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Jennifer M. Finefield Robert M. Williams, Advisor Colorado State University December 6, 2011

Selective HDAC Inhibitor. Biosynthetic Studies. Novel Drug Delivery Method. Jennifer M. Finefield Robert M. Williams, Advisor Colorado State University December 6, 2011. Efforts Toward the Synthesis of a Selective Histone Deacetylase Inhibitor. DNA Packaging.

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Jennifer M. Finefield Robert M. Williams, Advisor Colorado State University December 6, 2011

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  1. Selective HDAC Inhibitor Biosynthetic Studies Novel Drug Delivery Method Jennifer M. Finefield Robert M. Williams, Advisor Colorado State University December 6, 2011

  2. Efforts Toward the Synthesis of a Selective Histone Deacetylase Inhibitor

  3. DNA Packaging • For DNA to fit within the nucleus, it must be condensed • DNA is packaged into chromatin • To begin packaging, DNA is wound around histones www.med.unc.edu www.christopher_vidal.com

  4. Gene Expression: Dynamic Wrapping and Unwrapping of DNA • Histone Acetyltransferase (HAT) readies DNA for transcription • Histone Deacetylase (HDAC) returns DNA to the inactive state • HDAC inhibitors prevent removal of acetyl residues X www.med.unc.edu www.christopher_vidal.com

  5. Transcriptional Control • HDAC inhibitors mimic the natural substrate • Deacetylation is prevented, eventually leading to cell death

  6. Zn-Dependent Histone Deacetylase Enzymes • HDAC enzymes are divided into different classes • Within each class, there are different isoforms • Many known HDAC inhibitors display very little selectivity for class or isoform Marks, P. A., et al., Advances in Cancer Research, 2005, 137

  7. HDAC Inhibitors and Enhancing Selectivity • Many known HDAC inhibitors display very little selectivity for class or isoform Wiest, O. et al., J. Med. Chem. 2004, 47, 3409; Methot, J. L., et al., Bioorg. Med. Chem. Lett.2008, 18, 973

  8. Improving Selectivity of HDACi:Targeting HDAC1 and HDAC2 Moradei, O. M., et al., J. Med. Chem. 2007, 50, 5543

  9. Improving Selectivity of HDACi:Targeting HDAC3 Finefield, J. M.; Williams, R. M.; Wiest, O.; Bradner, J. Unpublished results

  10. Improving Selectivity of HDACi:Targeting HDAC3 Ser118, present in HDAC1/2 (green) » Tyr118 in HDAC3 (blue) Finefield, J. M.; Williams, R. M.; Wiest, O.; Bradner, J. Unpublished results

  11. Key Disconnections

  12. Thiazoline-Pyridine Synthesis Bowers, A., et al., Org. Lett., 2009, 11, 1301

  13. Synthesis of the Amide Isostere Bowers, A., et al., J. Am. Chem. Soc., 2009, 131, 2900

  14. Alternate Route

  15. 2-Thiophenyl Biaryl Synthesis

  16. Final Steps and Future Direction ______________________________________________________________________________________________________________________________

  17. Design and Synthesis of a Novel Drug Delivery Method Specifically Targeted to Multiple Myeloma Cells

  18. Multiple Myeloma • MM is a plasma cell malignancy that can lead to bone destruction, anaemia, hypercalcaemia, and renal insufficiency • MM is associated with older age (median age 66 years) and is found to occur more often in men than women • Cause of MM remains unknown • Current treatments include a single high-dose of melphalan, velcade, and various combination treatments Trialx.com, Mahindra, A., et al., Blood Reviews2010, 24, S5; Barlogie, B., et al., Blood2004, 103, 20

  19. Tumor Specific Oligonucleotide (MB8226) UAGGCUACGUACUUAAGCG

  20. The Trojan Horse Nakatani, K. et al., J. Am. Chem. Soc.2000, 122, 2172

  21. Naphthyridine Modified MM Drugs Currently undergoing clinical trials to be used as a combination treatment for multiple myeloma Given either as a high-dose treatment or as part of a combination for the treatment of multiple myeloma

  22. Naphthyridine Modified Vorinostat Brown, E. V., J.Org. Chem.1965, 30, 1607; Yoshida, M. et al., Synthesis2008, 1099; Gediya, L. K. et al. J. Med. Chem.2005, 48, 5047

  23. Naphthyridine Modified Vorinostat Mai, A. et al. OPPI Briefs2001, 33, 391

  24. Naphthyridine Modified Melphalan Nakatani, K. et al., Bioorg. Med. Chem. 2003, 11, 2347; Gullbo, J. et al., Oncol. Res. 2003, 14, 113

  25. Preliminary Test Results

  26. Preliminary Test Results

  27. Studies on the Biosynthesis of Reverse Prenylated Indole Secondary Metabolites from Aspergillus versicolor and Aspergillus sp. MF297-2

  28. Reverse Prenylated Indole Secondary Metabolites1969-2006

  29. Proposed Biosynthesis of the Bicyclo[2.2.2]diazaoctane Ring System Enzymatic Diels-Alder Reaction Porter and Sammes Diels-Alder Proposal (1970) Porter, A. E. A. et al., Chem. Commun. 1970, 1103; Williams, R. M., Chem. Pharm. Bull. 2002, 50, 711.

