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Hong, Jiyong

Overview:

Research in the Hong group focuses on using chemical tools, in particular small molecules, to understand the signaling pathways in biology. We synthesize biologically interesting natural products and screen small molecule libraries to identify modulators of biological processes. Then, we explore their modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. In addition, we design and develop unique and efficient synthetic strategies that will allow rapid access to molecular complexity and structural diversity. Through multidisciplinary approaches, including organic synthesis, molecular biology, and cell biology, the cellular components and molecular events that embody cancer, immune response, and GPCR signaling have systematically been explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases.


Synthesis of Natural Products and Study of Mode of Action: We synthesize biologically interesting natural products and explore the modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. Completed target molecules include largazole (a marine natural product with HDAC inhibitory activity), brasilibactin A (a cytotoxic siderophore), manassantins A and B (natural products with anti-HIF-1 activity), and subglutinols A and B (natural products with immunosuppressive activity).
Development of Novel Synthetic Methodology: We design and develop unique and efficient synthetic strategies which will allow rapid access to molecular complexity and structural diversity. A specific area of interest includes the development of novel methods for the stereoselective synthesis of substituted tetrahydrofurans and tetrahydropyrans.
Screen of Small Molecule Libraries for Identification of Small Molecule Modulators of Biological Processes: With the advent of combinatorial chemistry and other synthetic technologies, it is feasible to prepare large collections of synthetic organic molecules. These libraries are useful in providing molecules that can be used to probe relevant biological pathways. We are interested in identification of modulators of biological processes, including drug abuse and neurodegenerative diseases.

Through multidisciplinary approaches, the cellular components and molecular events that embody cancer, immune response, and neurodegenerative diseases are systematically explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases.

Positions:

Professor of Chemistry

Chemistry
Trinity College of Arts & Sciences

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1993

B.S. — Seoul National University

M.S. 1995

M.S. — Seoul National University

Ph.D. 2001

Ph.D. — The Scripps Research Institute

Grants:

Structural and Mechanistic Characterization of MraY Catalysis and Inhibition

Administered By
Biochemistry
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
January 01, 2017
End Date
November 30, 2020

Biosynthesis of peptidyl nucleoside antifungal antibiotics

Administered By
Biochemistry
AwardedBy
National Institutes of Health
Role
Collaborating Investigator
Start Date
July 01, 2015
End Date
June 30, 2020

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2020

Study of Subglutinol A as a Potential Immunomodulatory Agent

Administered By
Chemistry
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 09, 2016
End Date
November 30, 2018

Human Stringent Response as Novel Therapeutic Approaches for Breast Cancers

Administered By
Molecular Genetics and Microbiology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2015
End Date
September 29, 2018

GAANN - Department of Chemistry

Administered By
Chemistry
AwardedBy
Department of Education
Role
Mentor
Start Date
September 01, 2015
End Date
August 31, 2018

MRI: Acquisition of a Triple Quadrupole LC/MS System

Administered By
Chemistry
AwardedBy
National Science Foundation
Role
Major User
Start Date
August 01, 2015
End Date
July 31, 2018

Targeting Rev1-mediated Translesion Synthesis for Cancer Therapy

Administered By
Biochemistry
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2017

PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction

Administered By
Chemistry
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 15, 2009
End Date
December 30, 2011

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
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Publications:

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma.

Cancer cells can inhibit effector T cells (Teff) through both immunomodulatory receptors and the impact of cancer metabolism on the tumor microenvironment. Indeed, Teff require high rates of glucose metabolism, and consumption of essential nutrients or generation of waste products by tumor cells may impede essential T cell metabolic pathways. Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the tumor suppressor von Hippel-Lindau (VHL) and altered cancer cell metabolism. Here, we assessed how ccRCC influences the metabolism and activation of primary patient ccRCC tumor infiltrating lymphocytes (TIL). CD8 TIL were abundant in ccRCC, but they were phenotypically distinct and both functionally and metabolically impaired. ccRCC CD8 TIL were unable to efficiently uptake glucose or perform glycolysis and had small, fragmented mitochondria that were hyperpolarized and generated large amounts of ROS. Elevated ROS was associated with downregulated mitochondrial SOD2. CD8 T cells with hyperpolarized mitochondria were also visible in the blood of ccRCC patients. Importantly, provision of pyruvate to bypass glycolytic defects or scavengers to neutralize mitochondrial ROS could partially restore TIL activation. Thus, strategies to improve metabolic function of ccRCC CD8 TIL may promote the immune response to ccRCC.

Authors
Siska, PJ; Beckermann, KE; Mason, FM; Andrejeva, G; Greenplate, AR; Sendor, AB; Chiang, Y-CJ; Corona, AL; Gemta, LF; Vincent, BG; Wang, RC; Kim, B; Hong, J; Chen, C-L; Bullock, TN; Irish, JM; Rathmell, WK; Rathmell, JC
MLA Citation
Siska, PJ, Beckermann, KE, Mason, FM, Andrejeva, G, Greenplate, AR, Sendor, AB, Chiang, Y-CJ, Corona, AL, Gemta, LF, Vincent, BG, Wang, RC, Kim, B, Hong, J, Chen, C-L, Bullock, TN, Irish, JM, Rathmell, WK, and Rathmell, JC. "Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma." JCI insight 2.12 (June 15, 2017).
PMID
28614802
Source
epmc
Published In
JCI insight
Volume
2
Issue
12
Publish Date
2017
DOI
10.1172/jci.insight.93411

Synthesis and biological evaluation of largazole zinc-binding group analogs.

Histone acetylation is an extensively investigated post-translational modification that plays an important role as an epigenetic regulator. It is controlled by histone acetyl transferases (HATs) and histone deacetylases (HDACs). The overexpression of HDACs and consequent hypoacetylation of histones have been observed in a variety of different diseases, leading to a recent focus of HDACs as attractive drug targets. The natural product largazole is one of the most potent natural HDAC inhibitors discovered so far and a number of largazole analogs have been prepared to define structural requirements for its HDAC inhibitory activity. However, previous structure-activity relationship studies have heavily investigated the macrocycle region of largazole, while there have been only limited efforts to probe the effect of various zinc-binding groups (ZBGs) on HDAC inhibition. Herein, we prepared a series of largazole analogs with various ZBGs and evaluated their HDAC inhibition and cytotoxicity. While none of the analogs tested were as potent or selective as largazole, the Zn2+-binding affinity of each ZBG correlated with HDAC inhibition and cytotoxicity. We expect that our findings will aid in building a deeper understanding of the role of ZBGs in HDAC inhibition as well as provide an important basis for the future development of new largazole analogs with non-thiol ZBGs as novel therapeutics for cancer.

Authors
Kim, B; Ratnayake, R; Lee, H; Shi, G; Zeller, SL; Li, C; Luesch, H; Hong, J
MLA Citation
Kim, B, Ratnayake, R, Lee, H, Shi, G, Zeller, SL, Li, C, Luesch, H, and Hong, J. "Synthesis and biological evaluation of largazole zinc-binding group analogs." Bioorganic & medicinal chemistry 25.12 (June 2017): 3077-3086.
PMID
28416100
Source
epmc
Published In
Bioorganic & Medicinal Chemistry
Volume
25
Issue
12
Publish Date
2017
Start Page
3077
End Page
3086
DOI
10.1016/j.bmc.2017.03.071

Formal Synthesis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehydrative Alkoxylation.

8-Membered cyclic ethers are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. The gold(I)-catalyzed intramolecular dehydrative alkoxylation of ω-hydroxy allylic alcohols was explored to stereoselectively construct α,α'-cis-oxocenes and further applied in a formal synthesis of (+)-laurencin. The gold(I)-catalyzed intramolecular dehydrative alkoxylation may constitute an alternative method for the synthesis of molecular building blocks and natural products that contain highly functionalized 8-membered cyclic ethers.

Authors
Lanier, ML; Park, H; Mukherjee, P; Timmerman, JC; Ribeiro, AA; Widenhoefer, RA; Hong, J
MLA Citation
Lanier, ML, Park, H, Mukherjee, P, Timmerman, JC, Ribeiro, AA, Widenhoefer, RA, and Hong, J. "Formal Synthesis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehydrative Alkoxylation." Chemistry (Weinheim an der Bergstrasse, Germany) 23.30 (May 2017): 7180-7184.
PMID
28393406
Source
epmc
Published In
Chemistry - A European Journal
Volume
23
Issue
30
Publish Date
2017
Start Page
7180
End Page
7184
DOI
10.1002/chem.201700499

Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes.

T and B lymphocytes undergo metabolic re-programming upon activation that is essential to allow bioenergetics, cell survival, and intermediates for cell proliferation and function. To support changes in the activity of signaling pathways and to provide sufficient and necessary intracellular metabolites, uptake of extracellular nutrients increases sharply with metabolic re-programming. One result of increased metabolic activity can be reactive oxygen species (ROS), which can be toxic when accumulated in excess. Uptake of cystine allows accumulation of cysteine that is necessary for glutathione synthesis and ROS detoxification. Cystine uptake is required for T cell activation and function but measurements based on radioactive labeling do not allow analysis on single cell level. Here we show the critical role for cystine uptake in T cells using a method for measurement of cystine uptake using a novel CystineFITC probe. T cell receptor stimulation lead to upregulation of the cystine transporter xCT (SLC7a11) and increased cystine uptake in CD4+ and CD8+ human T cells. Similarly, lipopolysaccharide stimulation increased cystine uptake in human B cells. The CystineFITC probe was not toxic and could be metabolized to prevent cystine starvation induced cell death. Furthermore, blockade of xCT or competition with natural cystine decreased uptake of CystineFITC. CystineFITC is thus a versatile tool that allows measurement of cystine uptake on single cell level and shows the critical role for cystine uptake for T cell ROS regulation and activation.

Authors
Siska, PJ; Kim, B; Ji, X; Hoeksema, MD; Massion, PP; Beckermann, KE; Wu, J; Chi, J-T; Hong, J; Rathmell, JC
MLA Citation
Siska, PJ, Kim, B, Ji, X, Hoeksema, MD, Massion, PP, Beckermann, KE, Wu, J, Chi, J-T, Hong, J, and Rathmell, JC. "Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes." Journal of immunological methods 438 (November 2016): 51-58.
PMID
27594594
Source
epmc
Published In
Journal of Immunological Methods
Volume
438
Publish Date
2016
Start Page
51
End Page
58
DOI
10.1016/j.jim.2016.08.013

Advances in the synthesis of glycosidic macrolides: clavosolides A-D and cyanolide A.

Covering: 2005 to 2016Clavosolides A-D and cyanolide A are glycosidic macrolides and represent a new family of marine natural products. They possess a number of unusual structural features and have attracted considerable interest from the synthetic community. This review presents a comprehensive survey of all aspects of the clavosolides A-D and cyanolide A. Specific topics include isolation, structure determination, biological activity, and synthetic approaches.

