2015): 4843-4847.
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
25
Issue
21
Publish Date
2015
Start Page
4843
End Page
4847
DOI
10.1016/j.bmcl.2015.06.048

A prochelator with a modular masking group featuring hydrogen peroxide activation with concurrent fluorescent reporting.

Metal chelators masked with protecting groups for targeted release have the potential to conditionally modulate cellular metals. We report a new route to prepare cis-cinnamate protecting groups that enabled development of a prochelator with chemical stimulus response, fluorescent reporting and active compound release in a single structure.

Authors
Franks, AT; Franz, KJ
MLA Citation
Franks, AT, and Franz, KJ. "A prochelator with a modular masking group featuring hydrogen peroxide activation with concurrent fluorescent reporting." Chemical communications (Cambridge, England) 50.77 (October 2014): 11317-11320.
PMID
25116739
Source
epmc
Published In
Chemical Communications
Volume
50
Issue
77
Publish Date
2014
Start Page
11317
End Page
11320
DOI
10.1039/c4cc05076b

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Authors
Safi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; McDonnell, DP
MLA Citation
Safi, R, Nelson, ER, Chitneni, SK, Franz, KJ, George, DJ, Zalutsky, MR, and McDonnell, DP. "Copper signaling axis as a target for prostate cancer therapeutics." Cancer research 74.20 (October 2014): 5819-5831.
Website
http://hdl.handle.net/10161/9192
PMID
25320179
Source
epmc
Published In
Cancer Research
Volume
74
Issue
20
Publish Date
2014
Start Page
5819
End Page
5831
DOI
10.1158/0008-5472.can-13-3527

Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury.

Oxidative stress is a common denominator of numerous cardiovascular disorders. Free cellular iron catalyzes the formation of highly toxic hydroxyl radicals, and iron chelation may thus be an effective therapeutic approach. However, using classical iron chelators in diseases without iron overload poses risks that necessitate more advanced approaches, such as prochelators that are activated to chelate iron only under disease-specific oxidative stress conditions. In this study, three cell-membrane-permeable iron chelators (clinically used deferasirox and experimental SIH and HAPI) and five boronate-masked prochelator analogs were evaluated for their ability to protect cardiac cells against oxidative injury induced by hydrogen peroxide. Whereas the deferasirox-derived agents TIP and TRA-IMM displayed negligible protection and even considerable toxicity, the aroylhydrazone prochelators BHAPI and BSIH-PD provided significant cytoprotection and displayed lower toxicity after prolonged cellular exposure compared to their parent chelators HAPI and SIH, respectively. Overall, the most favorable properties in terms of protective efficiency and low inherent cytotoxicity were observed with the aroylhydrazone prochelator BSIH. BSIH efficiently protected both H9c2 rat cardiomyoblast-derived cells and isolated primary rat cardiomyocytes against hydrogen peroxide-induced mitochondrial and lysosomal dysregulation and cell death. At the same time, BSIH was nontoxic at concentrations up to its solubility limit (600 μM) and in 72-h incubation. Hence, BSIH merits further investigation for prevention and/or treatment of cardiovascular disorders associated with a known (or presumed) component of oxidative stress.

Authors
Jansová, H; Macháček, M; Wang, Q; Hašková, P; Jirkovská, A; Potůčková, E; Kielar, F; Franz, KJ; Simůnek, T
MLA Citation
Jansová, H, Macháček, M, Wang, Q, Hašková, P, Jirkovská, A, Potůčková, E, Kielar, F, Franz, KJ, and Simůnek, T. "Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury." Free radical biology & medicine 74 (September 2014): 210-221.
PMID
24992833
Source
epmc
Published In
Free Radical Biology & Medicine
Volume
74
Publish Date
2014
Start Page
210
End Page
221
DOI
10.1016/j.freeradbiomed.2014.06.019

Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection.

Recalcitrant microbial infections demand new therapeutic options. Here we present an approach that exploits two prongs of the host immune cell antimicrobial response: the oxidative burst and the compartmentalization of copper (Cu) within phagolysosomes. The prochelator QBP is a nontoxic protected form of 8-hydroxyquinoline (8HQ) in which a pinanediol boronic ester blocks metal ion coordination by 8HQ. QBP is deprotected via reactive oxygen species produced by activated macrophages, creating 8HQ and eliciting Cu-dependent killing of the fungal pathogen Cryptococcus neoformans in vitro and in mouse pulmonary infection. 8HQ ionophoric activity increases intracellular Cu, overwhelming the Cu-resistance mechanisms of C. neoformans to elicit fungal killing. The Cu-dependent antimicrobial activity of 8HQ against a spectrum of microbial pathogens suggests that this strategy may have broad utility. The conditional activation of Cu ionophores by innate immune cells intensifies the hostile antimicrobial environment and represents a promising approach to combat infectious disease.

Authors
Festa, RA; Helsel, ME; Franz, KJ; Thiele, DJ
MLA Citation
Festa, RA, Helsel, ME, Franz, KJ, and Thiele, DJ. "Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection." Chemistry & biology 21.8 (August 2014): 977-987.
PMID
25088681
Source
epmc
Published In
Chemistry & Biology
Volume
21
Issue
8
Publish Date
2014
Start Page
977
End Page
987
DOI
10.1016/j.chembiol.2014.06.009

Detection of Metal Ions, Anions and Small Molecules Using Metal Complexes

© 2014 John Wiley & Sons, Ltd.A chemical sensor reports the presence of an analyte by converting a recognition event into a spectroscopic signal. Currently used sensors largely rely on organic dyes, fluorescent bteins, nanoparticles, and metal complexes for responsive signal transduction. This chapter focuses exclusively on the use of metal complexes as design features for chemical sensors. A metal complex comprises a central metal ion surrounded by supporting ligands. The chapter expands on general design strategies for sensors with representative examples of metal complexes used to probe biologically important metal ions, anions, and small molecules. The examples presented here attest to the vast scope available for creative sensor design based on various aspects of metal coordination chemistry.

Authors
Wang, Q; Franz, KJ
MLA Citation
Wang, Q, and Franz, KJ. "Detection of Metal Ions, Anions and Small Molecules Using Metal Complexes." Inorganic Chemical Biology: Principles, Techniques and Applications. June 23, 2014. 233-274.
Source
scopus
Publish Date
2014
Start Page
233
End Page
274
DOI
10.1002/9781118682975.ch8

Innate immune cell activation of a copper-dependent anti-cryptococcal agent

Authors
Festa, RA; Helsel, ME; Franz, KJ; Thiele, DJ
MLA Citation
Festa, RA, Helsel, ME, Franz, KJ, and Thiele, DJ. "Innate immune cell activation of a copper-dependent anti-cryptococcal agent." MYCOSES 57 (May 2014): 56-57.
Source
wos-lite
Published In
Mycoses
Volume
57
Publish Date
2014
Start Page
56
End Page
57

Characterization of a photoswitching chelator with light-modulated geometric, electronic, and metal-binding properties.

Photoswitching molecules are utilized for a variety of applications where the rapid manipulation of the molecules' chemical properties and spatial orientations allows for new spatiotemporal control over molecular-scale interactions and processes. Here, we present a hydrazone-containing transition metal chelator, HAPI ((E)-N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide), that displays dual-wavelength photoswitching behavior. Several of its metal complexes, however, are inert to photoreaction and thereby add another layer of control over the photoswitch system. The light-induced twist in HAPI structure is accompanied by a dramatic change in electronic properties as well as chelator strength. This work introduces HAPI as the prototype for a class of molecules with properties that may be optimized for a variety of experimental applications that take advantage of phototriggered molecular changes.

Authors
Franks, AT; Peng, D; Yang, W; Franz, KJ
MLA Citation
Franks, AT, Peng, D, Yang, W, and Franz, KJ. "Characterization of a photoswitching chelator with light-modulated geometric, electronic, and metal-binding properties." Inorganic chemistry 53.3 (February 2014): 1397-1405.
PMID
24428136
Source
epmc
Published In
Inorganic Chemistry
Volume
53
Issue
3
Publish Date
2014
Start Page
1397
End Page
1405
DOI
10.1021/ic402221x

Bioinorganic Neurochemistry

Sodium, potassium, and calcium are, in many respects, the cornerstones of neuronal signaling, but d-block metal ions also play important roles in brain function. The brain has unique needs for metalloenzymes that use iron, zinc, copper, and manganese, and in some cases the metal ions themselves have distinct roles. This chapter provides an overview of the movement, allocation, and uses of metal ions in various brain regions, cell types, and diseases, with emphasis on areas of particular interest to bioinorganic chemists, especially those areas where molecular details await to be uncovered. © 2013 Elsevier Ltd. All rights reserved.

Authors
Folk, DS; Kielar, F; Franz, KJ
MLA Citation
Folk, DS, Kielar, F, and Franz, KJ. "Bioinorganic Neurochemistry." 3 (August 1, 2013): 207-240. (Chapter)
Source
scopus
Volume
3
Publish Date
2013
Start Page
207
End Page
240
DOI
10.1016/B978-0-08-097774-4.00315-6

The 62nd Annual Meeting of the Congress of Neurological Surgeons was held in Chicago, Illinois from October 6-10, 2012. Preface.

Authors
Grant, GA; Hankinson, T; Muh, C; Dumont, A
MLA Citation
Grant, GA, Hankinson, T, Muh, C, and Dumont, A. "The 62nd Annual Meeting of the Congress of Neurological Surgeons was held in Chicago, Illinois from October 6-10, 2012. Preface." Neurosurgery 60 Suppl 1 (August 2013): v-.
PMID
23839472
Source
epmc
Published In
Neurosurgery
Volume
60 Suppl 1
Publish Date
2013
Start Page
v
DOI
10.1227/neu.0000000000000006

Clawing back: broadening the notion of metal chelators in medicine.

The traditional notion of chelation therapy is the administration of a chemical agent to remove metals from the body. But formation of a metal-chelate can have biological ramifications that are much broader than metal elimination. Exploring these other possibilities could lead to pharmacological interventions that alter the concentration, distribution, or reactivity of metals in targeted ways for therapeutic benefit. This review highlights recent examples that showcase four general strategies of using principles of metal chelation in medicinal contexts beyond the traditional notion of chelation therapy. These strategies include altering metal biodistribution, inhibiting specific metalloenzymes associated with disease, enhancing the reactivity of a metal complex to promote cytotoxicity, and conversely, passivating the reactivity of metals by site-activated chelation to prevent cytotoxicity.

Authors
Franz, KJ
MLA Citation
Franz, KJ. "Clawing back: broadening the notion of metal chelators in medicine." Curr Opin Chem Biol 17.2 (April 2013): 143-149. (Review)
PMID
23332666
Source
pubmed
Published In
Current Opinion in Chemical Biology
Volume
17
Issue
2
Publish Date
2013
Start Page
143
End Page
149
DOI
10.1016/j.cbpa.2012.12.021

Light uncages a copper complex to induce nonapoptotic cell death.

Cu3G is a Cu(II) complex of a photoactive tetradentate ligand that is cleaved upon UV irradiation to release Cu. Here we show that the cytotoxicity of Cu3G increases in response to brief UV stimulation to result in extensive cytoplasmic vacuolization that is indicative of nonapoptotic cell death.

