Design and Synthesis of a Novel Thiolate Histone Deacetylase Inhibitor

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Information about Design and Synthesis of a Novel Thiolate Histone Deacetylase Inhibitor
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Published on March 18, 2014

Author: MaxTucker

Source: slideshare.net

Maxwell Tucker North Carolina School of Science and Mathematics DESIGN AND SYNTHESIS OF A NOVEL THIOLATE HISTONE DEACETYLASE INHIBITOR

Introduction | Molecular Modeling | Synthesis | Conclusions HISTONES AND HISTONE ACETYLATION • Histones are a major component of chromatin, the skeleton upon which DNA is stored • Acetylation and deacetylation of histones affects gene expression • A number of cancers show excess expression of class I HDACs1 Histone acetylation showing affect on gene expression Transcriptionally active Transcriptionally repressed HAT HDAC 1Dokmanovic, M., Clarke, C., & Marks, P. a. (2007). Histone deacetylase inhibitors: overview and perspectives. Molecular cancer research : MCR, 5(10), 981–9. 2

Introduction | Molecular Modeling | Synthesis | Conclusions HISTONE DEACETYLASE INHIBITORS (HDACI) • Competitive inhibitors • Consist of 3 main groups: surface recognition, linker, and chelating group • Act by chelating the zinc ion within metal cofactor-dependent HDACs 3

Introduction | Molecular Modeling | Synthesis | Conclusions HYDROXAMIC ACID INHIBITORS • Hydroxamic acid inhibitors are among the most structurally simple histone deacetylase inhibitors • Suberoylanilide hydroxamic acid (vorinostat) is one of only 2 HDACis currently approved by the FDA • A host of side effects, including fatigue, nausea, vomiting, and anemia2 2Ma, X., Ezzeldin, H. H., & Diasio, R. B. (2009). Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs, 69(14), 1911–34. 4

Introduction | Molecular Modeling | Synthesis | Conclusions DEPSIPEPTIDE/THIOLATE INHIBITORS • Contain large depsipeptide macrocycles • Prodrugs which form thiol active metabolite • Highly selective Romidepsin and largazole, 2 depsipeptide inhibitors and their active metabolites3 3Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., & Christianson, D. W. (2011). Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. Journal of the American Chemical Society, (133), 12474–12477. 5

Introduction | Molecular Modeling | Synthesis | Conclusions PROBLEMS WITH CURRENT INHIBITORS • Hydroxamic acid inhibitors have a host of side affects • Depsipeptide inhibitors are hard to synthesize and therefore costly Retrosynthetic Analysis for romidepsin4 4Greshock, T., Johns, D., Noguchi, Y., & Williams, R. (2008). Improved total synthesis of the potent HDAC inhibitor FK228 (FR-901228). Organic letters, 10(4), 613–616. 6

Introduction | Molecular Modeling | Synthesis | Conclusions EXPERIMENTAL DESIGN AND PROJECT GOALS • Design a synthetic inhibitor with simple synthesis and high anticipated selectivity and activity • Adapt simple surface recognition regions from hydroxamic acid inhibitors • Aliphatic linker • Thiol chelating agent 7

Introduction | Molecular Modeling | Synthesis | Conclusions MOLEGRO MOLECULAR DOCKING • Moldock engine uses heuristics with a genetic algorithm for accurate ligand-protein docking5 • Six novel ligands were tested alongside known hydroxamic acid inhibitors – TSA and SAHA 5Thomsen, R., & Christensen, M. H. (2006). MolDock: a new technique for high-accuracy molecular docking. Journal of Medicinal Chemistry, 49(11), 3315–21. 8

Introduction | Molecular Modeling | Synthesis | Conclusions DOCKING RESULTS 9

Introduction | Molecular Modeling | Synthesis | Conclusions SYNTHETIC TARGET The active metabolite, top, and the synthetic target, a disulfide dimer • Molecular Weight of 253, 504 for the dimer • Few hydrogen bonding sites • clogP between 3.2 and 3.6 10

Introduction | Molecular Modeling | Synthesis | Conclusions SYNTHESIS 11

Introduction | Molecular Modeling | Synthesis | Conclusions SYNTHESIS 12

Introduction | Molecular Modeling | Synthesis | Conclusions PRODUCT VERIFICATION • Intermediate products were verified using IR spectroscopy • Final verification was done using proton and carbon-13 NMR • C13 NMR shifts were predicted at the B3LYP/6-31G** level on a structure optimized at the 6-31G* level C-13 NMR spectrum of final product 13

Introduction | Molecular Modeling | Synthesis | Conclusions Active metabolite IR spectrum 14

Introduction | Molecular Modeling | Synthesis | Conclusions CONCLUSIONS • Successfully designed and synthesized a novel thiolate histone deacetylase inhibitor • Molecule is predicted to have high selectivity and activity, based on molecular modeling • May one day prove to be effective for the treatment of cancers 15

Introduction | Molecular Modeling | Synthesis | Conclusions FUTURE WORK • Additional molecular modeling to verify selectivity • Increased synthetic yields – better catalysis and optimized reaction conditions • Preliminary biological assays, first on enzyme samples in vitro, then established cell lines DMAP, a potential catalyst for the esterification 16

Introduction | Molecular Modeling | Synthesis | Conclusions ACKNOWLEDGMENTS Special Thanks to: Dr. Myra Halpin Dr. Darrell Spells The Research in Chemistry Program and Students The NCSSM Science Department Dr. W. Andrew Tucker of Queens University Additional Thanks to the Following: Dr. Amy Sheck, NCSSM Mr. John Woodmansee, NCSSM Ms. Leslie Brinson, NCSSM My Family 17

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