Authors
Lee, K; Lanier, ML; Kwak, J-H; Kim, H; Hong, J
MLA Citation
Lee, K, Lanier, ML, Kwak, J-H, Kim, H, and Hong, J. "Advances in the synthesis of glycosidic macrolides: clavosolides A-D and cyanolide A." Natural product reports 33.12 (November 2016): 1393-1424. (Review)
PMID
27714078
Source
epmc
Published In
Natural Product Reports
Volume
33
Issue
12
Publish Date
2016
Start Page
1393
End Page
1424
DOI
10.1039/c6np00073h

Discovery of Manassantin A Protein Targets Using Large-Scale Protein Folding and Stability Measurements.

Manassantin A is a natural product that has been shown to have anticancer activity in cell-based assays, but has a largely unknown mode-of-action. Described here is the use of two different energetics-based approaches to identify protein targets of manassantin A. Using the stability of proteins from rates of oxidation technique with an isobaric mass tagging strategy (iTRAQ-SPROX) and the pulse proteolysis technique with a stable isotope labeling with amino acids in cell culture strategy (SILAC-PP), over 1000 proteins in a MDA-MB-231 cell lysate grown under hypoxic conditions were assayed for manassantin A interactions (both direct and indirect). A total of 28 protein hits were identified with manassantin A-induced thermodynamic stability changes. Two of the protein hits (filamin A and elongation factor 1α) were identified using both experimental approaches. The remaining 26 hit proteins were only assayed in either the iTRAQ-SPROX or the SILAC-PP experiment. The 28 potential protein targets of manassantin A identified here provide new experimental avenues along which to explore the molecular basis of manassantin A's mode of action. The current work also represents the first application iTRAQ-SPROX and SILAC-PP to the large-scale analysis of protein-ligand binding interactions involving a potential anticancer drug with an unknown mode-of-action.

Authors
Geer Wallace, MA; Kwon, D-Y; Weitzel, DH; Lee, C-T; Stephenson, TN; Chi, J-T; Mook, RA; Dewhirst, MW; Hong, J; Fitzgerald, MC
MLA Citation
Geer Wallace, MA, Kwon, D-Y, Weitzel, DH, Lee, C-T, Stephenson, TN, Chi, J-T, Mook, RA, Dewhirst, MW, Hong, J, and Fitzgerald, MC. "Discovery of Manassantin A Protein Targets Using Large-Scale Protein Folding and Stability Measurements." Journal of proteome research 15.8 (August 2016): 2688-2696.
PMID
27322910
Source
epmc
Published In
Journal of Proteome Research
Volume
15
Issue
8
Publish Date
2016
Start Page
2688
End Page
2696
DOI
10.1021/acs.jproteome.6b00237

Structural insights into inhibition of lipid I production in bacterial cell wall synthesis.

Antibiotic-resistant bacterial infection is a serious threat to public health. Peptidoglycan biosynthesis is a well-established target for antibiotic development. MraY (phospho-MurNAc-pentapeptide translocase) catalyses the first and an essential membrane step of peptidoglycan biosynthesis. It is considered a very promising target for the development of new antibiotics, as many naturally occurring nucleoside inhibitors with antibacterial activity target this enzyme. However, antibiotics targeting MraY have not been developed for clinical use, mainly owing to a lack of structural insight into inhibition of this enzyme. Here we present the crystal structure of MraY from Aquifex aeolicus (MraYAA) in complex with its naturally occurring inhibitor, muraymycin D2 (MD2). We show that after binding MD2, MraYAA undergoes remarkably large conformational rearrangements near the active site, which lead to the formation of a nucleoside-binding pocket and a peptide-binding site. MD2 binds the nucleoside-binding pocket like a two-pronged plug inserting into a socket. Further interactions it makes in the adjacent peptide-binding site anchor MD2 to and enhance its affinity for MraYAA. Surprisingly, MD2 does not interact with three acidic residues or the Mg(2+) cofactor required for catalysis, suggesting that MD2 binds to MraYAA in a manner that overlaps with, but is distinct from, its natural substrate, UDP-MurNAc-pentapeptide. We have determined the principles of MD2 binding to MraYAA, including how it avoids the need for pyrophosphate and sugar moieties, which are essential features for substrate binding. The conformational plasticity of MraY could be the reason that it is the target of many structurally distinct inhibitors. These findings can inform the design of new inhibitors targeting MraY as well as its paralogues, WecA and TarO.

Authors
Chung, BC; Mashalidis, EH; Tanino, T; Kim, M; Matsuda, A; Hong, J; Ichikawa, S; Lee, S-Y
MLA Citation
Chung, BC, Mashalidis, EH, Tanino, T, Kim, M, Matsuda, A, Hong, J, Ichikawa, S, and Lee, S-Y. "Structural insights into inhibition of lipid I production in bacterial cell wall synthesis." Nature 533.7604 (May 2016): 557-560.
PMID
27088606
Source
epmc
Published In
Nature
Volume
533
Issue
7604
Publish Date
2016
Start Page
557
End Page
560
DOI
10.1038/nature17636

Preface.

Authors
Garbaccio, RM; Johnson, DS; Hong, J; Disney, MD
MLA Citation
Garbaccio, RM, Johnson, DS, Hong, J, and Disney, MD. "Preface." November 2015. 4714-.
PMID
26358161
Source
epmc
Volume
25
Publish Date
2015
Start Page
4714
DOI
10.1016/j.bmcl.2015.08.083

Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition.

To cope with hypoxia, tumor cells have developed a number of adaptive mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote angiogenesis and cell survival. Due to significant roles of HIF-1 in the initiation, progression, metastasis, and resistance to treatment of most solid tumors, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B (2) are potent inhibitors of HIF-1 activity. To define the structural requirements of manassantins for HIF-1 inhibition, we prepared and evaluated a series of manassantin analogues. Our SAR studies examined key regions of manassantin's structure in order to understand the impact of these regions on biological activity and to define modifications that can lead to improved performance and drug-like properties. Our efforts identified several manassantin analogues with reduced structural complexity as potential lead compounds for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression of the HIF-1α protein and reduced the levels of HIF-1 target genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial growth factor (VEGF). These findings provide an important framework to design potent and selective HIF-1α inhibitors, which is necessary to aid translation of manassantin-derived natural products to the clinic as novel therapeutics for cancers.

Authors
Kwon, D-Y; Lee, HE; Weitzel, DH; Park, K; Lee, SH; Lee, C-T; Stephenson, TN; Park, H; Fitzgerald, MC; Chi, J-T; Mook, RA; Dewhirst, MW; Lee, YM; Hong, J
MLA Citation
Kwon, D-Y, Lee, HE, Weitzel, DH, Park, K, Lee, SH, Lee, C-T, Stephenson, TN, Park, H, Fitzgerald, MC, Chi, J-T, Mook, RA, Dewhirst, MW, Lee, YM, and Hong, J. "Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition." Journal of medicinal chemistry 58.19 (October 2015): 7659-7671.
PMID
26394152
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
58
Issue
19
Publish Date
2015
Start Page
7659
End Page
7671
DOI
10.1021/acs.jmedchem.5b01220

Total Synthesis of Clavosolide A via Tandem Allylic Oxidation/Oxa-Conjugate Addition Reaction.

The tandem allylic oxidation/oxa-conjugate addition reaction promoted by the gem-disubstituent effect in conjunction with the NHC-mediated oxidative esterification was explored for the facile synthesis of clavosolide A.

Authors
Baker, JB; Kim, H; Hong, J
MLA Citation
Baker, JB, Kim, H, and Hong, J. "Total Synthesis of Clavosolide A via Tandem Allylic Oxidation/Oxa-Conjugate Addition Reaction." Tetrahedron letters 56.23 (June 2015): 3120-3122.
PMID
26236051
Source
epmc
Published In
Tetrahedron Letters
Volume
56
Issue
23
Publish Date
2015
Start Page
3120
End Page
3122
DOI
10.1016/j.tetlet.2014.11.135

Subglutinol A, an immunosuppressive α-pyrone diterpenoid from Fusarium subglutinans, acts as an estrogen receptor antagonist.

Subglutinol A is an immunosuppressive α-pyrone diterpenoid isolated from Fusarium subglutinans that exhibits osteogenic activity. Several non-steroid mycotoxins isolated from various strains of Fusarium fungi exhibit female steroid hormone activities. In this study, we characterized the estrogenic activity of subglutinol A (1). Subglutinol A blocked the 17β-estradiol-induced activation of reporter plasmids and endogenous estrogen-responsive target genes in a dose-dependent manner and efficiently destabilized ER proteins as shown using the estrogen receptor antagonist ICI 182,780. Subglutinol A also displaced the specific binding of [(3)H]17β-estradiol from ER in MCF-7 whole-cell ligand binding assays. These data demonstrate the potential of subglutinol A as an ER antagonist though its competition with 17β-estradiol for direct ER association.

Authors
Lim, W; Park, J; Lee, YH; Hong, J; Lee, Y
MLA Citation
Lim, W, Park, J, Lee, YH, Hong, J, and Lee, Y. "Subglutinol A, an immunosuppressive α-pyrone diterpenoid from Fusarium subglutinans, acts as an estrogen receptor antagonist." Biochemical and biophysical research communications 461.3 (June 2015): 507-512.
PMID
25896764
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
461
Issue
3
Publish Date
2015
Start Page
507
End Page
512
DOI
10.1016/j.bbrc.2015.04.053

An overview of naturally occurring histone deacetylase inhibitors.

Histone deacetylases (HDACs) have recently emerged as key elements in epigenetic control of gene expression. Due to the implication of HDACs in a variety of diseases ranging from cancer to neurodegenerative disorder, HDAC inhibitors have received increased attention in recent years. Over the last few decades, a myriad of HDAC inhibitors containing a wide variety of structural features have been identified from natural sources. Here, we review the discovery, synthesis, biological properties, and modes of action of these naturally occurring HDAC inhibitors and consider their implications for future research.

Authors
Kim, B; Hong, J
MLA Citation
Kim, B, and Hong, J. "An overview of naturally occurring histone deacetylase inhibitors." Current topics in medicinal chemistry 14.24 (January 2015): 2759-2782. (Review)
PMID
25487010
Source
epmc
Published In
Current Topics in Medicinal Chemistry
Volume
14
Issue
24
Publish Date
2015
Start Page
2759
End Page
2782
DOI
10.2174/1568026615666141208105614

Evaluation of class i HDAC isoform selectivity of largazole analogues

Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors. © 2014 Elsevier Ltd. All rights reserved.