Authors
Kumbhar, AA; Franks, AT; Butcher, RJ; Franz, KJ
MLA Citation
Kumbhar, AA, Franks, AT, Butcher, RJ, and Franz, KJ. "Light uncages a copper complex to induce nonapoptotic cell death." Chem Commun (Camb) 49.24 (March 25, 2013): 2460-2462.
PMID
23417227
Source
pubmed
Published In
Chemical Communications
Volume
49
Issue
24
Publish Date
2013
Start Page
2460
End Page
2462
DOI
10.1039/c3cc38927h

Clawing back: Broadening the notion of metal chelators in medicine

The traditional notion of chelation therapy is the administration of a chemical agent to remove metals from the body. But formation of a metal-chelate can have biological ramifications that are much broader than metal elimination. Exploring these other possibilities could lead to pharmacological interventions that alter the concentration, distribution, or reactivity of metals in targeted ways for therapeutic benefit. This review highlights recent examples that showcase four general strategies of using principles of metal chelation in medicinal contexts beyond the traditional notion of chelation therapy. These strategies include altering metal biodistribution, inhibiting specific metalloenzymes associated with disease, enhancing the reactivity of a metal complex to promote cytotoxicity, and conversely, passivating the reactivity of metals by site-activated chelation to prevent cytotoxicity. © 2013 Elsevier Ltd.

Authors
Franz, KJ
MLA Citation
Franz, KJ. "Clawing back: Broadening the notion of metal chelators in medicine." Current Opinion in Chemical Biology 17.2 (2013): 143-149.
Source
scival
Published In
Current Opinion in Chemical Biology
Volume
17
Issue
2
Publish Date
2013
Start Page
143
End Page
149
DOI
10.1016/j.cbpa.2012.12.021

A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding.

Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic iron overload. Deferasirox is a chelator used clinically for iron overload, but also is cytotoxic to cells in culture. In order to test whether a prodrug version of deferasirox could minimize its cytotoxicity but retain its protective properties against iron-induced oxidative damage, we synthesized a prochelator that contains a self-immolative boronic ester masking group that is removed upon exposure to hydrogen peroxide to release the bis-hydroxyphenyltriazole ligand deferasirox. We present here the synthesis and characterization of this triazole-based, self-immolative prochelator: TIP (4-(5-(2-((4-boronobenzyl)oxy)phenyl)-3-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid). TIP does not coordinate to Fe(3+) and shows only weak affinity for Cu(2+) or Zn(2+), in stark contrast to deferasirox, which avidly binds all three metal ions. TIP converts efficiently in vitro upon reaction with hydrogen peroxide to deferasirox. In cell culture, TIP protects retinal pigment epithelial cells from death induced by hydrogen peroxide; however, TIP itself is more cytotoxic than deferasirox in unstressed cells. These results imply that the cytotoxicity of deferasirox may not derive exclusively from its iron withholding properties.

Authors
Kielar, F; Wang, Q; Boyle, PD; Franz, KJ
MLA Citation
Kielar, F, Wang, Q, Boyle, PD, and Franz, KJ. "A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding." Inorganica Chim Acta 393 (December 1, 2012): 294-303.
PMID
23439614
Source
pubmed
Published In
Inorganica Chimica Acta
Volume
393
Publish Date
2012
Start Page
294
End Page
303
DOI
10.1016/j.ica.2012.06.011

Monitoring β-secretase activity in living cells with a membrane-anchored FRET probe.

Authors
Folk, DS; Torosian, JC; Hwang, S; McCafferty, DG; Franz, KJ
MLA Citation
Folk, DS, Torosian, JC, Hwang, S, McCafferty, DG, and Franz, KJ. "Monitoring β-secretase activity in living cells with a membrane-anchored FRET probe." Angew Chem Int Ed Engl 51.43 (October 22, 2012): 10795-10799.
PMID
23023944
Source
pubmed
Published In
Angewandte Chemie International Edition
Volume
51
Issue
43
Publish Date
2012
Start Page
10795
End Page
10799
DOI
10.1002/anie.201206673

Probing oxidative stress: Small molecule fluorescent sensors of metal ions, reactive oxygen species, and thiols.

Oxidative stress is a common feature shared by many diseases, including neurodegenerative diseases. Factors that contribute to cellular oxidative stress include elevated levels of reactive oxygen species, diminished availability of detoxifying thiols, and the misregulation of metal ions (both redox-active iron and copper as well as non-redox active calcium and zinc). Deciphering how each of these components interacts to contribute to oxidative stress presents an interesting challenge. Fluorescent sensors can be powerful tools for detecting specific analytes within a complicated cellular environment. Reviewed here are several classes of small molecule fluorescent sensors designed to detect several molecular participants of oxidative stress. We focus our review on describing the design, function and application of probes to detect metal cations, reactive oxygen species, and intracellular thiol-containing compounds. In addition, we highlight the intricacies and complications that are often faced in sensor design and implementation.

Authors
Hyman, LM; Franz, KJ
MLA Citation
Hyman, LM, and Franz, KJ. "Probing oxidative stress: Small molecule fluorescent sensors of metal ions, reactive oxygen species, and thiols." Coord Chem Rev 256.19-20 (October 1, 2012): 2333-2356.
PMID
23440254
Source
pubmed
Published In
Coordination Chemistry Reviews
Volume
256
Issue
19-20
Publish Date
2012
Start Page
2333
End Page
2356
DOI
10.1016/j.ccr.2012.03.009

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation.

A prochelator named BHAPI (N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide) based on the structure of experimental metal chelator HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) has been synthesized. The prochelator, which shows limited affinity for metal ions, is converted efficiently upon reaction with hydrogen peroxide into its chelator form, which binds di- and trivalent metal ions, including Zn(2+), Cu(2+) and Fe(3+). This work shows that the prochelator has a protective effect on cells under oxidative stress induced by either hydrogen peroxide or the cytotoxic herbicide paraquat. The effect of BHAPI and HAPI on cellular iron status was assessed by monitoring the mRNA level of the transferrin receptor. Whereas the chelator HAPI induces iron deficiency in cultured retinal pigment epithelial cells, the prochelator does not, providing evidence that the differential metal-binding capacity of these compounds observed in vitro is replicated in the cellular context.

Authors
Kielar, F; Helsel, ME; Wang, Q; Franz, KJ
MLA Citation
Kielar, F, Helsel, ME, Wang, Q, and Franz, KJ. "Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation." Metallomics 4.9 (August 2012): 899-909.
PMID
22700084
Source
pubmed
Published In
Metallomics
Volume
4
Issue
9
Publish Date
2012
Start Page
899
End Page
909
DOI
10.1039/c2mt20069d

Coordination chemistry of copper proteins: how nature handles a toxic cargo for essential function.

Biological copper is coordinated predominantly by just three ligand types: the side chains of histidine, cysteine, and methionine, with of course some exceptions. The arrangement of these components, however, is fascinating. The diversity provided by just these three ligands provides choices of nitrogen vs. sulfur, neutral vs. charged, hydrophilic vs. hydrophobic, susceptibility to oxidation, and degree of pH-sensitivity. In this review we examine how the total number of ligands, their spatial arrangement and solvent accessibility, the various combinations of imidazole, thiolate, and thioether donors, all work together to provide binding sites that either enable copper to carry out a function, or safely transport it in a way that prevents toxic reactivity. We separate copper proteins into two broad classes, those that utilize the metal as a cofactor, or those that traffic the metal. Enzymes and proteins that utilize copper as a cofactor use high affinity sites of high coordination numbers of 4-5 that prevent loss of the metal during redox cycling. Copper trafficking proteins, on the other hand, promote metal transfer either by having low affinity binding sites with moderate coordination number ~4, or by having lower coordinate binding sites of 2-3 ligands that bind with high affinity. Both strategies retain the metal but allow transfer under appropriate conditions. Analysis of studies from our own lab on model peptides, combined with those from other labs, raises an interesting hypothesis that various methionine/histidine/cysteine combinations provide organisms with dynamic, multifunctional domains on copper trafficking proteins that facilitate copper transfer under different extracellular, subcellular, and tissue-specific scenarios of pH, redox environment, and presence of other copper carriers or target proteins.

Authors
Rubino, JT; Franz, KJ
MLA Citation
Rubino, JT, and Franz, KJ. "Coordination chemistry of copper proteins: how nature handles a toxic cargo for essential function." J Inorg Biochem 107.1 (February 2012): 129-143. (Review)
PMID
22204943
Source
pubmed
Published In
Journal of Inorganic Biochemistry
Volume
107
Issue
1
Publish Date
2012
Start Page
129
End Page
143
DOI
10.1016/j.jinorgbio.2011.11.024

A Cell-Permeable Fluorescent Prochelator Responds to Hydrogen Peroxide and Metal Ions by Decreasing Fluorescence.

Described here is the development of two boronic ester-based fluorescent prochelators, FloB (2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-4(5)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene-hydrazinocarbonyl]-benzoic acid) and FloB-SI (2-(6-hydroxy-3-oxo-3Hxanthen-9-yl)-4(5)-[2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)-benzylidene-hydrazinocarbonyl]-benzoic acid) that show a fluorescence response to a variety of transition metal ions only after reaction with H(2)O(2). Both prochelators' boronic ester masks are oxidized by H(2)O(2) to reveal a fluorescein-tagged metal chelator, FloS (4(5)-(2-hydroxy-benzylidenehydrazinocarbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoic acid). Chelation of Fe(3+) or Cu(2+) elicits a 70% decrease in the emission signal of FloS, while Zn(2+), Ni(2+), and Co(2+) produce a more modest fluorescence decrease. The conversion of FloB to FloS proceeds in organic solvents, but hydrolytic decomposition of its hydrazone backbone is observed in aqueous solution. However, FloB-SI oxidizes cleanly with H(2)O(2) within 1 h in aqueous solutions to produce FloS. Fluorescence microscopy studies in HeLa cells with FloB-SI show that the sensor's fluorescence intensity remains unchanged until incubation with exogenous H(2)O(2), which results in a decreased fluorescent signal. Incubation with a competitive chelator restores the emission response, thus suggesting that FloB-SI can effectively report on a H(2)O(2)-induced increase in intracellular labilized metal.

Authors
Hyman, LM; Franz, KJ
MLA Citation
Hyman, LM, and Franz, KJ. "A Cell-Permeable Fluorescent Prochelator Responds to Hydrogen Peroxide and Metal Ions by Decreasing Fluorescence." Inorganica Chim Acta 380 (January 15, 2012): 125-134.
PMID
22287796
Source
pubmed
Published In
Inorganica Chimica Acta
Volume
380
Publish Date
2012
Start Page
125
End Page
134
DOI
10.1016/j.ica.2011.11.056

Application of inorganic chemistry for non-cancer therapeutics

Authors
Franz, KJ
MLA Citation
Franz, KJ. "Application of inorganic chemistry for non-cancer therapeutics." Dalton Transactions 41.21 (2012): 6333-6334.
PMID
22546812
Source
scival
Published In
Dalton Transactions
Volume
41
Issue
21
Publish Date
2012
Start Page
6333
End Page
6334
DOI
10.1039/c2dt90061k

Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress.