  30. Proposed Biosynthesis of the Bicyclo[2.2.2]diazaoctane Ring System • Enzyme Controlled Stereoselectivity

  31. Reverse Prenylated Indole Secondary Metabolites2007-2011

  32. Isolation of the Notoamides: New Addition to the Stephacidin Family • 2007: Aspergillus sp. MF297-2 Kato, H. et al., Angew. Chem. Int. Ed.2007, 46, 2254

  33. Isolation of the Notoamides: New Addition to the Stephacidin Family • 2008: Aspergillus versicolor NRRL 35600 Greshock, T. J. et al., Angew. Chem. Int. Ed. 2008, 47, 3573

  34. Antipodal Natural Products Tsukamoto, S. et al., Org. Lett. 2009, 11, 1297; Greshock, T. J. et al., Angew. Chem. Int. Ed. 2008, 47, 3573

  35. Isolation of the Notoamides: New Addition to the Stephacidin Family • 2008-2010: Aspergillus sp. MF297-2 Tsukamoto, S. et al: JACS, 2009, 131, 3834; JNP2008, 71, 2064; OL2009, 11, 1297; JNP2010, 73, 1438

  36. Isolation of Notoamide E: A Potential Biosynthetic Precursor • 2008-2010: Aspergillus sp. MF297-2 Tsukamoto, S. et al., J. Am. Chem. Soc. 2009, 131, 3834

  37. Proposed Biosynthetic Pathway:Notoamide E Greshock, T. J. et al., Angew. Chem. Int. Ed. 2008, 47, 3573

  38. Synthesis of [13C]2-Notoamide E Tsukamoto, S. et al., JACS 2009, 131, 3834; Grubbs, A. W. et al., TL 2005, 46, 9013; Grubbs, A. W. et al., ACIE 2007, 46, 2257

  39. Synthesis of [13C]2-Notoamide E Tsukamoto, S. et al., J. Am. Chem. Soc. 2009, 131, 3834

  40. [13C]2-Notoamide E Incorporation Study withAspergillus sp. MF297-2 • No labeled bicyclo[2.2.2]diazaoctane containing metabolites were produced Tsukamoto, S. et al., J. Am. Chem. Soc. 2009, 131, 3834

  41. [13C]2-Notoamide E Incorporation Study withAspergillus versicolor Finefield, J. M.; Williams, R. M. et al., Tetrahedron Lett. 2011, 52, 1987

  42. Possible Precursors Leading to Stephacidin A

  43. Synthesis of Deoxybrevianamide E and 6-Hydroxydeoxybrevianamide E Kato, H.; Nakamura, Y.; Finefield, J. M.; Umaoka, H.; Nakahara, T.; Williams, R. M.; Tsukamoto, S., TL 2011, 52, 6923

  44. Synthesis of Ketopremalbrancheamide

  45. Biosynthetic Breakthrough:Characterization of the ()-Notoamide Biosynthetic Gene Cluster Ding, Y.; de Wet, J. R.; Cavalcoli, J.; Li, S.; Greshock, T. J.; Miller, K. A.; Finefield, J. M.; Sunderhaus, J. D.; McAfoos, T. J.; Tsukamoto, S.; Williams, R. M.; Sherman, D. H., JACS2010, 132, 12733

  46. Biosynthetic Breakthrough:Identification of Two Prenyltransferases Ding, Y.; de Wet, J. R.; Cavalcoli, J.; Li, S.; Greshock, T. J.; Miller, K. A.; Finefield, J. M.; Sunderhaus, J. D.; McAfoos, T. J.; Tsukamoto, S.; Williams, R. M.; Sherman, D. H., JACS2010, 132, 12733

  47. Early Steps in the Biosynthetic Pathway

  48. Feeding Study with [13C]2-[15N]-6-Hydroxydeoxybrevianamide E No incorporation into advanced metabolites Finefield, J. M.; Williams, R. M. et al., JOC 2011, 76, 5954; Finefield, J. M.; Williams, R. M.; Tsukamoto, S. et al., TL 2011, 52, 6923

  49. Possible Enantio-diverging Pathways from Notoamide S

  50. Notoamide S Incorporation Study with Aspergillus versicolor Unlabeled synthesis of notoamide S: McAfoos, T. J. et al., Heterocycles 2010, 82, 461 Results from feeding study: Finefield, J. M.; Tsukamoto, S.; Williams, R. M. et al., unpublished results

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