Authors
Kim, B; Park, H; Salvador, LA; Serrano, PE; Kwan, JC; Zeller, SL; Chen, QY; Ryu, S; Liu, Y; Byeon, S; Luesch, H; Hong, J
MLA Citation
Kim, B, Park, H, Salvador, LA, Serrano, PE, Kwan, JC, Zeller, SL, Chen, QY, Ryu, S, Liu, Y, Byeon, S, Luesch, H, and Hong, J. "Evaluation of class i HDAC isoform selectivity of largazole analogues." Bioorganic and Medicinal Chemistry Letters 24.16 (August 15, 2014): 3728-3731.
Source
scopus
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
24
Issue
16
Publish Date
2014
Start Page
3728
End Page
3731
DOI
10.1016/j.bmcl.2014.07.006

Natural product synthesis at the interface of chemistry and biology.

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences.

Authors
Hong, J
MLA Citation
Hong, J. "Natural product synthesis at the interface of chemistry and biology." Chemistry (Weinheim an der Bergstrasse, Germany) 20.33 (August 2014): 10204-10212.
PMID
25043880
Source
epmc
Published In
Chemistry - A European Journal
Volume
20
Issue
33
Publish Date
2014
Start Page
10204
End Page
10212
DOI
10.1002/chem.201402804

Evaluation of class I HDAC isoform selectivity of largazole analogues.

Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors.

Authors
Kim, B; Park, H; Salvador, LA; Serrano, PE; Kwan, JC; Zeller, SL; Chen, Q-Y; Ryu, S; Liu, Y; Byeon, S; Luesch, H; Hong, J
MLA Citation
Kim, B, Park, H, Salvador, LA, Serrano, PE, Kwan, JC, Zeller, SL, Chen, Q-Y, Ryu, S, Liu, Y, Byeon, S, Luesch, H, and Hong, J. "Evaluation of class I HDAC isoform selectivity of largazole analogues." Bioorganic & medicinal chemistry letters 24.16 (August 2014): 3728-3731.
PMID
25070421
Source
epmc
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
24
Issue
16
Publish Date
2014
Start Page
3728
End Page
3731
DOI
10.1016/j.bmcl.2014.07.006

Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.

Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the "warhead" moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response.

Authors
Salvador, LA; Park, H; Al-Awadhi, FH; Liu, Y; Kim, B; Zeller, SL; Chen, Q-Y; Hong, J; Luesch, H
MLA Citation
Salvador, LA, Park, H, Al-Awadhi, FH, Liu, Y, Kim, B, Zeller, SL, Chen, Q-Y, Hong, J, and Luesch, H. "Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties." ACS Medicinal Chemistry Letters 5.8 (August 2014): 905-910.
PMID
25147612
Source
epmc
Published In
ACS Medicinal Chemistry Letters
Volume
5
Issue
8
Publish Date
2014
Start Page
905
End Page
910
DOI
10.1021/ml500170r

Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters.

Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively.

Authors
Johnson, ZL; Lee, J-H; Lee, K; Lee, M; Kwon, D-Y; Hong, J; Lee, S-Y
MLA Citation
Johnson, ZL, Lee, J-H, Lee, K, Lee, M, Kwon, D-Y, Hong, J, and Lee, S-Y. "Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters." eLife 3 (July 31, 2014): e03604-.
PMID
25082345
Source
epmc
Published In
eLife
Volume
3
Publish Date
2014
Start Page
e03604
DOI
10.7554/elife.03604

Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters

Authors
Johnson, ZL; Lee, J-H; Lee, K; Lee, M; Kwon, D-Y; Hong, J; Lee, S-Y
MLA Citation
Johnson, ZL, Lee, J-H, Lee, K, Lee, M, Kwon, D-Y, Hong, J, and Lee, S-Y. "Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters." ELIFE 3 (July 31, 2014).
Source
wos-lite
Published In
eLife
Volume
3
Publish Date
2014
DOI
10.7554/eLife.03604

Synthesis of α,α'-trans-oxepanes through an organocatalytic oxa-conjugate addition reaction.

Oxepanes are found in a wide range of natural products; however, they are challenging synthetic targets due to enthalpic and entropic barriers. Organocatalytic oxa-conjugate addition reactions promoted by the gem-disubstituent (Thorpe-Ingold) effect stereoselectively provided α,α'-trans-oxepanes. In addition, the potential of an organocatalytic tandem oxa-conjugate addition/α-oxidation was demonstrated in a rapid generation of molecular complexity. These organocatalytic oxa-conjugate addition reactions would provide powerful tools for the synthesis of natural products that contain highly functionalized oxepanes.

Authors
Lanier, ML; Kasper, AC; Kim, H; Hong, J
MLA Citation
Lanier, ML, Kasper, AC, Kim, H, and Hong, J. "Synthesis of α,α'-trans-oxepanes through an organocatalytic oxa-conjugate addition reaction." Organic letters 16.9 (May 2014): 2406-2409.
PMID
24724535
Source
epmc
Published In
Organic Letters
Volume
16
Issue
9
Publish Date
2014
Start Page
2406
End Page
2409
DOI
10.1021/ol500773w

Biological evaluation of subglutinol a as a novel immunosuppressive agent for inflammation intervention.

Subglutinol A (1) is an immunosuppressive natural product isolated from Fusarium subglutinans, an endophytic fungus from the vine Tripterygium wilfordii. We show that 1 exerts multimodal immune-suppressive effects on activated T cells in vitro: subglutinol A (1) effectively blocks T cell proliferation and survival while profoundly inhibiting pro-inflammatory IFNγ and IL-17 production by fully differentiated effector Th1 and Th17 cells. Our data further reveal that 1 may exert its anti-inflammatory effects by exacerbating mitochondrial damage in T cells. Additionally, we demonstrate that 1 significantly reduces lymphocytic infiltration into the footpad and ameliorates footpad swelling in the mouse model of Th1-driven delayed-type hypersensitivity. These results suggest the potential of 1 as a novel therapeutic for inflammatory diseases.

Authors
Lin, R; Kim, H; Hong, J; Li, Q-J
MLA Citation
Lin, R, Kim, H, Hong, J, and Li, Q-J. "Biological evaluation of subglutinol a as a novel immunosuppressive agent for inflammation intervention." ACS Medicinal Chemistry Letters 5.5 (May 2014): 485-490.
PMID
24900866
Source
epmc
Published In
ACS Medicinal Chemistry Letters
Volume
5
Issue
5
Publish Date
2014
Start Page
485
End Page
490
DOI
10.1021/ml4004809

Largazole pharmacokinetics in rats by LC-MS/MS.

A highly sensitive and specific LC-MS/MS method for the quantitation of largazole thiol, the active species of the marine-derived preclinical histone deacetylase inhibitor, largazole (prodrug), was developed and validated. Largazole thiol was extracted with ethyl acetate from human or rat plasma along with the internal standard, harmine. Samples were separated on an Onyx Monolithic C18 column by a stepwise gradient elution with 0.1% formic acid in methanol and 0.1% aqueous formic acid employing multiple reaction monitoring (MRM) detection. Linear calibration curves were obtained in the range of 12.5-400 ng/mL with 200 µL of human plasma. The overall intra-day precision was from 3.87% to 12.6%, and the inter-day precision was from 7.12% to 9.8%. The accuracy at low, medium and high concentrations ranged from 101.55% to 105.84%. Plasma protein bindings of largazole thiol in human and rat plasma as determined by an ultrafiltration method were 90.13% and 77.14%, respectively. Plasma drug concentrations were measured by this LC-MS/MS method. The pharmacokinetics of largazole thiol in rats was studied following i.v. administration at 10 mg/kg and found to follow a two-compartment model. Largazole thiol was rapidly eliminated from systemic circulation within 2 h. The established LC-MS/MS method is suitable for the analysis of largazole thiol in human plasma, as well.

Authors
Yu, M; Salvador, LA; Sy, SKB; Tang, Y; Singh, RSP; Chen, Q-Y; Liu, Y; Hong, J; Derendorf, H; Luesch, H
MLA Citation
Yu, M, Salvador, LA, Sy, SKB, Tang, Y, Singh, RSP, Chen, Q-Y, Liu, Y, Hong, J, Derendorf, H, and Luesch, H. "Largazole pharmacokinetics in rats by LC-MS/MS." Marine drugs 12.3 (March 20, 2014): 1623-1640.
PMID
24658499
Source
epmc
Published In
Marine drugs
Volume
12
Issue
3
Publish Date
2014
Start Page
1623
End Page
1640
DOI
10.3390/md12031623

Stereoselective synthesis of alpha,alpha '-trans-oxepanes through an organocatalytic oxa-conjugate addition reaction

Authors
Lanier, ML; Kasper, AC; Kim, H; Hong, J
MLA Citation
Lanier, ML, Kasper, AC, Kim, H, and Hong, J. "Stereoselective synthesis of alpha,alpha '-trans-oxepanes through an organocatalytic oxa-conjugate addition reaction." March 16, 2014.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
247
Publish Date
2014

Crystal Structure of MraY, an Essential Membrane Enzyme for Bacterial Cell Wall Synthesis

Authors
Chung, BC; Zhao, J; Gillespie, R; Kwon, DY; Guan, Z; Hong, J; Zhou, P; Lee, S-Y
MLA Citation
Chung, BC, Zhao, J, Gillespie, R, Kwon, DY, Guan, Z, Hong, J, Zhou, P, and Lee, S-Y. "Crystal Structure of MraY, an Essential Membrane Enzyme for Bacterial Cell Wall Synthesis." January 28, 2014.
Source
wos-lite
Published In
Biophysical Journal
Volume
106
Issue
2
Publish Date
2014
Start Page
14A
End Page
14A

False-positive rate determination of protein target discovery using a covalent modification- and mass spectrometry-based proteomics platform.

Detection and quantitation of protein-ligand binding interactions is important in many areas of biological research. Stability of proteins from rates of oxidation (SPROX) is an energetics-based technique for identifying the proteins targets of ligands in complex biological mixtures. Knowing the false-positive rate of protein target discovery in proteome-wide SPROX experiments is important for the correct interpretation of results. Reported here are the results of a control SPROX experiment in which chemical denaturation data is obtained on the proteins in two samples that originated from the same yeast lysate, as would be done in a typical SPROX experiment except that one sample would be spiked with the test ligand. False-positive rates of 1.2-2.2% and <0.8% are calculated for SPROX experiments using Q-TOF and Orbitrap mass spectrometer systems, respectively. Our results indicate that the false-positive rate is largely determined by random errors associated with the mass spectral analysis of the isobaric mass tag (e.g., iTRAQ®) reporter ions used for peptide quantitation. Our results also suggest that technical replicates can be used to effectively eliminate such false positives that result from this random error, as is demonstrated in a SPROX experiment to identify yeast protein targets of the drug, manassantin A. The impact of ion purity in the tandem mass spectral analyses and of background oxidation on the false-positive rate of protein target discovery using SPROX is also discussed.