Prochelators are agents that have little affinity for metal ions until they undergo a chemical conversion. Three new aryl boronate prochelators are presented that are responsive to hydrogen peroxide to provide hexadentate ligands for chelating metal ions. TRENBSIM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)-2-aminoethyl]amine), TRENBSAM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-2-aminoethyl]amine), and TB (tris[(2-boronic acid-benzyl)2-aminoethyl]amine) convert to TRENSIM (tris[(salicylideneamino)ethyl]amine), TRENSAM (tris[(2-hydroxybenzoyl)-2-aminoethyl]amine), and TS (tris[2-hydroxybenzyl)2-aminoethyl]amine), respectively. The prochelators were characterized by (11)B NMR, and the structures of TRENBSAM, TRENBSIM, and the Fe(III) complex of TS were determined by X-ray crystallography. Of the three prochelator/chelator pairs, TB/TS was identified as the most promising for biological applications, as they prevent iron and copper-induced hydroxyl radical generation in an in vitro assay. TB has negligible interactions with metal ions, whereas TS has apparent binding constants (log K') at pH 7.4 of 15.87 for Cu(II), 9.67 Zn(II) and 14.42 for Fe(III). Up to 1 mMTB was nontoxic to retinal pigment epithelial cells, whereas 10 μM TS induced cell death. TS protected cells against H(2)O(2)-induced death, but only within a 1-10 μM range. TB, on the other hand, had a much broader window of protection, suggesting that it may be a useful agent for preventing metal-promoted oxidative damage.

Authors
Leed, MGD; Wolkow, N; Pham, DM; Daniel, CL; Dunaief, JL; Franz, KJ
MLA Citation
Leed, MGD, Wolkow, N, Pham, DM, Daniel, CL, Dunaief, JL, and Franz, KJ. "Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress." J Inorg Biochem 105.9 (September 2011): 1161-1172.
PMID
21708101
Source
pubmed
Published In
Journal of Inorganic Biochemistry
Volume
105
Issue
9
Publish Date
2011
Start Page
1161
End Page
1172
DOI
10.1016/j.jinorgbio.2011.05.023

Model peptides provide new insights into the role of histidine residues as potential ligands in human cellular copper acquisition via Ctr1.

Cellular acquisition of copper in eukaryotes is primarily accomplished through the Ctr family of copper transport proteins. In both humans and yeast, methionine-rich "Mets" motifs in the amino-terminal extracellular domain of Ctr1 are thought to be responsible for recruitment of copper at the cell surface. Unlike yeast, mammalian Ctr1 also contains extracellular histidine-rich motifs, although a role for these regions in copper uptake has not been explored in detail. Herein, synthetic model peptides containing the first 14 residues of the extracellular domain of human Ctr1 (MDHSHHMGMSYMDS) have been prepared and evaluated for their apparent binding affinity to both Cu(I) and Cu(II). These studies reveal a high affinity Cu(II) binding site (log K = 11.0 ± 0.3 at pH 7.4) at the amino-terminus of the peptide as well as a high affinity Cu(I) site (log K = 10.2 ± 0.2 at pH 7.4) that utilizes adjacent HH residues along with an additional His or Met ligand. These model studies suggest that the histidine domains may play a direct role in copper acquisition from serum copper-binding proteins and in facilitating the reduction of Cu(II) to the active Ctr1 substrate, Cu(I). We tested this hypothesis by expressing a Ctr1 mutant lacking only extracellular histidine residues in Ctr1-knockout mouse embryonic fibroblasts. Results from live cell studies support the hypothesis that extracellular amino-terminal His residues directly participate in the copper transport function of Ctr1.

Authors
Haas, KL; Putterman, AB; White, DR; Thiele, DJ; Franz, KJ
MLA Citation
Haas, KL, Putterman, AB, White, DR, Thiele, DJ, and Franz, KJ. "Model peptides provide new insights into the role of histidine residues as potential ligands in human cellular copper acquisition via Ctr1." J Am Chem Soc 133.12 (March 30, 2011): 4427-4437.
PMID
21375246
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
133
Issue
12
Publish Date
2011
Start Page
4427
End Page
4437
DOI
10.1021/ja108890c

Keys for unlocking photolabile metal-containing cages.

Photolabile metal-containing cages are metal complexes that undergo a change in coordination environment upon exposure to light of an appropriate wavelength. The light-responsive functionality can either be a component of the encapsulating ligand or a property of the metal complex itself. The altered coordination properties of light-responsive complexes can result in release of the coordinated metal ion into its surroundings, a differential reactivity of the metal center, or the liberation of a reactive molecule that had been passivated by binding to the metal center. These triggerable agents can be useful tools for manipulating the bioavailability of metals or their coordinating ligands in order to study biological pathways or for potential therapeutic purposes.

Authors
Ciesienski, KL; Franz, KJ
MLA Citation
Ciesienski, KL, and Franz, KJ. "Keys for unlocking photolabile metal-containing cages." Angew Chem Int Ed Engl 50.4 (January 24, 2011): 814-824. (Review)
PMID
21246677
Source
pubmed
Published In
Angewandte Chemie International Edition
Volume
50
Issue
4
Publish Date
2011
Start Page
814
End Page
824
DOI
10.1002/anie.201002542

A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments.

The N-terminal, extracellular regions of eukaryotic high affinity copper transport (Ctr) proteins vary in composition of the Cu(i) binding amino acids: methionine, histidine, and cysteine. To examine why certain amino acids are exploited over others in Ctrs from different organisms, the relative Cu(i) binding affinity and the dependence of binding on pH were examined for 3 peptides of the sequence MG(2)XG(2)MK, where X is either Met, His, or Cys. Cu(i) affinity was examined using an ascorbic acid oxidation assay, an electrospray ionization mass spectrometry technique, and spectrophotometric titration with a competitive Cu(i) chelator. The relative affinities of the peptides with Cu(i) reveal a trend whereby Cys > His > Met at pH 7.4 and Cys > Met > His at pH 4.5. Ligand geometry and metric parameters were determined with X-ray absorption spectroscopy. Susceptibility of the peptides to oxidation by hydrogen peroxide and copper-catalyzed oxidative conditions was evaluated by mass spectrometry. These results support hypotheses as to why certain Cu(i) binding amino acids are preferred over others in proteins expressed at different pH and exposed to oxidative environments. The results also have implications for interpreting site-directed mutagenesis studies aimed at identifying copper binding amino acids in copper trafficking proteins.

Authors
Rubino, JT; Chenkin, MP; Keller, M; Riggs-Gelasco, P; Franz, KJ
MLA Citation
Rubino, JT, Chenkin, MP, Keller, M, Riggs-Gelasco, P, and Franz, KJ. "A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments." Metallomics 3.1 (January 2011): 61-73.
PMID
21553704
Source
pubmed
Published In
Metallomics
Volume
3
Issue
1
Publish Date
2011
Start Page
61
End Page
73

A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments.

The N-terminal, extracellular regions of eukaryotic high affinity copper transport (Ctr) proteins vary in composition of the Cu(i) binding amino acids: methionine, histidine, and cysteine. To examine why certain amino acids are exploited over others in Ctrs from different organisms, the relative Cu(i) binding affinity and the dependence of binding on pH were examined for 3 peptides of the sequence MG(2)XG(2)MK, where X is either Met, His, or Cys. Cu(i) affinity was examined using an ascorbic acid oxidation assay, an electrospray ionization mass spectrometry technique, and spectrophotometric titration with a competitive Cu(i) chelator. The relative affinities of the peptides with Cu(i) reveal a trend whereby Cys > His > Met at pH 7.4 and Cys > Met > His at pH 4.5. Ligand geometry and metric parameters were determined with X-ray absorption spectroscopy. Susceptibility of the peptides to oxidation by hydrogen peroxide and copper-catalyzed oxidative conditions was evaluated by mass spectrometry. These results support hypotheses as to why certain Cu(i) binding amino acids are preferred over others in proteins expressed at different pH and exposed to oxidative environments. The results also have implications for interpreting site-directed mutagenesis studies aimed at identifying copper binding amino acids in copper trafficking proteins.

Authors
Rubino, JT; Chenkin, MP; Keller, M; Riggs-Gelasco, P; Franz, KJ
MLA Citation
Rubino, JT, Chenkin, MP, Keller, M, Riggs-Gelasco, P, and Franz, KJ. "A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments." Metallomics 3.1 (January 2011): 61-73.
PMID
21305075
Source
pubmed
Published In
Metallomics
Volume
3
Issue
1
Publish Date
2011
Start Page
61
End Page
73
DOI
10.1039/c0mt00044b

Development of next-generation photolabile copper cages with improved copper binding properties.

Seven new nitrogen-donor ligands that contain a photoactive nitrophenyl group within the ligand backbone have been prepared and evaluated for their binding affinity for copper(ii) and zinc(ii). Among this series, the ligand 3Gcage (pyridine-2-carboxylic acid {1-(2-nitro-phenyl)-3-[(pyridin-2-ylmethyl)-amino]-propyl}-amide) has the best affinity for copper(ii), with an apparent dissociation constant at pH 7.4 of 0.18 fM. Exposure of buffered aqueous solutions of 3Gcage or Cu(ii)-bound 3Gcage to UV light induces bond cleavage in the ligand backbone, which reduces the denticity of the ligands. The quantum yields of photolysis for 3Gcage in the absence and presence of Cu(ii) are 0.66 and 0.43, respectively. Prior to photolysis, the 3Gcage ligand inhibits copper from generating hydroxyl radicals in the presence of hydrogen peroxide and ascorbic acid; however, hydroxyl radical formation increases by more than 300% following light activation, showing that the reactivity of the copper center can be triggered by light.

Authors
Ciesienski, KL; Haas, KL; Franz, KJ
MLA Citation
Ciesienski, KL, Haas, KL, and Franz, KJ. "Development of next-generation photolabile copper cages with improved copper binding properties." Dalton Trans 39.40 (October 28, 2010): 9538-9546.
Website
http://hdl.handle.net/10161/4132
PMID
20740238
Source
pubmed
Published In
Dalton Transactions
Volume
39
Issue
40
Publish Date
2010
Start Page
9538
End Page
9546
DOI
10.1039/c0dt00770f

Methionine motifs of copper transport proteins provide general and flexible thioether-only binding sites for Cu(I) and Ag(I).

Cellular acquisition of copper in eukaryotic organisms is primarily accomplished through high-affinity copper transport proteins (Ctr). The extracellular N-terminal regions of both human and yeast Ctr1 contain multiple methionine residues organized in copper-binding Mets motifs. These motifs comprise combinations of methionine residues arranged in clusters of MXM and MXXM, where X can be one of several amino acids. Model peptides corresponding to 15 different Mets motifs were synthesized and determined to selectively bind Cu(I) and Ag(I), with no discernible affinity for divalent metal ions. These are rare examples of biological thioether-only metal binding sites. Effective dissociation constant (KD) values for the model Mets peptides and Cu(I) were determined by an ascorbic acid oxidation assay and validated through electrospray ionization mass spectrometry and range between 2 and 11 microM. Affinity appears to be independent of pH, the arrangement of the motif, and the composition of intervening amino acids, all of which reveal the generality and flexibility of the MX1-2MX1-2M domain. Circular dichroism spectroscopy, 1H-NMR spectroscopy, and X-ray absorption spectroscopy were also used to characterize the binding event. These results are intended to aid the development of the still unknown mechanism of copper transport across the cell membrane.

Authors
Rubino, JT; Riggs-Gelasco, P; Franz, KJ
MLA Citation
Rubino, JT, Riggs-Gelasco, P, and Franz, KJ. "Methionine motifs of copper transport proteins provide general and flexible thioether-only binding sites for Cu(I) and Ag(I)." J Biol Inorg Chem 15.7 (September 2010): 1033-1049.
PMID
20437064
Source
pubmed
Published In
JBIC Journal of Biological Inorganic Chemistry
Volume
15
Issue
7
Publish Date
2010
Start Page
1033
End Page
1049
DOI
10.1007/s00775-010-0663-9

Toward the detection of cellular copper(II) by a light-activated fluorescence increase.