Authors
Strickland, EC; Geer, MA; Hong, J; Fitzgerald, MC
MLA Citation
Strickland, EC, Geer, MA, Hong, J, and Fitzgerald, MC. "False-positive rate determination of protein target discovery using a covalent modification- and mass spectrometry-based proteomics platform." J Am Soc Mass Spectrom 25.1 (January 2014): 132-140.
PMID
24114261
Source
pubmed
Published In
Journal of The American Society for Mass Spectrometry
Volume
25
Issue
1
Publish Date
2014
Start Page
132
End Page
140
DOI
10.1007/s13361-013-0754-2

Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis.

MraY (phospho-MurNAc-pentapeptide translocase) is an integral membrane enzyme that catalyzes an essential step of bacterial cell wall biosynthesis: the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl phosphate. MraY has long been considered a promising target for the development of antibiotics, but the lack of a structure has hindered mechanistic understanding of this critical enzyme and the enzyme superfamily in general. The superfamily includes enzymes involved in bacterial lipopolysaccharide/teichoic acid formation and eukaryotic N-linked glycosylation, modifications that are central in many biological processes. We present the crystal structure of MraY from Aquifex aeolicus (MraYAA) at 3.3 Å resolution, which allows us to visualize the overall architecture, locate Mg(2+) within the active site, and provide a structural basis of catalysis for this class of enzyme.

Authors
Chung, BC; Zhao, J; Gillespie, RA; Kwon, D-Y; Guan, Z; Hong, J; Zhou, P; Lee, S-Y
MLA Citation
Chung, BC, Zhao, J, Gillespie, RA, Kwon, D-Y, Guan, Z, Hong, J, Zhou, P, and Lee, S-Y. "Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis." Science 341.6149 (August 30, 2013): 1012-1016.
PMID
23990562
Source
pubmed
Published In
Science
Volume
341
Issue
6149
Publish Date
2013
Start Page
1012
End Page
1016
DOI
10.1126/science.1236501

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms

Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-Type E-cadherin or E-cadherin fused to glutathione S-Transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin. © 2013 Macmillan Publishers Limited.

Authors
Law, ME; Corsino, PE; Jahn, SC; Davis, BJ; Chen, S; Patel, B; Pham, K; Lu, J; Sheppard, B; Nørgaard, P; Hong, J; Higgins, P; Kim, J-S; Luesch, H; Law, BK
MLA Citation
Law, ME, Corsino, PE, Jahn, SC, Davis, BJ, Chen, S, Patel, B, Pham, K, Lu, J, Sheppard, B, Nørgaard, P, Hong, J, Higgins, P, Kim, J-S, Luesch, H, and Law, BK. "Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms." Oncogene 32.10 (2013): 1316-1329.
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Volume
32
Issue
10
Publish Date
2013
Start Page
1316
End Page
1329
DOI
10.1038/onc.2012.138

Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis

MraY (phospho-MurNAc-pentapeptide translocase) is an integral membrane enzyme that catalyzes an essential step of bacterial cell wall biosynthesis: the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl phosphate. MraY has long been considered a promising target for the development of antibiotics, but the lack of a structure has hindered mechanistic understanding of this critical enzyme and the enzyme superfamily in general. The superfamily includes enzymes involved in bacterial lipopolysaccharide/teichoic acid formation and eukaryotic N-linked glycosylation, modifications that are central in many biological processes. We present the crystal structure of MraY from Aquifex aeolicus (MraYAA) at 3.3 Å resolution, which allows us to visualize the overall architecture, locate Mg2+ within the active site, and provide a structural basis of catalysis for this class of enzyme.

Authors
Chung, BC; Zhao, J; Gillespie, RA; Kwon, D-Y; Guan, Z; Hong, J; Zhou, P; Lee, S-Y
MLA Citation
Chung, BC, Zhao, J, Gillespie, RA, Kwon, D-Y, Guan, Z, Hong, J, Zhou, P, and Lee, S-Y. "Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis." Science 341.6149 (2013): 1012-1016.
Source
scival
Published In
Science
Volume
341
Issue
6149
Publish Date
2013
Start Page
1012
End Page
1016
DOI
10.1126/science.1240985

N-Heterocyclic carbene catalyzed oxidative macrolactonization: total synthesis of (+)-dactylolide.

Authors
Lee, K; Kim, H; Hong, J
MLA Citation
Lee, K, Kim, H, and Hong, J. "N-Heterocyclic carbene catalyzed oxidative macrolactonization: total synthesis of (+)-dactylolide." Angew Chem Int Ed Engl 51.23 (June 4, 2012): 5735-5738.
PMID
22539442
Source
pubmed
Published In
Angewandte Chemie International Edition
Volume
51
Issue
23
Publish Date
2012
Start Page
5735
End Page
5738
DOI
10.1002/anie.201201653

Largazole: from discovery to broad-spectrum therapy.

The cyclic depsipeptide largazole from a cyanobacterium of the genus Symploca is a marine natural product with a novel chemical scaffold and potently inhibits class I histone deacetylases (HDACs). Largazole possesses highly differential growth-inhibitory activity, preferentially targeting transformed over non-transformed cells. The intriguing structure and biological activity of largazole have attracted strong interest from the synthetic chemistry community to establish synthetic routes to largazole and to investigate its potential as a cancer therapeutic. This Highlight surveys recent advances in this area with a focus on the discovery, synthesis, target identification, structure-activity relationships, HDAC8-largazole thiol crystal structure, and biological studies, including in vivo anticancer and osteogenic activities.

Authors
Hong, J; Luesch, H
MLA Citation
Hong, J, and Luesch, H. "Largazole: from discovery to broad-spectrum therapy." Nat Prod Rep 29.4 (April 2012): 449-456. (Review)
PMID
22334030
Source
pubmed
Published In
Natural Product Reports
Volume
29
Issue
4
Publish Date
2012
Start Page
449
End Page
456
DOI
10.1039/c2np00066k

Stereoselective synthesis of tetrahydropyrans through tandem and organocatalytic oxa-Michael reactions: Synthesis of the tetrahydropyran cores of ent-(+)-sorangicin A

Tandem and organocatalytic oxa-Michael reactions of α,β- unsaturated aldehydes were explored for the stereoselective synthesis of structurally complex tetrahydropyrans. Thestereoselective synthesis of 2,6-trans-tetrahydropyrans, which are thermodynamically unfavorable, was accomplished through a reagent-controlled, organocatalytic oxa-Michael reaction. A temperature-dependent configurational switch allowed the preparation of both 2,3-trans-2,6-trans-and 2,3-cis-2,6-cis-tetrahydropyrans from a common substrate. This switch was then used to synthesize the precursors of the C21-C29 and C30-C37 fragments of ent-(+)-sorangicin A. The tandem and organocatalytic oxa-Michael reactions of α,β-unsaturated aldehydes were explored and applied to the stereoselective synthesis of structurally complex tetrahydropyrans. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Authors
Lee, K; Kim, H; Hong, J
MLA Citation
Lee, K, Kim, H, and Hong, J. "Stereoselective synthesis of tetrahydropyrans through tandem and organocatalytic oxa-Michael reactions: Synthesis of the tetrahydropyran cores of ent-(+)-sorangicin A." European Journal of Organic Chemistry 5 (2012): 1025-1032.
Source
scival
Published In
European Journal of Organic Chemistry
Issue
5
Publish Date
2012
Start Page
1025
End Page
1032
DOI
10.1002/ejoc.201101549

Immunosuppressive Effects of Subglutinol Derivatives

Authors
Lee, W-G; Kim, W-S; Park, S-G; Kim, H; Hong, J; Ko, H; Kim, Y-C
MLA Citation
Lee, W-G, Kim, W-S, Park, S-G, Kim, H, Hong, J, Ko, H, and Kim, Y-C. "Immunosuppressive Effects of Subglutinol Derivatives." ChemMedChem 7.2 (2012): 218-222.
PMID
22114006
Source
scival
Published In
Chemmedchem
Volume
7
Issue
2
Publish Date
2012
Start Page
218
End Page
222
DOI
10.1002/cmdc.201100409

Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms

Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti-invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with γ-catenin. This effect on E-cadherin/γ-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin.Oncogene advance online publication, 30 April 2012; doi:10.1038/onc.2012.138.

Authors
Law, ME; Corsino, PE; Jahn, SC; Davis, BJ; Chen, S; Patel, B; Pham, K; Lu, J; Sheppard, B; Nørgaard, P; al, E
MLA Citation
Law, ME, Corsino, PE, Jahn, SC, Davis, BJ, Chen, S, Patel, B, Pham, K, Lu, J, Sheppard, B, Nørgaard, P, and al, E. "Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms." Oncogene (2012).
PMID
22543582
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Publish Date
2012
DOI
10.1038/onc.2012.138

Manipulating JNK signaling with (-)-zuonin A

Recently, in a virtual screening strategy to identify new compounds targeting the D-recruitment site (DRS) of the c-Jun N-terminal kinases (JNKs), we identified the natural product (-)-zuonin A. Here we report the asymmetric synthesis of (-)-zuonin A and its enantiomer (+)-zuonin A. A kinetic analysis for the inhibition of c-Jun phosphorylation by (-)-zuonin A revealed a mechanism of partial competitive inhibition. Its binding is proposed to weaken the interaction of c-Jun to JNK by approximately 5-fold, without affecting the efficiency of phosphorylation within the complex. (-)-Zuonin A inhibits the ability of both MKK4 and MKK7 to phosphorylate and activate JNK. The binding site of (-)-zuonin A is predicted by docking and molecular dynamics simulation to be located in the DRS of JNK. (+)-Zuonin A also binds JNK but barely impedes the binding of c-Jun. (-)-Zuonin A inhibits the activation of JNK, as well as the phosphorylation of c-Jun in anisomycin-treated HEK293 cells, with the inhibition of JNK activation being more pronounced. (-)-Zuonin A also inhibits events associated with constitutive JNK2 activity, including c-Jun phosphorylation, basal Akt activation, and MDA-MB-231 cell migration. Mutations in the predicted binding site for (-)-zuonin A can render it significantly more or less sensitive to inhibition than wild type JNK2, allowing for the design of potential chemical genetic experiments. These studies suggest that the biological activity reported for other lignans, such as saucerneol F and zuonin B, may be the result of their ability to impede protein-protein interactions within MAPK cascades. © 2012 American Chemical Society.

Authors
Kaoud, TS; Park, H; Mitra, S; Yan, C; Tseng, C-C; Shi, Y; Jose, J; Taliaferro, JM; Lee, K; Ren, P; Hong, J; Dalby, KN
MLA Citation
Kaoud, TS, Park, H, Mitra, S, Yan, C, Tseng, C-C, Shi, Y, Jose, J, Taliaferro, JM, Lee, K, Ren, P, Hong, J, and Dalby, KN. "Manipulating JNK signaling with (-)-zuonin A." ACS Chemical Biology 7.11 (2012): 1873-1883.
PMID
22916726
Source
scival
Published In
ACS Chemical Biology
Volume
7
Issue
11
Publish Date
2012
Start Page
1873
End Page
1883
DOI
10.1021/cb300261e

From in silico discovery to intracellular activity: Targeting JNK-protein interactions with small molecules

The JNK-JIP1 interaction represents an attractive target for the selective inhibition of JNK-mediated signaling. We report a virtual screening (VS) workflow, based on a combination of three-dimensional shape and electrostatic similarity, to discover novel scaffolds for the development of non-ATP competitive inhibitors of JNK targeting the JNK-JIP interaction. Of 352 (0.13%) compounds selected from the NCI Diversity Set, more than 22% registered as hits in a biochemical kinase assay. Several compounds discovered to inhibit JNK activity under standard kinase assay conditions also impeded JNK activity in HEK293 cells. These studies led to the discovery that the lignan (-)-zuonin A inhibits JNK-protein interactions with a selectivity of 100-fold over ERK2 and p38 MAPKα. These results demonstrate the utility of a virtual screening protocol to identify novel scaffolds for highly selective, cell-permeable inhibitors of JNK-protein interactions. © 2012 American Chemical Society.

Authors
Kaoud, TS; Yan, C; Mitra, S; Tseng, C-C; Jose, J; Taliaferro, JM; Tuohetahuntila, M; Devkota, A; Sammons, R; Park, J; Park, H; Shi, Y; Hong, J; Ren, P; Dalby, KN
MLA Citation
Kaoud, TS, Yan, C, Mitra, S, Tseng, C-C, Jose, J, Taliaferro, JM, Tuohetahuntila, M, Devkota, A, Sammons, R, Park, J, Park, H, Shi, Y, Hong, J, Ren, P, and Dalby, KN. "From in silico discovery to intracellular activity: Targeting JNK-protein interactions with small molecules." ACS Medicinal Chemistry Letters 3.9 (2012): 721-725.
PMID
23002419
Source
scival
Published In
ACS Medicinal Chemistry Letters
Volume
3
Issue
9
Publish Date
2012
Start Page
721
End Page
725
DOI
10.1021/ml300129b

Preface

Authors
Toone, EJ
MLA Citation
Toone, EJ. Preface. December 1, 2011.
Source
scopus
Volume
78 1
Publish Date
2011

Stereoselective synthesis of 2,6-trans-tetrahydropyran via primary diamine-catalyzed oxa-conjugate addition reaction of α,β-unsaturated ketone: total synthesis of psymberin.

The total synthesis of psymberin was achieved employing a readily available chiral epoxide to prepare two of the three subunits in the natural product. The key reaction was a highly stereoselective organocatalytic oxa-conjugate addition reaction of α,β-unsaturated ketone catalyzed by primary diamine for the synthesis of the 2,6-trans-tetrahydropyran embedded in psymberin.

Authors
Byeon, SR; Park, H; Kim, H; Hong, J
MLA Citation
Byeon, SR, Park, H, Kim, H, and Hong, J. "Stereoselective synthesis of 2,6-trans-tetrahydropyran via primary diamine-catalyzed oxa-conjugate addition reaction of α,β-unsaturated ketone: total synthesis of psymberin." Org Lett 13.21 (November 4, 2011): 5816-5819.
PMID
21988493
Source
pubmed
Published In
Organic Letters
Volume
13
Issue
21
Publish Date
2011
Start Page
5816
End Page
5819
DOI
10.1021/ol2024289

Stereoselective formal synthesis of leucascandrolide A

Authors
Lee, K; Kim, H; Hong, J
MLA Citation
Lee, K, Kim, H, and Hong, J. "Stereoselective formal synthesis of leucascandrolide A." August 28, 2011.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
242
Publish Date
2011

A formal synthesis of SCH 351448.

An efficient formal synthesis of SCH 351448 was accomplished through the tandem cross-metathesis (CM)/oxa-Michael, the 1,4-syn aldol, the tandem oxidation/oxa-Michael, and the Suzuki coupling reaction.

Authors
Park, H; Kim, H; Hong, J
MLA Citation
Park, H, Kim, H, and Hong, J. "A formal synthesis of SCH 351448." Org Lett 13.14 (July 15, 2011): 3742-3745.
PMID
21692467
Source
pubmed
Published In
Organic Letters
Volume
13
Issue
14
Publish Date
2011
Start Page
3742
End Page
3745
DOI
10.1021/ol201426c

A Formal Synthesis of SCH 351448

Authors
Park, H; Kim, H; Hong, J
MLA Citation
Park, H, Kim, H, and Hong, J. "A Formal Synthesis of SCH 351448." ORGANIC LETTERS 13.14 (July 15, 2011): 3742-3745.
Source
wos-lite
Published In
Organic Letters
Volume
13
Issue
14
Publish Date
2011
Start Page
3742
End Page
3745
DOI
10.1021/ol201426c

Role of natural product diversity in chemical biology.

Through the natural selection process, natural products possess a unique and vast chemical diversity and have been evolved for optimal interactions with biological macromolecules. Owing to their diversity, target affinity, and specificity, natural products have demonstrated enormous potential as modulators of biomolecular function, been an essential source for drug discovery, and provided design principles for combinatorial library development.

Authors
Hong, J
MLA Citation
Hong, J. "Role of natural product diversity in chemical biology." Curr Opin Chem Biol 15.3 (June 2011): 350-354. (Review)
PMID
21489856
Source
pubmed
Published In
Current Opinion in Chemical Biology
Volume
15
Issue
3
Publish Date
2011
Start Page
350
End Page
354
DOI
10.1016/j.cbpa.2011.03.004

A stereoselective formal synthesis of leucascandrolide A.

A stereoselective formal synthesis of leucascandrolide A was accomplished through the tandem and organocatalytic oxa-Michael reactions, which were promoted by the gem-disubstituent effect, in conjunction with the dithiane coupling reaction.

Authors
Lee, K; Kim, H; Hong, J
MLA Citation
Lee, K, Kim, H, and Hong, J. "A stereoselective formal synthesis of leucascandrolide A." Org Lett 13.10 (May 20, 2011): 2722-2725.
PMID
21528873
Source
pubmed
Published In
Organic Letters
Volume
13
Issue
10
Publish Date
2011
Start Page
2722
End Page
2725
DOI
10.1021/ol200824r

Characterization of Fe(III) sequestration by an analog of the cytotoxic siderophore brasilibactin A: implications for the iron transport mechanism in mycobacteria.

Mycobacteria such as M. tuberculosis represent a significant health concern throughout much of the developing world. In mycobacteria and other pathogenic bacteria, an important virulence factor is the ability of the bacterium to obtain iron from its host. One means of obtaining iron is through the use of siderophores. Brasilibactin A is a membrane bound siderophore produced by Nocardia brasiliensis with structural similarity to the mycobactin class of siderophore in mycobacteria. A characterization of the protonation constants and Fe(III) affinity of a water soluble Brasilibactin A analog (Bbtan) has been performed. Using protonation constants and competition with EDTA, the stability constant of the 1 : 1 Fe(III)-Bbtan complex was found to be log β(110) = 26.96. The pFe of Bbtan is 22.73, somewhat low for a proposed siderophore molecule. The redox potential of the Fe-Bbtan complex was found to be -300 mV vs. NHE, very high for an iron-siderophore complex. The combination of relatively low complex stability and ease of iron reduction may play a crucial role in the mechanism of mycobactin siderophore-mediated iron uptake in mycobacteria and related organisms.

Authors
Harrington, JM; Park, H; Ying, Y; Hong, J; Crumbliss, AL
MLA Citation
Harrington, JM, Park, H, Ying, Y, Hong, J, and Crumbliss, AL. "Characterization of Fe(III) sequestration by an analog of the cytotoxic siderophore brasilibactin A: implications for the iron transport mechanism in mycobacteria." Metallomics 3.5 (May 1, 2011): 464-471.
PMID
21442123
Source
pubmed
Published In
Metallomics
Volume
3
Issue
5
Publish Date
2011
Start Page
464
End Page
471
DOI
10.1039/c0mt00109k

Stereoselective synthesis of 2,6-cis- and 2,6-trans-piperidines through organocatalytic aza-Michael reactions: a facile synthesis of (+)-myrtine and (-)-epimyrtine.

Both 2,6-cis- and 2,6-trans-piperidines were prepared from common substrates through organocatalytic aza-Michael reactions promoted by the gem-disubstituent effect in conjunction with dithiane coupling reactions. The organocatalytic aza-Michael reaction enabled a facile synthesis of (+)-myrtine and (-)-epimyrtine from a common substrate.

Authors
Ying, Y; Kim, H; Hong, J
MLA Citation
Ying, Y, Kim, H, and Hong, J. "Stereoselective synthesis of 2,6-cis- and 2,6-trans-piperidines through organocatalytic aza-Michael reactions: a facile synthesis of (+)-myrtine and (-)-epimyrtine." Org Lett 13.4 (February 18, 2011): 796-799.
PMID
21250755
Source
pubmed
Published In
Organic Letters
Volume
13
Issue
4
Publish Date
2011
Start Page
796
End Page
799
DOI
10.1021/ol103064f

Intramolecular Michael reactions of aliphatic aldehyde enolates generated by imidazolium carbenes

Due to the high reactivity of the formyl group under either basic or acidic reaction conditions required for the direct generation of aldehyde enolates, intramolecular Michael additions of aldehyde enolates to α,β- unsaturated carbonyl compounds have been underexplored for the stereoselective synthesis of carbocyclic compounds. The intramolecular Michael reaction of aldehyde enolates generated by imidazolium carbenes was explored for the synthesis of cyclopentane aldehydes. The imidazolium carbenes were used as Brønsted bases to directly generate the aldehydes enolates. © 2011 Elsevier Ltd. All rights reserved.

Authors
Kim, H; Byeon, SR; Leed, MGD; Hong, J
MLA Citation
Kim, H, Byeon, SR, Leed, MGD, and Hong, J. "Intramolecular Michael reactions of aliphatic aldehyde enolates generated by imidazolium carbenes." Tetrahedron Letters 52.19 (2011): 2468-2470.
Source
scival
Published In
Tetrahedron Letters
Volume
52
Issue
19
Publish Date
2011
Start Page
2468
End Page
2470
DOI
10.1016/j.tetlet.2011.03.008

In vitro and in vivo osteogenic activity of largazole

Due to their capability of modifying chromatin structure and thereby regulating gene transcription, histone deacetylases (HDACs) have been reported to play important roles in osteogenesis and considered a promising potential therapeutic target for bone diseases, including osteoporosis. We showed that the novel marine-derived HDAC inhibitor largazole exhibits in vitro and in vivo osteogenic activity. Largazole significantly induced the expression of ALP and OPN. The osteogenic activity of largazole was mediated through the increased expression of Runx2 and BMPs. Importantly, largazole showed in vivo bone-forming efficacy in the mouse calvarial bone formation assay and the rabbit calvarial bone fracture healing model. The dual action of largazole to stimulate bone formation and inhibit bone resorption would be a useful feature in drug development for bone-related disorders. © 2011 American Chemical Society.