Authors
Ciesienski, KL; Hyman, LM; Derisavifard, S; Franz, KJ
MLA Citation
Ciesienski, KL, Hyman, LM, Derisavifard, S, and Franz, KJ. "Toward the detection of cellular copper(II) by a light-activated fluorescence increase." Inorg Chem 49.15 (August 2, 2010): 6808-6810.
Website
http://hdl.handle.net/10161/4032
PMID
20590142
Source
pubmed
Published In
Inorganic Chemistry
Volume
49
Issue
15
Publish Date
2010
Start Page
6808
End Page
6810
DOI
10.1021/ic1004165

A prochelator activated by beta-secretase inhibits Abeta aggregation and suppresses copper-induced reactive oxygen species formation.

The intersection of the amyloid cascade hypothesis and the implication of metal ions in Alzheimer's disease progression has sparked an interest in using metal-binding compounds as potential therapeutic agents. In the present work, we describe a prochelator SWH that is enzymatically activated by beta-secretase to produce a high affinity copper chelator CP. Because beta-secretase is responsible for the amyloidogenic processing of the amyloid precursor protein, this prochelator strategy imparts disease specificity toward copper chelation not possible with general metal chelators. Furthermore, once activated, CP efficiently sequesters copper from amyloid-beta, prevents and disassembles copper-induced amyloid-beta aggregation, and diminishes copper-promoted reactive oxygen species formation.

Authors
Folk, DS; Franz, KJ
MLA Citation
Folk, DS, and Franz, KJ. "A prochelator activated by beta-secretase inhibits Abeta aggregation and suppresses copper-induced reactive oxygen species formation." J Am Chem Soc 132.14 (April 14, 2010): 4994-4995.
Website
http://hdl.handle.net/10161/4038
PMID
20297791
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
132
Issue
14
Publish Date
2010
Start Page
4994
End Page
4995
DOI
10.1021/ja100943r

Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease.

Neurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.

Authors
Perez, LR; Franz, KJ
MLA Citation
Perez, LR, and Franz, KJ. "Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease." Dalton Trans 39.9 (March 7, 2010): 2177-2187.
Website
http://hdl.handle.net/10161/4119
PMID
20162187
Source
pubmed
Published In
Dalton Transactions
Volume
39
Issue
9
Publish Date
2010
Start Page
2177
End Page
2187
DOI
10.1039/b919237a

Toward the development of prochelators as fluorescent probes of copper-mediated oxidative stress.

A fluorescent sensor prochelator, FlamB (fluorescein hydrizido 2-imidophenylboronic ester), has been developed that selectively probes for copper under conditions of oxidative stress. High levels of hydrogen peroxide trigger the release of a boronic ester masking group from the prochelator to unveil a metal chelator, FlamS (fluorescein hydrizido 2-imidophenol), that provides a modest fluorescence increase in response to Cu(2+) but not other metal ions. X-Ray crystal structures of FlamB, FlamS, and Cu-bound FlamS are all reported. The fluorescence turn-on results from opening of a fluorescein spirolactam ring upon Cu(2+) binding to FlamS in aqueous solution. Oxidation of the aryl boronic ester of FlamB to the metal-binding phenol of FlamS proceeds in organic solvents. However, in aqueous solution a competing mechanism occurs due to hydrolytic instability of the masked prochelator. Hydrolysis of FlamB leads to formation of fluorescein hydrazide, which interacts with copper or H(2)O(2) to produce fluorescein and a significant fluorescence increase.

Authors
Hyman, LM; Stephenson, CJ; Dickens, MG; Shimizu, KD; Franz, KJ
MLA Citation
Hyman, LM, Stephenson, CJ, Dickens, MG, Shimizu, KD, and Franz, KJ. "Toward the development of prochelators as fluorescent probes of copper-mediated oxidative stress." Dalton Trans 2 (January 14, 2010): 568-576.
PMID
20023995
Source
pubmed
Published In
Dalton Transactions
Issue
2
Publish Date
2010
Start Page
568
End Page
576
DOI
10.1039/b914568k

A prochelator activated by hydrogen peroxide prevents metal-induced amyloid Beta aggregation.

Authors
Dickens, MG; Franz, KJ
MLA Citation
Dickens, MG, and Franz, KJ. "A prochelator activated by hydrogen peroxide prevents metal-induced amyloid Beta aggregation." Chembiochem 11.1 (January 4, 2010): 59-62.
PMID
19937900
Source
pubmed
Published In
Chembiochem
Volume
11
Issue
1
Publish Date
2010
Start Page
59
End Page
62
DOI
10.1002/cbic.200900597

Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1.

Platinum therapeutic agents are widely used in the treatment of several forms of cancer. Various mechanisms for the transport of the drugs have been proposed including passive diffusion across the cellular membrane and active transport via proteins. The copper transport protein Ctr1 is responsible for high affinity copper uptake but has also been implicated in the transport of cisplatin into cells. Human hCtr1 contains two methionine-rich Mets motifs on its extracellular N-terminus that are potential platinum-binding sites: the first one encompasses residues 7-14 with amino acid sequence Met-Gly-Met-Ser-Tyr-Met-Asp-Ser and the second one spans residues 39-46 with sequence Met-Met-Met-Met-Pro-Met-Thr-Phe. In these studies, we use liquid chromatography and mass spectrometry to compare the binding interactions between cisplatin, carboplatin and oxaliplatin with synthetic peptides corresponding to hCtr1 Mets motifs. The interactions of cisplatin and carboplatin with Met-rich motifs that contain three or more methionines result in removal of the carrier ligands of both platinum complexes. In contrast, oxaliplatin retains its cyclohexyldiamine ligand upon platinum coordination to the peptide.

Authors
Crider, SE; Holbrook, RJ; Franz, KJ
MLA Citation
Crider, SE, Holbrook, RJ, and Franz, KJ. "Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1." Metallomics 2.1 (January 2010): 74-83.
Website
http://hdl.handle.net/10161/4118
PMID
21072377
Source
pubmed
Published In
Metallomics
Volume
2
Issue
1
Publish Date
2010
Start Page
74
End Page
83
DOI
10.1039/b916899k

The highways and byways of bioinorganic chemistry

Authors
Franz, KJ; He, C
MLA Citation
Franz, KJ, and He, C. "The highways and byways of bioinorganic chemistry." Current Opinion in Chemical Biology 14.2 (2010): 208-210.
PMID
20207579
Source
scival
Published In
Current Opinion in Chemical Biology
Volume
14
Issue
2
Publish Date
2010
Start Page
208
End Page
210
DOI
10.1016/j.cbpa.2010.02.011

A photo-caged platinum(II) complex that increases cytotoxicity upon light activation

A novel platinum(II) photocaged complex called [Pt(cage)] has been prepared and characterized by X-ray crystallography. The complex contains a photolabile nitrophenyl group incorporated into the backbone of a tetradentate ligand that contains two pyridyl and two amide nitrogen donor sites. The intact complex is unreactive toward ligand-exchange reactions until activation with UV light cleaves the ligand backbone, releasing a PtII complex that more readily exchanges its ligands, as verified by reaction with a methioninc-containing peptide. [Pt(cage)] is non-toxic to MCF-7 cells in the dark, whereas brief UV exposure induces cell death of human breast cancer MCF-7 cells at a level approaching that of cisplatin. By using light to alter the coordination chemistry around the metal center, [Pt(cage)] represents a new strategy for potentially delivering metal-based drugs in a site and time specific manner. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Authors
Ciesienski, KL; Hyman, LM; Yang, DT; Haas, KL; Dickens, MG; Holbrook, RJ; Franz, KJ
MLA Citation
Ciesienski, KL, Hyman, LM, Yang, DT, Haas, KL, Dickens, MG, Holbrook, RJ, and Franz, KJ. "A photo-caged platinum(II) complex that increases cytotoxicity upon light activation." European Journal of Inorganic Chemistry 15 (2010): 2224-2228.
Source
scival
Published In
European Journal of Inorganic Chemistry
Issue
15
Publish Date
2010
Start Page
2224
End Page
2228
DOI
10.1002/ejic.201000098

Electronic structure of a paramagnetic {MNO}6 complex: MnNO 5,5-tropocoronand

Using density functional theory (OLYP/STO-TZP) calculations, we have investigated the electronic structure of [Mn(5,5-tropocoronand)(NO)], a rare paramagnetic {MNO}6 complex. Experimental methods, including magnetic susceptibility measurements and high-field electron paramagnetic resonance spectroscopy, have not provided an unambiguous spin state assignment for this complex. In other respects, however, the compound was fully characterized, including by means of single-crystal X-ray structure determination. The optimized S = 1 OLYP geometry reproduced all key aspects of the trigonal-bipyramidal molecular structure, including a short Mn-N(O) distance (∼1.7 Å;) and an essentially linear MnNO angle. In contrast, the S = O and S = 2 optimized structures disagreed with the crystal structure in critical respects. Moreover, three different exchange-correlation functionals (OLYP, B3LYP, and B3LYP) indicated an S = 1 ground state by a clear margin of energy. An examination of the Kohn-Sham MOs of this state indicated a primarily d xz2/dyz2dxy1dx2-z21 electronic configuration, where the z axis is identified with the nearly linear MnNO axis. The y2 orbital is formally unoccupied in this state, interacting, as it does, head-on with two tropocoronand nitrogens lying along the y axis, the pseudo-3-fold axis of the trigonal bipyramid. The doubly occupied dxz and dyz orbitais are in actuality dπ(Fe)-π(NO)-based π-bonding molecular orbitais, the a and ß "components" of which are significantly offset spatially. This offset results in excess minority spin density on the NO unit. Thus, the OLYP/TZP atomic spin populations are Mn, 2.85; N(O), -0.52; and O, -0.35. © 2010 American Chemical Society.

Authors
Tangen, E; Conradie, J; Franz, K; Friedle, S; Telser, J; Lippard, SJ; Ghosh, A
MLA Citation
Tangen, E, Conradie, J, Franz, K, Friedle, S, Telser, J, Lippard, SJ, and Ghosh, A. "Electronic structure of a paramagnetic {MNO}6 complex: MnNO 5,5-tropocoronand." Inorganic Chemistry 49.6 (2010): 2701-2705.
PMID
20166686
Source
scival
Published In
Inorganic Chemistry
Volume
49
Issue
6
Publish Date
2010
Start Page
2701
End Page
2705
DOI
10.1021/ic901860x

Application of metal coordination chemistry to explore and manipulate cell biology.

Authors
Haas, KL; Franz, KJ
MLA Citation
Haas, KL, and Franz, KJ. "Application of metal coordination chemistry to explore and manipulate cell biology." Chem Rev 109.10 (October 2009): 4921-4960. (Review)
PMID
19715312
Source
pubmed
Published In
Chemical Reviews
Volume
109
Issue
10
Publish Date
2009
Start Page
4921
End Page
4960
DOI
10.1021/cr900134a

Introduction to cellular metal homeostasis and trafficking

Authors
Palmer, AE; Franz, KJ
MLA Citation
Palmer, AE, and Franz, KJ. "Introduction to cellular metal homeostasis and trafficking." Chemical Reviews 109.10 (2009): 4533-4535.
PMID
19778037
Source
scival
Published In
Chemical Reviews
Volume
109
Issue
10
Publish Date
2009
Start Page
4533
End Page
4535
DOI
10.1021/cr900293t

Iron prochelator BSIH protects retinal pigment epithelial cells against cell death induced by hydrogen peroxide.