Authors
Lee, S-U; Kwak, HB; Pi, S-H; You, H-K; Byeon, SR; Ying, Y; Luesch, H; Hong, J; Kim, SH
MLA Citation
Lee, S-U, Kwak, HB, Pi, S-H, You, H-K, Byeon, SR, Ying, Y, Luesch, H, Hong, J, and Kim, SH. "In vitro and in vivo osteogenic activity of largazole." ACS Medicinal Chemistry Letters 2.3 (2011): 248-251.
PMID
21666868
Source
scival
Published In
ACS Medicinal Chemistry Letters
Volume
2
Issue
3
Publish Date
2011
Start Page
248
End Page
251
DOI
10.1021/ml1002794

Total synthesis, assignment of the absolute stereochemistry, and structure-activity relationship studies of subglutinols A and B.

Immunosuppressive drugs are used to prevent rejection of transplanted organs and treat autoimmune diseases. Clinically approved immunosuppressive drugs possess undesirable side effects, including acute neurological toxicity, chronic nephrotoxicity, and osteoporosis. As a result, considerable efforts have been devoted to the identification of immunosuppressive natural products that lack cytotoxicity and undesirable side effects on bone structure. Subglutinols A (1 a) and B (1 b) are diterpene pyrones isolated from Fusarium subglutinans. Compounds 1 a and 1 b are equipotent in the mixed lymphocyte reaction assay and thymocyte proliferation assay (IC(50) = 0.1 microM). Owing to the lack of toxicity, 1 a and 1 b are expected to be promising new immunosuppressive drugs. Herein, we detail our efforts that have culminated in a stereoselective synthesis of 1 a and 1 b from the (S)-(+)-5-methyl-Wieland-Miescher ketone and determined their absolute stereochemistries. We also present initial biological data to show the great potential of 1 a as an immunosuppressive drug with dose-dependent osteogenic activity.

Authors
Kim, H; Baker, JB; Park, Y; Park, H-B; DeArmond, PD; Kim, SH; Fitzgerald, MC; Lee, D-S; Hong, J
MLA Citation
Kim, H, Baker, JB, Park, Y, Park, H-B, DeArmond, PD, Kim, SH, Fitzgerald, MC, Lee, D-S, and Hong, J. "Total synthesis, assignment of the absolute stereochemistry, and structure-activity relationship studies of subglutinols A and B." Chem Asian J 5.8 (August 2, 2010): 1902-1910.
PMID
20564278
Source
pubmed
Published In
Chemistry - An Asian Journal
Volume
5
Issue
8
Publish Date
2010
Start Page
1902
End Page
1910
DOI
10.1002/asia.201000147

Total synthesis of cyanolide A and confirmation of its absolute configuration.

The tandem allylic oxidation/oxa-Michael reaction promoted by the gem-disubstituent effect and the 2-methyl-6-nitrobenzoic anhydride (MNBA)-mediated dimerization were explored for the efficient and facile synthesis of cyanolide A.

Authors
Kim, H; Hong, J
MLA Citation
Kim, H, and Hong, J. "Total synthesis of cyanolide A and confirmation of its absolute configuration." Org Lett 12.12 (June 18, 2010): 2880-2883.
Website
http://hdl.handle.net/10161/4106
PMID
20491466
Source
pubmed
Published In
Organic Letters
Volume
12
Issue
12
Publish Date
2010
Start Page
2880
End Page
2883
DOI
10.1021/ol101022z

Efficient and stereoselective synthesis of 2,6-disubstituted piperidines through an organocatalytic aza-Michael reaction promoted by the gem-disubstituent effect

Authors
Ying, Y; Kim, H; Hong, J
MLA Citation
Ying, Y, Kim, H, and Hong, J. "Efficient and stereoselective synthesis of 2,6-disubstituted piperidines through an organocatalytic aza-Michael reaction promoted by the gem-disubstituent effect." March 21, 2010.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
239
Publish Date
2010

Anticolon cancer activity of largazole, a marine-derived tunable histone deacetylase inhibitor

Histone deacetylases (HDACs) are validated targets for anti-cancer therapy as attested by the approval of suberoylanilide hydroxamic acid (SAHA) and romidepsin (FK228) for treating cutaneous T cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases a potent HDAC inhibitor, largazole thiol. Here, we characterize the anticancer activity of largazole by using in vitro and in vivo cancer models. Screening against the National Cancer Institute's 60 cell lines revealed that largazole is particularly active against several colon cancer cell types. Consequently, we tested largazole, along with several synthetic analogs, for HDAC inhibition in human HCT116 colon cancer cells. Enzyme inhibition strongly correlated with the growth inhibitory effects, and differential activity of largazole analogs was rationalized by molecular docking to an HDAC1 homology model. Comparative genomewide transcript profiling revealed a close overlap of genes that are regulated by largazole, FK228, and SAHA. Several of these genes can be related to largazole's ability to induce cell cycle arrest and apoptosis. Stability studies suggested reasonable bioavailability of the active species, largazole thiol. We established that largazole inhibits HDACs in tumor tissue in vivo by using a human HCT116 xenograft mouse model. Largazole strongly stimulated histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth, and induced apoptosis in the tumor. This effect probably is mediated by the modulation of levels of cell cycle regulators, antagonism of the AKT pathway through insulin receptor substrate 1 down-regulation, and reduction of epidermal growth factor receptor levels. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

Authors
Liu, Y; Salvador, LA; Byeon, S; Ying, Y; Kwan, JC; Law, BK; Hong, J; Luesch, H
MLA Citation
Liu, Y, Salvador, LA, Byeon, S, Ying, Y, Kwan, JC, Law, BK, Hong, J, and Luesch, H. "Anticolon cancer activity of largazole, a marine-derived tunable histone deacetylase inhibitor." Journal of Pharmacology and Experimental Therapeutics 335.2 (2010): 351-361.
PMID
20739454
Source
scival
Published In
The Journal of pharmacology and experimental therapeutics
Volume
335
Issue
2
Publish Date
2010
Start Page
351
End Page
361
DOI
10.1124/jpet.110.172387

A facile and efficient synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans via tandem cross-metathesis/thermal S(N)2' reaction: protecting-group-free synthesis of (+/-)-diospongin A.

The tandem cross-metathesis/thermal S(N)2' reaction was explored for the facile and efficient synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans. The mildness of the thermal conditions allowed for the synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans from base-sensitive substrates without the use of protecting groups. The tandem reaction enabled a protecting-group-free synthesis of (+/-)-diospongin A.

Authors
Lee, K; Kim, H; Hong, J
MLA Citation
Lee, K, Kim, H, and Hong, J. "A facile and efficient synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans via tandem cross-metathesis/thermal S(N)2' reaction: protecting-group-free synthesis of (+/-)-diospongin A." Org Lett 11.22 (November 19, 2009): 5202-5205.
PMID
19824665
Source
pubmed
Published In
Organic Letters
Volume
11
Issue
22
Publish Date
2009
Start Page
5202
End Page
5205
DOI
10.1021/ol902125d

Identification of 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones as isoform-selective PKC-zeta inhibitors and potential therapeutics for psychostimulant abuse.

From a screen of small molecule libraries to identify potential therapeutics for psychostimulant abuse, 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones were shown to be isoform-selective PKC-zeta inhibitors.

Authors
Yuan, L; Seo, J-S; Kang, NS; Keinan, S; Steele, SE; Michelotti, GA; Wetsel, WC; Beratan, DN; Gong, Y-D; Lee, TH; Hong, J
MLA Citation
Yuan, L, Seo, J-S, Kang, NS, Keinan, S, Steele, SE, Michelotti, GA, Wetsel, WC, Beratan, DN, Gong, Y-D, Lee, TH, and Hong, J. "Identification of 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones as isoform-selective PKC-zeta inhibitors and potential therapeutics for psychostimulant abuse." Mol Biosyst 5.9 (September 2009): 927-930.
PMID
19668856
Source
pubmed
Published In
Molecular BioSystems
Volume
5
Issue
9
Publish Date
2009
Start Page
927
End Page
930
DOI
10.1039/b903036k

Thermodynamic characterization of iron(III) and zinc binding by Brasilibactin A

Authors
Harrington, JM; Park, H; Ying, Y; Hong, J; Crumbliss, AL
MLA Citation
Harrington, JM, Park, H, Ying, Y, Hong, J, and Crumbliss, AL. "Thermodynamic characterization of iron(III) and zinc binding by Brasilibactin A." August 16, 2009.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
238
Publish Date
2009

Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations.

We have shown that manassantin A downregulated the HIF-1alpha expression and inhibited the secretion of VEGF. We have also demonstrated that the 2,3-cis-3,4-trans-4,5-cis-configuration of the tetrahydrofuran is critical to the HIF-1 inhibition of manassantin A.

Authors
Kasper, AC; Moon, EJ; Hu, X; Park, Y; Wooten, CM; Kim, H; Yang, W; Dewhirst, MW; Hong, J
MLA Citation
Kasper, AC, Moon, EJ, Hu, X, Park, Y, Wooten, CM, Kim, H, Yang, W, Dewhirst, MW, and Hong, J. "Analysis of HIF-1 inhibition by manassantin A and analogues with modified tetrahydrofuran configurations." Bioorg Med Chem Lett 19.14 (July 15, 2009): 3783-3786.
PMID
19423348
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
19
Issue
14
Publish Date
2009
Start Page
3783
End Page
3786
DOI
10.1016/j.bmcl.2009.04.071

The end game of chemical genetics: target identification.

The use of classical genetic and molecular biology methods along with the sequencing of many genomes has proven crucial for elucidating complex biological processes. Despite being invaluable tools, their limitations have led to a search for more versatile alternatives and, thus, to the use of small molecules. Chemical genetics is a rapidly emerging field that uses small-molecule techniques to probe biological systems and is composed of three parts: natural product or small-molecule libraries, phenotypic screening and target identification. Currently, the biggest hurdle in the overall process of chemical genetics is target identification. Efforts to overcome this obstacle have led to advances in the areas of affinity chromatography, yeast haploinsufficiency, complementary DNA (cDNA) overexpression, DNA microarray, small-molecule microarray and RNA interference (RNAi) technologies. While these technologies continue to undergo further optimization, they have been integral in the identification and/or confirmation of many cellular targets and have seen an increase in applications to the drug-development process.

Authors
Kasper, AC; Baker, JB; Kim, H; Hong, J
MLA Citation
Kasper, AC, Baker, JB, Kim, H, and Hong, J. "The end game of chemical genetics: target identification." Future Med Chem 1.4 (July 2009): 727-736. (Review)
PMID
21426035
Source
pubmed
Published In
Future medicinal chemistry
Volume
1
Issue
4
Publish Date
2009
Start Page
727
End Page
736
DOI
10.4155/fmc.09.52

Stereoselective synthesis and osteogenic activity of subglutinols A and B.

Since clinically approved immunosuppressive drugs (e.g., cyclosporin A, FK506) possess dose-dependent biphasic effects that cause undesirable side effects on bone structure, including osteopenia, osteoporosis, and increased incidence of bone fractures, considerable effort has been devoted to the identification of immunosuppressive drugs that promote bone formation in a dose-dependent manner. Herein, we report the stereoselective synthesis of subglutinols A and B and present initial biological data showing the significant potential of subglutinol A as an immunosuppressive drug with dose-dependent osteogenic activity. We also show that activating protein 1 (AP-1) family transcription factors could be one of the key regulators for the anabolic activity of subglutinol A. Such drugs with dose-dependent osteogenic activity might help reduce bone-associated side effects and be clinically useful for bone tissue transplantation.

Authors
Kim, H; Baker, JB; Lee, S-U; Park, Y; Bolduc, KL; Park, H-B; Dickens, MG; Lee, D-S; Kim, Y; Kim, SH; Hong, J
MLA Citation
Kim, H, Baker, JB, Lee, S-U, Park, Y, Bolduc, KL, Park, H-B, Dickens, MG, Lee, D-S, Kim, Y, Kim, SH, and Hong, J. "Stereoselective synthesis and osteogenic activity of subglutinols A and B." J Am Chem Soc 131.9 (March 11, 2009): 3192-3194.
PMID
19216570
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
131
Issue
9
Publish Date
2009
Start Page
3192
End Page
3194
DOI
10.1021/ja8101192

Nucleophilic addition of organozinc reagents to 2-sulfonyl cyclic ethers: stereoselective synthesis of manassantins A and B.

A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural products. Preliminary structure-activity relationships suggested that the (R)-configuration at C-7 and C-7''' is not critical for HIF-1 inhibition. In addition, the hydroxyl group at C-7 and C-7''' can be replaced with a carbonyl group without loss of activity.

Authors
Kim, H; Kasper, AC; Moon, EJ; Park, Y; Wooten, CM; Dewhirst, MW; Hong, J
MLA Citation
Kim, H, Kasper, AC, Moon, EJ, Park, Y, Wooten, CM, Dewhirst, MW, and Hong, J. "Nucleophilic addition of organozinc reagents to 2-sulfonyl cyclic ethers: stereoselective synthesis of manassantins A and B." Org Lett 11.1 (January 1, 2009): 89-92.
PMID
19111058
Source
pubmed
Published In
Organic Letters
Volume
11
Issue
1
Publish Date
2009
Start Page
89
End Page
92
DOI
10.1021/ol8024617

A small molecule inhibitor of α4 integrin-dependent cell migration

A small molecule inhibitor of α4 integrin-dependent cell migration was identified through a cell-based screen of small molecule libraries. Biochemical and cellular experiments suggest that this molecule functions by interacting with γ-parvin. This molecule should serve as a useful tool to study α4 integrin signaling and may lead to new therapeutics for the treatment of autoimmune diseases. © 2008 Elsevier Ltd. All rights reserved.

Authors
Lee, J; Hong, J; Nam, T-G; Peters, EC; Orth, AP; Geierstanger, BH; Goldfinger, LE; Ginsberg, MH; Cho, CY; Schultz, PG
MLA Citation
Lee, J, Hong, J, Nam, T-G, Peters, EC, Orth, AP, Geierstanger, BH, Goldfinger, LE, Ginsberg, MH, Cho, CY, and Schultz, PG. "A small molecule inhibitor of α4 integrin-dependent cell migration." Bioorganic and Medicinal Chemistry 17.3 (2009): 977-980.
PMID
18329275
Source
scival
Published In
Bioorganic & Medicinal Chemistry
Volume
17
Issue
3
Publish Date
2009
Start Page
977
End Page
980
DOI
10.1016/j.bmc.2008.02.067

Stereoselective synthesis of 2,6-cis-tetrahydropyrans through a tandem allylic oxidation/oxa-Michael reaction promoted by the gem-disubstituent effect: synthesis of (+)-neopeltolide macrolactone.

Authors
Kim, H; Park, Y; Hong, J
MLA Citation
Kim, H, Park, Y, and Hong, J. "Stereoselective synthesis of 2,6-cis-tetrahydropyrans through a tandem allylic oxidation/oxa-Michael reaction promoted by the gem-disubstituent effect: synthesis of (+)-neopeltolide macrolactone." Angew Chem Int Ed Engl 48.41 (2009): 7577-7581.
PMID
19739173
Source
pubmed
Published In
Angewandte Chemie International Edition
Volume
48
Issue
41
Publish Date
2009
Start Page
7577
End Page
7581
DOI
10.1002/anie.200903690

Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B (Org. Lett., (2009) 11:7 (1671-1671)

Authors
Kim, H; Kasper, AC; Moon, EJ; Park, Y; Wooten, CM; Dewhirst, MW; Hong, J
MLA Citation
Kim, H, Kasper, AC, Moon, EJ, Park, Y, Wooten, CM, Dewhirst, MW, and Hong, J. "Nucleophilic Addition of Organozinc Reagents to 2-Sulfonyl Cyclic Ethers: Stereoselective Synthesis of Manassantins A and B (Org. Lett., (2009) 11:7 (1671-1671)." Organic Letters 11.7 (2009): 1671--.
Source
scival
Published In
Organic Letters
Volume
11
Issue
7
Publish Date
2009
Start Page
1671-
DOI
10.1021/ol900421x

Synthesis and activity of largazole analogues with linker and macrocycle modification.

To characterize largazole's structural requirements for histone deacetylase (HDAC) inhibitory and antiproliferative activities, a series of analogues with modifications to the side chain or 16-membered macrocycle were prepared and biologically evaluated. Structure-activity relationships suggested that the four-atom linker between the macrocycle and octanoyl group in the side chain and the (S)-configuration at the C17 position are critical to repression of HDAC activity. However, the valine residue in the macrocycle can be replaced with alanine without significant loss of activity.

Authors
Ying, Y; Liu, Y; Byeon, SR; Kim, H; Luesch, H; Hong, J
MLA Citation
Ying, Y, Liu, Y, Byeon, SR, Kim, H, Luesch, H, and Hong, J. "Synthesis and activity of largazole analogues with linker and macrocycle modification." Org Lett 10.18 (September 18, 2008): 4021-4024.
PMID
18707106
Source
pubmed
Published In
Organic Letters
Volume
10
Issue
18
Publish Date
2008
Start Page
4021
End Page
4024
DOI
10.1021/ol801532s

ORGN 523-Total synthesis of largazole

Authors
Ying, Y; Kim, H; Taori, K; Luesch, H; Hong, J
MLA Citation
Ying, Y, Kim, H, Taori, K, Luesch, H, and Hong, J. "ORGN 523-Total synthesis of largazole." August 17, 2008.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
236
Publish Date
2008

Total synthesis and molecular target of largazole, a histone deacetylase inhibitor.

Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the preparation of a series of key analogues, and the molecular target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biological evaluation of largazole and its key analogues, including an acetyl analogue, a thiol analogue, and a hydroxyl analogue, suggested that histone deacetylases (HDACs) are molecular targets of largazole and largazole is a class I HDAC inhibitor. In addition, structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.

Authors
Ying, Y; Taori, K; Kim, H; Hong, J; Luesch, H
MLA Citation
Ying, Y, Taori, K, Kim, H, Hong, J, and Luesch, H. "Total synthesis and molecular target of largazole, a histone deacetylase inhibitor." J Am Chem Soc 130.26 (July 2, 2008): 8455-8459.
PMID
18507379
Source
pubmed
Published In
Journal of the American Chemical Society
Volume
130
Issue
26
Publish Date
2008
Start Page
8455
End Page
8459
DOI
10.1021/ja8013727

A general strategy for construction of both 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans: Substrate-controlled asymmetric total synthesis of (+)-scanlonenyne

(Chemical Equation Presented) A synthetic three-ring circus: The asymmetric total synthesis of (+)-scanlonenyne includes a sequential epimerization and intramolecular hetero-Michael addition for the construction of pyrano-γ-lactones (see scheme; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene), a highly efficient one-carbon homologation/bromination strategy, and a Weinreb ketone synthesis/cross-metathesis protocol for the elaboration of a sensitive side chain. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

Authors
Lee, H; Kim, KW; Park, J; Kim, H; Kim, S; Kim, D; Hu, X; Yang, W; Hong, J
MLA Citation
Lee, H, Kim, KW, Park, J, Kim, H, Kim, S, Kim, D, Hu, X, Yang, W, and Hong, J. "A general strategy for construction of both 2,6-cis- and 2,6-trans-disubstituted tetrahydropyrans: Substrate-controlled asymmetric total synthesis of (+)-scanlonenyne." Angewandte Chemie - International Edition 47.22 (2008): 4200-4203.
PMID
18435525
Source
scival
Published In
Angewandte Chemie International Edition
Volume
47
Issue
22
Publish Date
2008
Start Page
4200
End Page
4203
DOI
10.1002/anie.200705663

Stereoselective synthesis of tetrahydrofuran lignans via BF(3) x OEt(2)-promoted reductive deoxygenation/epimerization of cyclic hemiketal: synthesis of (-)-odoratisol C, (-)-futokadsurin A, (-)-veraguensin, (+)-fragransin A(2), (+)-galbelgin, and (+)-talaumidin.

A versatile route to the synthesis of 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans, (-)-odoratisol C (1), (-)-futokadsurin A (2), (-)-veraguensin (3), (+)-fragransin A2 (4), (+)-galbelgin (5), and (+)-talaumidin (6), is described. Central to the synthesis of the lignans is BF(3) x OEt(2)-promoted deoxygenation/epimerization of the hemiketal 9a followed by stereoselective reduction of the oxocarbenium ion intermediates 8a,b.