Dysregulation of localized iron homeostasis is implicated in several degenerative diseases, including Parkinson's, Alzheimer's, and age-related macular degeneration, wherein iron-mediated oxidative stress is hypothesized to contribute to cell death. Inhibiting toxic iron without altering normal metal-dependent processes presents significant challenges for standard small molecule chelating agents. We previously introduced BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelators that are converted by hydrogen peroxide into SIH (salicylaldehyde isonicotinoyl hydrazone) chelating agents that inhibit iron-catalyzed hydroxyl radical generation. Here, we show that BSIH protects a cultured cell model for retinal pigment epithelium against cell death induced by hydrogen peroxide. BSIH is more stable than SIH in cell culture medium and is more protective during long-term experiments. Repetitive exposure of cells to BSIH is nontoxic, whereas SIH and desferrioxamine induce cell death after repeated exposure. Combined, our results indicate that cell protection by BSIH involves iron sequestration that occurs only when the cells are stressed by hydrogen peroxide. These findings suggest that prochelators discriminate toxic iron from healthy iron and are promising candidates for neuro- and retinal protection.

Authors
Charkoudian, LK; Dentchev, T; Lukinova, N; Wolkow, N; Dunaief, JL; Franz, KJ
MLA Citation
Charkoudian, LK, Dentchev, T, Lukinova, N, Wolkow, N, Dunaief, JL, and Franz, KJ. "Iron prochelator BSIH protects retinal pigment epithelial cells against cell death induced by hydrogen peroxide." J Inorg Biochem 102.12 (December 2008): 2130-2135.
PMID
18835041
Source
pubmed
Published In
Journal of Inorganic Biochemistry
Volume
102
Issue
12
Publish Date
2008
Start Page
2130
End Page
2135
DOI
10.1016/j.jinorgbio.2008.08.001

A photolabile ligand for light-activated release of caged copper.

A photosensitive caged copper complex has been prepared from a tetradentate ligand (H2cage) composed of two pyridyl-amide arms connected by a photoreactive nitrophenyl group. H2cage binds Cu2+ in aqueous solution with a stability constant (log beta) of 10.8, which corresponds to a KD of 16 pM at pH 7.4. The neutral Cu2+ complex, [Cu(OH2)(cage)], crystallizes as a distorted trigonal bipyramid coordinated by two amide and two pyridyl N atoms, with a water molecule bound in the trigonal plane. Photolysis with 350 nm UV light cleaves the ligand backbone to release photoproducts with significantly diminished affinity for Cu2+, thereby uncaging the metal ion. When coordinated as the caged complex, copper has diminished reactivity to produce hydroxyl radicals from Fenton-like reaction mixtures containing hydrogen peroxide and ascorbic acid. Postphotolysis, uncaged copper promotes hydroxyl radical formation under the same conditions. The strategy of caging copper is promising for applications where light could be used to trigger release of copper as a pro-oxidant to increase oxidative stress or as a tool to release copper intracellularly to study mechanisms of copper trafficking.

Authors
Ciesienski, KL; Haas, KL; Dickens, MG; Tesema, YT; Franz, KJ
MLA Citation
Ciesienski, KL, Haas, KL, Dickens, MG, Tesema, YT, and Franz, KJ. "A photolabile ligand for light-activated release of caged copper." J Am Chem Soc 130.37 (September 17, 2008): 12246-12247.
PMID
18714999
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
130
Issue
37
Publish Date
2008
Start Page
12246
End Page
12247
DOI
10.1021/ja8047442

Counterions influence reactivity of metal ions with cysteinyldopa model compounds.

Cysteinyldopas are naturally occurring conjugates of cysteine and dopa (3,4-dihydroxy-l-phenylalanine) that are precursors to red pheomelanin pigments. Metal ions are known to influence pheomelanogenesis in vitro and may be regulatory factors in vivo. Cydo (3-[(2-amino-ethyl)sulfanyl]-4,6-di-tert-butylbenzene-1,2-diol) and CarboxyCydo (2-amino-3-(4,6-di-tert-butyl-2,3-dihydroxyphenylsulfanyl)-propionic acid) are model compounds of cysteinyldopa that retain its metal-binding functionalities but cannot polymerize due to the presence of blocking tert-butyl groups. Cydo reacts readily with zinc(II) acetate or nickel(II) acetate to form a cyclized 1,4-benzothiazine (zine) intermediate that undergoes ring contraction to form benzothiazole (zole) unless it is stabilized by coordination to a metal ion. The crystal structure of [Ni(zine)2] is reported. The acetate counteranion is required for the zinc-promoted reactivity, as neither zinc(II) sulfate nor zinc(II) chloride alone promotes the transformation. The counterion is less important for redox-active copper and iron, which both readily promote the oxidation of Cydo to zine and zole species; Cu(II) complexes of both zine and zole have been characterized by X-ray crystallography. In the case of CarboxyCydo, a 3-carboxy-1,4-benzothiazine intermediate decarboxylates to form [Cu(zine)2] under basic conditions, but in the absence of base forms a mixture of products that includes the carboxylated dimer 2,2'-bibenzothiazine (bi-zine). These products are consistent with species implicated in the pheomelanogenesis biosynthetic pathway and emphasize how metal ions, their counteranions, and reaction conditions can alter pheomelanin product distribution.

Authors
Tesema, YT; Pham, DM; Franz, KJ
MLA Citation
Tesema, YT, Pham, DM, and Franz, KJ. "Counterions influence reactivity of metal ions with cysteinyldopa model compounds." Inorg Chem 47.3 (February 4, 2008): 1087-1095.
PMID
18163613
Source
pubmed
Published In
Inorganic Chemistry
Volume
47
Issue
3
Publish Date
2008
Start Page
1087
End Page
1095
DOI
10.1021/ic701889w

Copper shares a piece of the π

Recent crystal structures of a bacterial copper tolerance protein reveal an intriguing copper binding site that includes tryptophan. Its close proximity coupled with spectroscopic data suggests an unusual cation-π interaction between Cu(I) and the aromatic ring of tryptophan. © 2008 Nature Publishing Group.

Authors
Franz, KJ
MLA Citation
Franz, KJ. "Copper shares a piece of the π." Nature Chemical Biology 4.2 (2008): 85-86.
PMID
18202673
Source
scival
Published In
Nature Chemical Biology
Volume
4
Issue
2
Publish Date
2008
Start Page
85
End Page
86
DOI
10.1038/nchembio0208-85

Modifications of boronic ester pro-chelators triggered by hydrogen peroxide tune reactivity to inhibit metal-promoted oxidative stress.

Several new analogs of salicylaldehyde isonicotinoyl hydrazone (SIH) and salicylaldehyde benzoyl hydrazone (SBH) that contain an aryl boronic ester (BSIH, BSBH) or acid (BASIH) in place of an aryl hydroxide have been synthesized and characterized as masked metal ion chelators. These pro-chelators show negligible interaction with iron(III), although the boronic acid versions exhibit some interaction with copper(II), zinc(II) and nickel(II). Hydrogen peroxide oxidizes the aryl boronate to phenol, thus converting the pro-chelators to tridentate ligands with high affinity metal binding properties. An X-ray crystal structure of a bis-ligated iron(III) complex, [Fe(SBH(m-OMe)(3))(2)]NO(3), confirms the meridonal binding mode of these ligands. Modifications of the aroyl ring of the chelators tune their iron affinity, whereas modifications on the boron-containing ring of the pro-chelators attenuate their reaction rates with hydrogen peroxide. Thus, the methoxy derivative pro-chelator (p-OMe)BASIH reacts with hydrogen peroxide nearly 5 times faster than the chloro derivative (m-Cl)BASIH. Both the rate of pro-chelator to chelator conversion as well as the metal binding affinity of the chelator influence the overall ability of these molecules to inhibit hydroxyl radical formation catalyzed by iron or copper in the presence of hydrogen peroxide and ascorbic acid. This pro-chelator strategy has the potential to improve the efficacy of medicinal chelators for inhibiting metal-promoted oxidative stress.

Authors
Charkoudian, LK; Pham, DM; Kwon, AM; Vangeloff, AD; Franz, KJ
MLA Citation
Charkoudian, LK, Pham, DM, Kwon, AM, Vangeloff, AD, and Franz, KJ. "Modifications of boronic ester pro-chelators triggered by hydrogen peroxide tune reactivity to inhibit metal-promoted oxidative stress." Dalton Trans 43 (November 21, 2007): 5031-5042.
PMID
17992288
Source
pubmed
Published In
Dalton Transactions
Issue
43
Publish Date
2007
Start Page
5031
End Page
5042
DOI
10.1039/b705199a

Phosphorylation-dependent metal binding by alpha-synuclein peptide fragments.

Alpha-synuclein (alpha-syn) is the major protein component of the insoluble fibrils that make up Lewy bodies, the hallmark lesions of Parkinson's disease. Its C-terminal region contains motifs of charged amino acids that potentially bind metal ions, as well as several identified phosphorylation sites. We have investigated the metal-binding properties of synthetic model peptides and phosphopeptides that correspond to residues 119-132 of the C-terminal, polyacidic stretch of human alpha-syn, with the sequence Ac-Asp-Pro-Asp-Asn-Glu-Ala-Tyr-Glu-Met-Pro-Ser-Glu-Glu-Gly (alpha-syn119-132). The peptide pY125 replaces tyrosine with phosphotyrosine, whereas pS129 replaces serine with phosphoserine. By using Tb(3+) as a luminescent probe of metal binding, we find a marked selectivity of pY125 for Tb(3+) compared with pS129 and alpha-syn119-132, a result confirmed by isothermal titration calorimetry. Truncated or alanine-substituted peptides show that the phosphoester group on tyrosine provides a metal-binding anchor that is supplemented by carboxylic acid groups at positions 119, 121, and 126 to establish a multidentate ligand, while two glutamic acid residues at positions 130 and 131 contribute to binding additional Tb(3+) ions. The interaction of other metal ions was investigated by electrospray ionization mass spectrometry, which confirmed that pY125 is selective for trivalent metal ions over divalent metal ions, and revealed that Fe(3+) and Al(3+) induce peptide dimerization through metal ion cross-links. Circular dichroism showed that Fe(3+) can induce a partially folded structure for pY125, whereas no change was observed for pS129 or the unphosphorylated analog. The results of this study show that the type and location of a phosphorylated amino acid influence a peptide's metal-binding specificity and affinity as well as its overall conformation.

Authors
Liu, LL; Franz, KJ
MLA Citation
Liu, LL, and Franz, KJ. "Phosphorylation-dependent metal binding by alpha-synuclein peptide fragments." J Biol Inorg Chem 12.2 (February 2007): 234-247.
PMID
17082919
Source
pubmed
Published In
JBIC Journal of Biological Inorganic Chemistry
Volume
12
Issue
2
Publish Date
2007
Start Page
234
End Page
247
DOI
10.1007/s00775-006-0181-y

A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation.

The synthesis and structural characterization of a new pro-chelating agent, isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide (BSIH), are presented. BSIH only weakly interacts with iron unless hydrogen peroxide (H2O2) is present to remove the boronic ester protecting group to reveal a phenol that is a key metal-binding group of tridentate salicylaldehyde isonicotinoyl hydrazone (SIH). BSIH prevents deoxyribose degradation caused by hydroxyl radicals that are generated from H2O2 and redox-active iron by sequestering Fe3+ and preventing iron-promoted hydroxyl radical formation. The rate-determining step for iron sequestration is conversion of BSIH to SIH, followed by rapid Fe3+ complexation. The pro-chelate approach of BSIH represents a promising strategy for chelating a specific pool of detrimental metal ions without disturbing healthy metal ion distribution.