Authors
Kim, H; Wooten, CM; Park, Y; Hong, J
MLA Citation
Kim, H, Wooten, CM, Park, Y, and Hong, J. "Stereoselective synthesis of tetrahydrofuran lignans via BF(3) x OEt(2)-promoted reductive deoxygenation/epimerization of cyclic hemiketal: synthesis of (-)-odoratisol C, (-)-futokadsurin A, (-)-veraguensin, (+)-fragransin A(2), (+)-galbelgin, and (+)-talaumidin." Org Lett 9.20 (September 27, 2007): 3965-3968.
PMID
17764190
Source
pubmed
Published In
Organic Letters
Volume
9
Issue
20
Publish Date
2007
Start Page
3965
End Page
3968
DOI
10.1021/ol7016388

A small-molecule antagonist of the Hedgehog signaling pathway

(Chemical Equation Presented) Shadow the Hedgehog. JK184 (illustrated in the scheme) was identified as an antagonist of Hedgehog signaling through a cell-based screen of chemical libraries. Results from biochemical and cellular experiments suggest that JK184 functions by inhibiting class IV alcohol dehydrogenase. This molecule should serve as a useful tool for studying Hedgehog signaling. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

Authors
Lee, J; Wu, X; Magliano, MPD; Peters, EC; Wang, Y; Hong, J; Hebrok, M; Ding, S; Cho, CY; Schultz, PG
MLA Citation
Lee, J, Wu, X, Magliano, MPD, Peters, EC, Wang, Y, Hong, J, Hebrok, M, Ding, S, Cho, CY, and Schultz, PG. "A small-molecule antagonist of the Hedgehog signaling pathway." ChemBioChem 8.16 (2007): 1916-1919.
PMID
17886323
Source
scival
Published In
Chembiochem
Volume
8
Issue
16
Publish Date
2007
Start Page
1916
End Page
1919
DOI
10.1002/cbic.200700403

Identification and characterization of small-molecule inducers of epidermal keratinocyte differentiation

An essential function of the human epidermis is the maintenance of a protective barrier against the environment. As a consequence, keratinocytes, which make up this layer of the skin, undergo an elaborate process of self-renewal, terminal differentiation, and cell death. Misregulation of these processes can lead to several human diseases, including psoriasis and basal cell and squamous cell carcinomas. To identify novel regulators of keratinocyte differentiation, a cell-based screen of small-molecule libraries was carried out for molecules that induce terminal differentiation of normal human epidermal keratinocytes. One class of molecules was identified, the 2-(3,4,5-trimethoxyphenylamino)-pyrrolo[2,3-d]pyrimidines, which were shown to induce differentiation of epidermal progenitor cells to terminally differentiated keratinocytes. These molecules serve as useful mechanistic probes of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis and may lead to novel therapeutic approaches for the treatment of skin hyperproliferative disorders. © 2007 by American Chemical Society.

Authors
Hong, J; Lee, J; Min, KH; Walker, JR; Peters, EC; Gray, NS; Cho, CY; Schultz, PG
MLA Citation
Hong, J, Lee, J, Min, KH, Walker, JR, Peters, EC, Gray, NS, Cho, CY, and Schultz, PG. "Identification and characterization of small-molecule inducers of epidermal keratinocyte differentiation." ACS Chemical Biology 2.3 (2007): 171-175.
PMID
17348628
Source
scival
Published In
ACS Chemical Biology
Volume
2
Issue
3
Publish Date
2007
Start Page
171
End Page
175
DOI
10.1021/cb600435t

Synthesis of brasilibactin A and confirmation of absolute configuration of β-hydroxy acid fragment

A synthesis of brasilibactin A, a cytotoxic siderophore from the actinomycete of Nocardia brasiliensis, and three unnatural diastereomers of the natural product is described. Four possible diastereomers of the β-hydroxy acid fragment were prepared via asymmetric aldol reactions and used to synthesize brasilibactin A and its diastereomers. Careful analysis of 1H NMR data confirmed that brasilibactin A possesses the 17S,18R absolute stereochemistry. © 2007 Elsevier Ltd. All rights reserved.

Authors
Ying, Y; Hong, J
MLA Citation
Ying, Y, and Hong, J. "Synthesis of brasilibactin A and confirmation of absolute configuration of β-hydroxy acid fragment." Tetrahedron Letters 48.46 (2007): 8104-8107.
Source
scival
Published In
Tetrahedron Letters
Volume
48
Issue
46
Publish Date
2007
Start Page
8104
End Page
8107
DOI
10.1016/j.tetlet.2007.09.112

A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase

Cell motility is a complex biological process, involved in development, inflammation, homeostasis, and pathological processes such as the invasion and metastatic spread of cancer. Here, we describe a genomic screen designed to identify inhibitors of cell migration. A library of 10,996 small interfering RNAs (targeting 5,234 human genes) was screened for their ability to block the migration of a highly motile ovarian carcinoma cell line, SKOV-3, by using a 384-well wound-healing assay coupled with automated microscopy and wound quantification. Two or more small interfering RNAs against four genes, CDK7, DYRK1B, MAP4K4 (NIK/HGK) (MAP4K4, mitogen-activated protein 4 kinase 4), and SCCA-1 (SerpinB3), potently blocked the migration of SKOV-3 cells, concordant with reduced transcript levels. Further studies of the promigratory role of MAP4K4 showed that the knockdown of this transcript inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility and potently suppressed the invasion of SKOV-3 cells in vitro. The effect of MAP4K4 on cellular migration was found to be mediated through c-Jun N-terminal kinase, independent of AP1 activation and downstream transcription. Accordingly, small molecule inhibition of c-Jun N-terminal kinase suppressed SKOV-3 cell migration, underscoring the potential therapeutic utility of mitogen-activated protein kinase pathway inhibition in cancer progression. © 2006 by The National Academy of Sciences of the USA.

Authors
Collins, CS; Hong, J; Sapinoso, L; Zhou, Y; Liu, Z; Micklash, K; Schultz, PG; Hampton, GM
MLA Citation
Collins, CS, Hong, J, Sapinoso, L, Zhou, Y, Liu, Z, Micklash, K, Schultz, PG, and Hampton, GM. "A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase." Proceedings of the National Academy of Sciences of the United States of America 103.10 (2006): 3775-3780.
PMID
16537454
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
103
Issue
10
Publish Date
2006
Start Page
3775
End Page
3780
DOI
10.1073/pnas.0600040103

First synthesis and structural elucidation of (-)-presphaerene

The first total synthesis of (-)-presphaerene (1) was achieved from (R)-glyceraldehyde 9 in 19 steps, demonstrating the novel "folding and allylic strain-controlled" intramolecular ester enolate S N2′ alkylation strategy could be extended to the stereoselective synthesis of cyclopentanoid natural products. The present study also established the relative and absolute stereochemistry of 1, and the absolute structures of co-occurring sphaeroanes from the red alga Sphaerococcus coronopifolius.

Authors
Lee, J; Hong, J
MLA Citation
Lee, J, and Hong, J. "First synthesis and structural elucidation of (-)-presphaerene." Journal of Organic Chemistry 69.19 (2004): 6433-6440.
PMID
15357605
Source
scival
Published In
Journal of Organic Chemistry
Volume
69
Issue
19
Publish Date
2004
Start Page
6433
End Page
6440
DOI
10.1021/jo049351c

Asymmetric total synthesis of ent-(-)-roseophilin: Assignment of absolute configuration

An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine → 1,2-diazine → pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([α]25D, CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing ah unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.

Authors
Boger, DL; Hong, J
MLA Citation
Boger, DL, and Hong, J. "Asymmetric total synthesis of ent-(-)-roseophilin: Assignment of absolute configuration." Journal of the American Chemical Society 123.35 (2001): 8515-8519.
PMID
11525659
Source
scival
Published In
Journal of the American Chemical Society
Volume
123
Issue
35
Publish Date
2001
Start Page
8515
End Page
8519
DOI
10.1021/ja011271s

Total synthesis of phomazarin

A concise total synthesis of phomazarin (1) is detailed enlisting a heterocyclic azadiene inverse electron demand Diels-Alder reaction (1,2,4- triazine → pyridine) for preparation of the fully substituted and appropriately functionalized pyridine C-ring. Thus, [4 + 2] cycloaddition (85%) of triethyl 1,2,4-triazine3,5,6-tricarboxylate (2) with trimethoxyethylene (3) followed by conversion of the cycloadduct 11 to the cyclic anhydride 13 provided the phomazarin C-ring with the three carboxylates suitably differentiated. Linkage of the A- and C-rings through selective nucleophilic addition of the aryllithium reagent 9 to the least hindered anhydride carbonyl of 13 followed by Friedel-Crafts closure of the B-ring provided the fully functionalized phomazarin skeleton. The successful structural correlation of synthetic 1 with natural material and its derivatives confirmed the latest structural assignment for the natural product.

Authors
Boger, DL; Hong, J; Hikota, M; Ishida, M
MLA Citation
Boger, DL, Hong, J, Hikota, M, and Ishida, M. "Total synthesis of phomazarin." Journal of the American Chemical Society 121.11 (1999): 2471-2477.
Source
scival
Published In
Journal of the American Chemical Society
Volume
121
Issue
11
Publish Date
1999
Start Page
2471
End Page
2477
DOI
10.1021/ja983631q

Total synthesis of nothapodytine b and (-)-mappicine

Concise total syntheses of naturally occurring nothapodytine B (1, mappicine ketone) and ( - )-mappicine (3) are detailed. The approach is based on the implememation of a room-temperature, inverse electron demand Diels-Alder reaction of the N-sulfonyl-1-aza-1.3-butadiene 11 for assemblage of a pyridone 1) ring precursor central to the structure. A Friedlander condensation is utilized for constructing the AB ring system of 1 and 3. An acid-catalyzed reaction sequence is used to accomplish a deprotection with subsequent ring-closure for introduction of the C ring in a single step.

Authors
Boger, DL; Hong, J
MLA Citation
Boger, DL, and Hong, J. "Total synthesis of nothapodytine b and (-)-mappicine." Journal of the American Chemical Society 120.6 (1998): 1218-1222.
Source
scival
Published In
Journal of the American Chemical Society
Volume
120
Issue
6
Publish Date
1998
Start Page
1218
End Page
1222
DOI
10.1021/ja973007y

An asymmetric synthesis of (+)-isonitramine by 'triple allylic strain-controlled' intramolecular SN2' alkylation

The spirocyclic alkaloid (+)-isonitramine (1) has been synthesized in a stereoselective manner utilizing a novel 'triple allylic strain-controlled' intramolecular lactam enolate SN2' alkylation.

Authors
Kim, D; Choi, WJ; Hong, JY; II, YP; Kim, YB
MLA Citation
Kim, D, Choi, WJ, Hong, JY, II, YP, and Kim, YB. "An asymmetric synthesis of (+)-isonitramine by 'triple allylic strain-controlled' intramolecular SN2' alkylation." Tetrahedron Letters 37.9 (1996): 1433-1434.
Source
scival
Published In
Tetrahedron Letters
Volume
37
Issue
9
Publish Date
1996
Start Page
1433
End Page
1434
DOI
10.1016/0040-4039(96)00023-8
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