Authors
Charkoudian, LK; Pham, DM; Franz, KJ
MLA Citation
Charkoudian, LK, Pham, DM, and Franz, KJ. "A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation." J Am Chem Soc 128.38 (September 27, 2006): 12424-12425.
PMID
16984186
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
128
Issue
38
Publish Date
2006
Start Page
12424
End Page
12425
DOI
10.1021/ja064806w

Synthesis and characterization of copper(II) complexes of cysteinyldopa and benzothiazine model ligands related to pheomelanin.

A new cysteinyldopa model ligand Cydo {3-[(2-aminoethyl)sulfanyl]-4,6-di-tert-butylbenzene-1,2-diol} was prepared and its reactivity with Cu(II) explored. Under anaerobic conditions, tetranuclear [Cu4(Cydo)4] is isolated, but in the presence of O2, a benzothiazine intermediate accumulates that is trapped as the Cu(II) complex [Cu(zine)2]. Under slightly different reaction conditions, the benzothiazine further oxidizes to benzothiazole (zole). All three compounds were characterized by X-ray crystallography, and the reactions were monitored spectrophotometrically.

Authors
Tesema, YT; Pham, DM; Franz, KJ
MLA Citation
Tesema, YT, Pham, DM, and Franz, KJ. "Synthesis and characterization of copper(II) complexes of cysteinyldopa and benzothiazine model ligands related to pheomelanin." Inorg Chem 45.16 (August 7, 2006): 6102-6104.
PMID
16878910
Source
pubmed
Published In
Inorganic Chemistry
Volume
45
Issue
16
Publish Date
2006
Start Page
6102
End Page
6104
DOI
10.1021/ic060262n

Fe(III)-coordination properties of neuromelanin components: 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid.

The Fe(III)-coordination chemistry of neuromelanin building-block compounds, 5,6-dihydroxyindole (DHI), 5,6-dihydroxyindole-2-carboxylic acid (DHICA), and 5,6-dihydroxy-N-methyl-indole (Me-DHI), and the neurotransmitter dopamine were explored in aqueous solution by anaerobic pH-dependent spectrophotometric titrations. The Fe(III)-binding constants and pH-dependent speciation parallel those of catechol in that mono, bis, and tris FeLx species are present at concentrations dependent on the pH. The bis FeL2 dihydroxyindole species are favorable for L = DHI and DHICA under neutral to mildly acidic conditions. DHI and DHICA are stronger Fe(III) chelates than catechol, dopamine, and Me-DHI at pH values from 3 to 10. Oxidation studies reveal that iron accelerates the air oxidation of DHI and DHICA.

Authors
Charkoudian, LK; Franz, KJ
MLA Citation
Charkoudian, LK, and Franz, KJ. "Fe(III)-coordination properties of neuromelanin components: 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid." Inorg Chem 45.9 (May 1, 2006): 3657-3664.
PMID
16634598
Source
pubmed
Published In
Inorganic Chemistry
Volume
45
Issue
9
Publish Date
2006
Start Page
3657
End Page
3664
DOI
10.1021/ic060014r

A Mets motif peptide found in copper transport proteins selectively binds Cu(I) with methionine-only coordination.

Mets motifs, which refer to methionine-rich sequences found in the high-affinity copper transporter Ctr1, also appear in other proteins involved in copper trafficking and homeostasis, including other Ctrs as well as Pco and Cop proteins isolated from copper-resistant bacteria. To understand the coordination chemistry utilized by these proteins, we studied the copper binding properties of a peptide labeled Mets7-PcoC with the sequence Met-Thr-Gly-Met-Lys-Gly-Met-Ser. By comparing this sequence to a series of mutants containing noncoordinating norleucine in place of methionine, we confirm that all three methionine residues are involved in a thioether-only binding site that is selective for Cu(I). Two independent methods, one based on mass spectrometry and one based on rate differences for the copper-catalyzed oxidation of ascorbic acid, provide an effective K(D) of approximately 2.5 microM at pH 4.5 for the 1:1 complex of Mets7-PcoC with Cu(I). These results establish that a relatively simple peptide containing an MX(2)MX(2)M motif is sufficient to bind Cu(I) with an affinity that corresponds well with its proposed biological function of extracellular copper acquisition.

Authors
Jiang, J; Nadas, IA; Kim, MA; Franz, KJ
MLA Citation
Jiang, J, Nadas, IA, Kim, MA, and Franz, KJ. "A Mets motif peptide found in copper transport proteins selectively binds Cu(I) with methionine-only coordination." Inorg Chem 44.26 (December 26, 2005): 9787-9794.
PMID
16363848
Source
pubmed
Published In
Inorganic Chemistry
Volume
44
Issue
26
Publish Date
2005
Start Page
9787
End Page
9794
DOI
10.1021/ic051180m

Phosphorylation of an alpha-synuclein peptide fragment enhances metal binding.

By using Tb3+ as a luminescent probe, we demonstrate that the phosphorylation state of a 14-residue peptide fragment of alpha-synuclein, a protein implicated in Parkinson's Disease, dramatically affects the metal ion affinity of the peptide. Whereas the unphosphorylated peptide and its phosphoserine analogue show weak Tb3+ binding, its phosphotyrosine analogue shows tight 1:1 binding as well as 2:1 and 3:1 Tb:peptide adducts. Our data suggest that the phosphorylated amino acid must be appropriately positioned among additional ligating residues to establish this phosphorylation-dependent metal binding.

Authors
Liu, LL; Franz, KJ
MLA Citation
Liu, LL, and Franz, KJ. "Phosphorylation of an alpha-synuclein peptide fragment enhances metal binding." J Am Chem Soc 127.27 (July 13, 2005): 9662-9663.
PMID
15998051
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
127
Issue
27
Publish Date
2005
Start Page
9662
End Page
9663
DOI
10.1021/ja043247v

Structural origin of the high affinity of a chemically evolved lanthanide-binding peptide

Playing tag with terbium: New hydrophobic contacts and ligating amino acids are revealed in the 2.0-Å resolution X-ray crystal structure of a chemically evolved 17-residue lanthanide-binding peptide complexed with a Tb3+ ion (see ribbon diagram). The crystal structure agrees well with luminescence-lifetime measurements in solution, which indicate that no first-shell-coordinating water molecules are present in the complex.

Authors
Nitz, M; Sherawat, M; Franz, KJ; Peisach, E; Allen, KN; Imperiali, B
MLA Citation
Nitz, M, Sherawat, M, Franz, KJ, Peisach, E, Allen, KN, and Imperiali, B. "Structural origin of the high affinity of a chemically evolved lanthanide-binding peptide." Angewandte Chemie - International Edition 43.28 (2004): 3682-3685.
PMID
15248272
Source
scival
Published In
Angewandte Chemie - International Edition
Volume
43
Issue
28
Publish Date
2004
Start Page
3682
End Page
3685
DOI
10.1002/anie.200460028

Lanthanide-binding tags as versatile protein coexpression probes

Comprehensive proteomic analyses require new methodologies to accelerate the correlation of gene sequence with protien function. Key tools for such efforts include biophysical probes that integrate into the covalent architecture of proteins. Lanthanide-binding tags (LBTs) are expressible, multitasking fusion partners that are optimized to bind lanthanide ions and have several desirable attributes, which include long-lived luminescence, excellent X-ray scattering power for phase determination, and magnetic properties to facilitate NMR spectroscopic structure elucidation. Herein, we present peptide sequences with a 40-fold higher affinity for Tb3+ ions and significantly brighter luminescence intensity compared with existing peptides. Incorporation of an LBT onto ubiquitin as a prototype fusion protien allows the use of powerful protien-visualization techniques, which include rapid luminescence detection of LBT-tagged proteins in SDS-PAGE gels, as well as determination of protien concentrations in complex mixtures. The LBT strategy is a new alternative for expressing fluorescent fusion proteins by routine molecular biological techniques.

Authors
Franz, KJ; Nitz, M; Imperiali, B
MLA Citation
Franz, KJ, Nitz, M, and Imperiali, B. "Lanthanide-binding tags as versatile protein coexpression probes." ChemBioChem 4.4 (2003): 265-271.
PMID
12672105
Source
scival
Published In
ChemBioChem
Volume
4
Issue
4
Publish Date
2003
Start Page
265
End Page
271
DOI
10.1002/cbic.200390046

A powerful combinatorial screen to identify high-affinity terbium(III)-binding peptides

Lanthanide-binding tags (LBTs) are protein fusion partners consisting of encoded amino acids that bind lanthanide ions with high affinity. Herein, we present a new screening methodology for the identification of new LBT sequences with high affinity for Tb3+ ions and intense luminescence properties. This methodology utilizes solid-phase split-and-pool combinatorial peptide synthesis. Orthogonally cleavable linkers allow an efficient two-step screening procedure. The initial screen avoids the interference caused by onbead screening by photochemically releasing a portion of the peptides into an agarose matrix for evaluation. The secondary screen further characterizes each winning sequence in a defined aqueous solution. Employment of this methodology on a series of focused combinatorial libraries yielded a linear peptide sequence of 17 encoded amino acids that demonstrated a 140-fold increase in affinity (57 nM dissociation constant, KD) over previously reported lanthanide-binding peptides. This linear sequence was macrocyclized by introducing a disulfide bond between flanking cysteine residues to produce a peptide with a 2-nM apparent dissociation constant for Tb3+ ions.

Authors
Nitz, M; Franz, KJ; Maglathlin, RL; Imperiali, B
MLA Citation
Nitz, M, Franz, KJ, Maglathlin, RL, and Imperiali, B. "A powerful combinatorial screen to identify high-affinity terbium(III)-binding peptides." ChemBioChem 4.4 (2003): 272-276.
PMID
12672106
Source
scival
Published In
ChemBioChem
Volume
4
Issue
4
Publish Date
2003
Start Page
272
End Page
276
DOI
10.1002/cbic.200390047

Protein Alignment by a Coexpressed Lanthanide-Binding Tag for the Measurement of Residual Dipolar Couplings

A protein fusion construct of human ubiquitin with an N-terminal lanthanide binding tag (LBT) enables observation of long-range orientational restraints in solution NMR from residual dipolar couplings (RDCs) due to paramagnetic alignment of the protein. The paramagnetic lanthanide ions Tb3+, Dy3+, and Tm3+ are shown to bind to the LBT and induce different alignment tensors, in agreement with theory. RDCs, measured relative to the diamagnetic Lu3+, range from ?7.6 to 5.5 Hz for Tb3+ and ?6.6 to 6.1 Hz for Dy3+, while an opposite alignment tensor is observed for Tm3+ (4.5 to ?2.9 Hz) at 800 MHz. Experimental RDCs are in excellent agreement with those predicted on the basis of the X-ray structure of the protein. Copyright © 2003 American Chemical Society.

Authors
Wöhnert, J; Franz, KJ; Nitz, M; Imperiali, B; Schwalbe, H
MLA Citation
Wöhnert, J, Franz, KJ, Nitz, M, Imperiali, B, and Schwalbe, H. "Protein Alignment by a Coexpressed Lanthanide-Binding Tag for the Measurement of Residual Dipolar Couplings." Journal of the American Chemical Society 125.44 (2003): 13338-13339.
PMID
14583012
Source
scival
Published In
Journal of the American Chemical Society
Volume
125
Issue
44
Publish Date
2003
Start Page
13338
End Page
13339
DOI
10.1021/ja036022d

Pentacoordinate cobalt(III) thiolate and nitrosyl tropocoronand compounds

Reaction of [Co(TC-n,m)]+ with (Me4N)(SC6F5), where (TC-n,m) is a tropocoronand with n and m linker chain methylene groups, yielded the thiolate complexes [Co(SC6F5)(TC-3,3)] (1a), and [Co(SC6F5)(TC-4,4)] (2a), which were structurally characterized. Use of more electron-releasing thiolates afforded the [Co(TC-n,m)] reduction product and the corresponding disulfide. The bent nitrosyl complexes [Co(NO)(TC-3,3)] (1b) and [Co(NO)(TC-4,4)] (2b) were synthesized from [Co(TC-n,m)] and NO and their structures were also determined. Compounds 1a and 1b have square-pyramidal geometry like all other structurally characterized [MX(TC-3,3)] complexes. Compounds 2a and 2b have trigonal-bipyramidal stereochemistry, formerly rare for Co(III). Although 1a, 1b, and 2a are paramagnetic, 2b is diamagnetic due to the strong antibonding π-interaction between the metal and NO π* orbitals. In the presence of excess NO, [Co(TC-4,4)] exhibited novel reactivity in which a putative Co(N2) adduct formed.

Authors
Franz, KJ; Doerrer, LH; Spingler, B; Lippard, SJ
MLA Citation
Franz, KJ, Doerrer, LH, Spingler, B, and Lippard, SJ. "Pentacoordinate cobalt(III) thiolate and nitrosyl tropocoronand compounds." Inorganic Chemistry 40.15 (2001): 3774-3780.
PMID
11442376
Source
scival
Published In
Inorganic Chemistry
Volume
40
Issue
15
Publish Date
2001
Start Page
3774
End Page
3780
DOI
10.1021/ic010181l

Metal-based NO sensing by selective ligand dissociation

Nitric oxide reacts selectively with the O2 stable, weakly fluorescent complex [Co(DATI-4)] in dichloromethane solution to dissociate a fluorophore- substituted arm of the aminotroponiminate ligand DATI-4. The resulting cobalt-dinitrosyl adduct (see picture) effects a positive fluorescence response. The detection limit of 2 is 50-100 μm for NO.

Authors
Franz, KJ; Singh, N; Lippard, SJ
MLA Citation
Franz, KJ, Singh, N, and Lippard, SJ. "Metal-based NO sensing by selective ligand dissociation." Angewandte Chemie - International Edition 39.12 (June 16, 2000): 2120-2122.
Source
scopus
Published In
Angewandte Chemie International Edition
Volume
39
Issue
12
Publish Date
2000
Start Page
2120
End Page
2122
DOI
10.1002/1521-3773(20000616)39

Metal-based NO sensing by selective ligand dissociation

Nitric oxide reacts selectively with the O2 stable, weakly fluorescent complex [Co(DATI-4)] in dichloromethane solution to dissociate a fluorophore- substituted arm of the aminotroponiminate ligand DATI-4. The resulting cobalt-dinitrosyl adduct (see picture) effects a positive fluorescence response. The detection limit of 2 is 50-100 μm for NO.

Authors
Franz, KJ; Singh, N; Lippard, SJ
MLA Citation
Franz, KJ, Singh, N, and Lippard, SJ. "Metal-based NO sensing by selective ligand dissociation." Angewandte Chemie - International Edition 39.12 (2000): 2120-2122.
Source
scival
Published In
Angewandte Chemie - International Edition
Volume
39
Issue
12
Publish Date
2000
Start Page
2120
End Page
2122
DOI
10.1002/1521-3773(20000616)39:12<2120::AID-ANIE2120>3.0.CO;2-M

Aminotroponiminates as ligands for potential metal-based nitric oxide sensors

A family of new fluorescently labeled ligands, H(R)DATI, was prepared to develop transition-metal-based NO sensing strategies. The ligands are composed of aminotroponiminates (ATIs) with a dansyl fluorophore on one of the imine nitrogen atoms and an alkyl substituent, either i-Pr (8), t-Bu (9), or Bz (10), on the other. Bis(chelate) Co2+ ([Co((i-Pr)DATI)2] (12), [Co((t-Bu)DATI)2] (14), [Co((Bz)DATI)2] (15)) and Zn2+ ([Zn((i-Pr)DATI)2] (13)) complexes were prepared and characterized by X-ray crystallography. The bis(ATI) complex [Co(i-Pr2ATI)2] (11) was also prepared and its X-ray crystal structure determined. Cyclic voltammetry reveals reversible redox waves at -2.57 and -0.045 V (vs Cp2Fe/Cp2Fe+) in THF for the Co2+/Co+ and Co3+/Co2+ couples, respectively, of 11. Only a Co2+/Co+ wave at -2.09 V is observed for 12. When excited at 350 nm, the H(R)DATI ligands and the diamagnetic Zn2+ complex 13 fluoresce around 500 nm, whereas the paramagnetic Co2+ complexes quench the fluorescence. These air-stable cobalt compounds react with nitric oxide to dissociate a DATI ligand and form neutral dinitrosyl complexes, [Co(NO)2((R)DATI)]. The release of the fluorophore-containing ligand is accompanied by an increase in fluorescence intensity, thus providing a strategy for fluorescent NO sensing. Linking two DATI moieties via a tetramethylene chain affords the ligand H2DATI-4 (18). The Co2+ complex [Co(DATI-4)] (19) reacts more readily with NO than the bis(DATI) compounds and also displays an increase in fluorescence intensity upon NO binding.

Authors
Franz, KJ; Singh, N; Spingler, B; Lippard, SJ
MLA Citation
Franz, KJ, Singh, N, Spingler, B, and Lippard, SJ. "Aminotroponiminates as ligands for potential metal-based nitric oxide sensors." Inorganic Chemistry 39.18 (2000): 4081-4092.
PMID
11198863
Source
scival
Published In
Inorganic Chemistry
Volume
39
Issue
18
Publish Date
2000
Start Page
4081
End Page
4092
DOI
10.1021/ic000344q

Nitrosyl transfer from manganese to iron in tropocoronand complexes

A nitrosyl transfer reaction is described in which the NO ligand from [Mn(NO)(TC-5,5)] quantitatively transfers to [Fe(TC-5,5)] to form [Fe(NO)(TC-5,5)]. The reaction was monitored by in situ IR spectroscopy to reveal data consistent with NO dissociation from Mn prior to interaction with Fe.

Authors
Franz, KJ; Lippard, SJ
MLA Citation
Franz, KJ, and Lippard, SJ. "Nitrosyl transfer from manganese to iron in tropocoronand complexes." Inorganic Chemistry 39.16 (2000): 3722-3723.
PMID
11196841
Source
scival
Published In
Inorganic Chemistry
Volume
39
Issue
16
Publish Date
2000
Start Page
3722
End Page
3723
DOI
10.1021/ic000360n

NO disproportionation reactivity of Fe tropocoronand complexes

The synthesis and characterization of divalent [Fe(TC-5,5)] (1) and trivalent [Fe(OTf)(TC-5,5)] (2) tropocoronand complexes are described. Compound 1 reacts with 1 equiv of NO to form the {FeNO}7 complex 3. A single-crystal X-ray structure determination of 3 reveals a trigonal bipyramidal geometry with a linearly coordinated nitrosyl (Fe-N-O = 174.3(4)°) having a short Fe-N distance of 1.670(4) Å. EPR and Mossbauer spectroscopy, SQUID susceptometry, and normal coordinate analysis indicate 3 to be a low-spin {Fe(III)(NO-)}2+ species. In the presence of excess NO, 3 converts to a metastable nitrosyl-nitrito complex that decomposes by losing NO2, which subsequently nitrates the aromatic tropolone rings of the ligand. The final products of the NO disproportionation reaction are N2O and [Fe(NO)(TC-5,5-NO2)] (4). The v(NO) stretching band of 4 is increased to 1716 cm-1 from its value of 1692 cm-1 in 3, owing to the electron- withdrawing nitro groups on the ligand, and the compound no longer promotes the disproportionation of NO. Mechanistic aspects of the reaction are discussed.

Authors
Franz, KJ; Lippard, SJ
MLA Citation
Franz, KJ, and Lippard, SJ. "NO disproportionation reactivity of Fe tropocoronand complexes." Journal of the American Chemical Society 121.45 (1999): 10504-10512.
Source
scival
Published In
Journal of the American Chemical Society
Volume
121
Issue
45
Publish Date
1999
Start Page
10504
End Page
10512
DOI
10.1021/ja991664f

Disproportionation of nitric oxide promoted by a Mn tropocoronand

Authors
Franz, KJ; Lippard, SJ; Marlin, D; Mascharak, P
MLA Citation
Franz, KJ, Lippard, SJ, Marlin, D, and Mascharak, P. "Disproportionation of nitric oxide promoted by a Mn tropocoronand." Chemtracts 12.2 (1999): 135-140.
Source
scival
Published In
Chemtracts
Volume
12
Issue
2
Publish Date
1999
Start Page
135
End Page
140

Disproportionation of nitric oxide promoted by a Mn tropocoronand

The synthesis and characterization of the divalent tropocoronand, [Mn(THF)(TC-5,5)] (1), are described. Compound 1 reacts with NO to afford a discrete mononitrosyl [Mn(NO)(TC-5,5)] (2), which was isolated and shown formally to contain the {Mn(III)NO-}2+ fragment by infrared spectroscopy, normal coordinate analysis, X-ray crystallography, and SQUID susceptometry. The Mn center in 2 has idealized trigonal bipyramidal geometry with the NO ligand occupying a coordination site in the equatorial plane. The Mn-N-O bond angle is nearly linear, 174.1(3)°. Compounds 1 and 2 react with excess NO to afford N2O and [Mn(NO2)(TC-5,5)] (3). The X-ray structure of 3 reveals coordination of the nitrito ligand through one oxygen atom, the Mn-O bond length being 2.09(4) Å. The other oxygen atom interacts weakly with the manganese center at a distance of 2.61(5) Å. Quantitation by gas chromatographic analysis of released N2O confirms the 1 equiv forms for each molecule of 2 which converts to 3. Infrared spectroscopic experiments with 14NO and 15NO suggest that a dinitrosyl intermediate is present during the reaction, mechanistic aspects of which are discussed.

Authors
Franz, KJ; Lippard, SJ
MLA Citation
Franz, KJ, and Lippard, SJ. "Disproportionation of nitric oxide promoted by a Mn tropocoronand." Journal of the American Chemical Society 120.35 (1998): 9034-9040.
Source
scival
Published In
Journal of the American Chemical Society
Volume
120
Issue
35
Publish Date
1998
Start Page
9034
End Page
9040
DOI
10.1021/ja981410e

Supramolecular Alcohol-Amine Crystals and Their Hydrogen-Bond Patterns

An analysis of the structures of five new cocrystals with saturated hydrogen bonding between amines and alcohols is presented. These five are all cocrystals with p-phenylenediamine (PDA) and a mono- or diol. The cocrystals are p-phenylenediamine-phenol (1/2) [PDA·2 phenol, (I)], p-phenylenediamine-p-phenylphenol (1/2) [PDA·2 p-phenylphenol (II)], p-phenylenediamine-2,6-dihydroxynaphthalene (1/1) [PDA·2,6-dihydroxynaphthalene (III)], p-phenylenediamine-1,6-hexanediol (1/1) [PDA-1,6-hexanediol (IV)] and p-phenylenediamine-p-chlorophenol (1/2) [PDA·2 p-chlorophenol (V)]. These crystals have two distinctly different supramolecular hydrogen-bond patterns, when considering only the hydroxyl and amine groups. There are, in addition, variations in the ways covalently bonded crosslinks connect these hydrogen-bond networks. The graph sets of the hydrogen-bond networks of these and other published saturated amine-alcohol crystals are compared and suggestions made on how to present the graph-set descriptions, especially those involving infinite two- and three-dimensional networks of intersecting chains which are characteristic of most of these materials.

Authors
Loehlin, JH; Franz, KJ; Gist, L; Moore, RH
MLA Citation
Loehlin, JH, Franz, KJ, Gist, L, and Moore, RH. "Supramolecular Alcohol-Amine Crystals and Their Hydrogen-Bond Patterns." Acta Crystallographica Section B: Structural Science 54.5 (1998): 695-704.
Source
scival
Published In
Acta Crystallographica Section B: Structural Science
Volume
54
Issue
5
Publish Date
1998
Start Page
695
End Page
704

Polymer pendant ligand chemistry-5. The selective and competitive removal of Ag+, Hg2+, Cu2+, Pb2+ and Cd2+ ions from aqueous solution utilizing a N-sulfonylethylenebis(dithiocarbamate) ligand anchored on macroporous polystyrene-divinylbenzene beads

An important new focus for environmental inorganic chemistry is the selective removal and recovery of metal ions from aqueous solution with organic ligands anchored to modified polymer backbones. Several significant criteria for facile metal ion removal from aqueous solution includes the hydrophilicity of the pendant organic ligand when it is anchored to a hydrophobic, pH stable polymer backbone such as modified, macroporous polystyrene - divinylbenzene beads, as well as the kinetics and thermodynamics of the pendant ligand reaction with the selected metal ion. We report on an example of a polymer pendant ligand that is highly selective for the removal of metal ions from aqueous solution at pH 3.0 in a competitive environment. Thus, a predisposed polymer pendant N-sulfonyl-ethylenebis(dithiocarbamate) ligand (PS-SED, 1.12 mmol/g), anchored on modified, macroporous 6% polystyrene-divinylbenzene beads, was synthesized and found to be highly selective for the removal of Ag+ ions (2.17 mmol/g, 2:1 Ag+/PS-SED complex, t1/2 = 7 min) from aqueous solution at pH 3.0 in the presence of a variety of competing tri-and divalent metal ions such as Fe3+ , Cr3+, Al3+, Cu2+, Ni2+, Zn2+, Mg2+, and Pb2+. When Hg2+ ions (1.24 mmol/g, 1:1 Hg2+/PS-SED complex, t1/2 = 10 min) are added to this mixture of metal ions, including Ag+ ions, there is a pronounced selectivity toward Hg2+ ions for the PS-SED ligand. In the absence of Ag+ and Hg2+, then Pb2+ ions (1.06 mmol/g, 1:1 Pb2+/PS-SED complex, t1/2 = 6 min) are moderately selective in the presence of other competing metal ions including Cd2+ ions; Cu2+ ions are the exception (0.93 mmol/g, ∼ 1:1 Cu2+/PS-SED complex, t1/2 = 3 min). As well, in the absence of Pb2+ ions, Cd2+ ions (0.65 mmol/g, ∼ 1:1 Cd2+/PS-SED complex, t1/2 ≥ 10 min) also are moderately selective in the presence of other competing metal ions; but again, Cu2+ is the exception. Whereas Cu2+ has a selectivity over Pb2+ and Cd2+ in a competitive reaction, Fe3+ ion is more selective in competition with Cu2+, while in competition with Fe3+ ion, Ag+, Hg2+, Pb2+ and Cd2+ are all more selective. The overall selectivity was found to be : Hg2+ ≥ Ag+ > Cu2+ > Pb2+ > Cd2+ > Fe3+ ∼ Al3+ ∼ Cr3+ > Ni2+ > Zn2+ ∼ Co2+ > Mn2+ ≫ Mg2+. Furthermore, a facile recovery of Ag+, Cu2+, and Cd2+ ions from the respective metal-ion-PS-SED complexes on the beads were readily accomplished (∼99% recovery) using a 10% NaCN solution at pH 11. A full discussion of these results will be presented. Copyright © 1996 Elsevier Science Ltd.

Authors
Huang, S-P; Franz, KJ; Arnold, EH; Devenyi, J; Fish, RH
MLA Citation
Huang, S-P, Franz, KJ, Arnold, EH, Devenyi, J, and Fish, RH. "Polymer pendant ligand chemistry-5. The selective and competitive removal of Ag+, Hg2+, Cu2+, Pb2+ and Cd2+ ions from aqueous solution utilizing a N-sulfonylethylenebis(dithiocarbamate) ligand anchored on macroporous polystyrene-divinylbenzene beads." Polyhedron 15.23 (1996): 4241-4254.
Source
scival
Published In
Polyhedron
Volume
15
Issue
23
Publish Date
1996
Start Page
4241
End Page
4254
DOI
10.1016/0277-5387(96)00171-4

Polymer pendant ligand chemistry. 3. A biomimetic approach to selective metal ion removal and recovery from aqueous solution with polymer-supported sulfonated catechol and linear catechol amide ligands

The design of organic ligands to selectively remove and recover metal ions from aqueous solution is a new and important area of environmental inorganic chemistry. One approach to designing organic ligands for these purposes is to use biological systems as examples for selective metal ion complexation. Thus, we report on our results on the synthesis of several biomimetically important polymer-supported, sulfonated catechol (PS-CATS), sulfonated bis(catechol) linear amide (PS-2-6-LICAMS), and sulfonated 3,3-linear tris(catechol) amide (PS-3,3-LICAMS) ligands that are chemically bonded to modified 6% cross-linked macroporous polystyrene-divinylbenzene beads (PS-DVB) for selective removal and recovery of environmentally and economically important metal ions from aqueous solution, as a function of pH. The Fe3+ ion selectivity was dramatically shown for PS-CATS, PS-2-6-LICAMS and PS-3,3-LICAMS polymer beads in competition with a similar concentration of Cu2+, Zn2+, Mn2+, Ni2+, Mg2+, Al3+, and Cr3+ ions at pH 1-3, while metal ion selectivity could be changed at higher pH values in the absence of Fe3+ (for example, Hg2+ at pH 3). Rates of removal and recovery of the Fe3+ ion with the PS-CATS, PS-2-6-LICAMS and PS-3,3-LICAMS polymer beads were also studied as well as relative equilibrium selectivity coefficient (Km) values for all metal competition studies. The chelate effect for the octahedrally predisposed PS-3,3-LICAMS polymer pendant ligand, as shown for the homogeneous ligand, appears to be the reason that this polymer pendant ligand has a more pronounced selectivity for Fe3+ ion in comparison to the PS-CATS polymer beads, while the square planar predisposed PS-2-6-LICAMS series of polymer pendant ligands were more selective to divalent metal ions, Cu2+, Zn2+, Mn2+, Ni2+, and Mg2+, than either PS-CATS or PS-3,3-LICAMS, although Fe3+ ion still dominated in competition with other divalent and trivalent metal ions. It is interesting to note that changing the cavity size from two CH2 groups to six CH2 groups in the PS-2-6-LICAMS polymer pendant ligand series did not affect the order of metal ion selectivity. © 1995 American Chemical Society.

Authors
Huang, S-P; Li, W; Franz, KJ; Albright, RL; Fish, RH
MLA Citation
Huang, S-P, Li, W, Franz, KJ, Albright, RL, and Fish, RH. "Polymer pendant ligand chemistry. 3. A biomimetic approach to selective metal ion removal and recovery from aqueous solution with polymer-supported sulfonated catechol and linear catechol amide ligands." Inorganic Chemistry 34.11 (1995): 2813-2819.
Source
scival
Published In
Inorganic Chemistry
Volume
34
Issue
11
Publish Date
1995
Start Page
2813
End Page
2819

Synthetic and structural studies of a linear bis-catechol amide, N,N′-bis(2,3-dihydroxybenzoyl)-1,7-diazaheptane (5-LICAM), and its complexes with Ni2+ and Co2+: Utilization of a polymer-supported, sulfonated analog, 5-LICAMS, as a biomimetic ligand for divalent metal ion removal from aqueous solution

The synthesis and structural characterization of the linear bis(catechol) amide ligand, N,N′-bis(2,3-dihydroxybenzoyl)-1,7-diazaheptane (5-LICAM, 1), was studied along with several metal complexes, namely, Ni2+ and Co2+. We were able to obtain a single-crystal X-ray analysis of a derivative of 1, the hemimethoxy ligand, 5-LICAM(OCH3)2, 2, where partial demethylation of the fully methylated derivative of 1 was serendipitiously obtained in the presence of a deficiency of BBr3. The X-ray structure showed why we retained the methoxy group, during the partial demethylation reaction, in each catechol amide ring by the fact that a selective intramolecular hydrogen bond occurs between the one demethylated OH group in each catechol ring and the amide carbonyl in the adjacent position (C=O⋯HO, 1.67 Å). Reaction of 1 with a Ni2+ salt provided the first structurally characterized square planar, linear bis-catechol amide, dianionic metal complex, with cesium as the counterion, Cs2[5-LICAM-Ni]·3DMF, 3, (Ni-O, 1.87 Å, O-Ni-O, 87.9-92.5°). It is also interesting to note that one of the cesium atoms was cis-bonded to the catechol oxygens in each ring (O2⋯Cs1, O6-Cs1 = 3.23 Å, 3.03 Å) and to the carbonyl oxygen of one of the three DMF solvent molecules (Cs1-O=C, 3.13 Å), while the other cesium atom was bonded to all three carbonyl oxygens of the DMF molecules in the structure (Cs2-O7, O8 = 3.13, 3.12 A⋯). A Co2+ analogue of 3, Cs2[5-LICAM-Co]·DMF, 4, provided a similar structure as ascertained by FT-IR, FAB/MS, and elemental analysis. In order to test the utilization of 1 in removing Ni2+ from aqueous solution for environmental inorganic applications, we synthesized the polymer pendant ligand version, PS-5-LICAM, bonded to modified 6% macroporous divinylbenzene-polystyrene beads (0.55 mmol/g), with an important modification of a sulfonate group on the catechol ring, PS-5-LICAMS, to impart hydrophilicity to the ligand site. Indeed, we found that the PS-5-LICAMS ligand removed 0.35 mmol of Ni/g of polymer beads from aqueous solution at pH 2.5, but unfortunately, was not selective to Ni2+ in competition with other divalent metal ions. An in depth discussion of the X-ray structure of ligand 2 and that of the Ni complex, 3, will be presented. © 1995 American Chemical Society.

Authors
Huang, S-P; Franz, KJ; Olmstead, MM; Fish, RH
MLA Citation
Huang, S-P, Franz, KJ, Olmstead, MM, and Fish, RH. "Synthetic and structural studies of a linear bis-catechol amide, N,N′-bis(2,3-dihydroxybenzoyl)-1,7-diazaheptane (5-LICAM), and its complexes with Ni2+ and Co2+: Utilization of a polymer-supported, sulfonated analog, 5-LICAMS, as a biomimetic ligand for divalent metal ion removal from aqueous solution." Inorganic Chemistry 34.11 (1995): 2820-2825.
Source
scival
Published In
Inorganic Chemistry
Volume
34
Issue
11
Publish Date
1995
Start Page
2820
End Page
2825
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