Bryostatin 1 is a marine derived macrocyclic lactone now in phase II clinical trials as a cancer chemotherapeutic. It exhibits exceptionally potent and unique biological activities: it restores apoptotic function, synergizes the effect of other anti-cancer agents, bolsters the immune system, and reverses multidrug resistance. Remarkably, it has also been shown to enhance learning and extend memory in animal models. In light of this activity, a clinical trial has opened for the treatment of Alzheimer’s disease using bryostatin. More recently, bryostatin has been shown to activate latent HIV viral reservoirs. This unique combination of functions makes bryostatin 1 a particularly promising agent for the treatment of human disease. However, its complexity and low natural abundance make it inaccessible in useful amounts, precluding access to derivatives that could contribute to our understanding of its mode of action. Like other natural products, bryostatin was not “designed” for human use. In order to address these issues related to supply and therapeutic optimization, we have turned to function-oriented synthesis: the design of superior analogs of bryostatin that retain the activity and potency of the natural product and are accessible in a step-economical fashion through chemical synthesis. Our studies include the development of novel strategies for the synthesis of bryostatin analogs, computer modeling directed at understanding how bryostatin is recognized by its receptor, NMR studies designed to determine dynamic function and mode of action, binding assays, and in vitro as well as ex vivo and in vivo studies on biological function. We have developed analogs that are more potent than bryostatin as well as analogs that display unique selectivity profiles for proteins believed to be responsible for bryostatin’s biological activities. These analogs are accessed in a step-economical fashion using novel macrocyclization strategies. Ultimately, this research could not only provide superior agents for the treatment and understanding of cancer, but of other diseases as well, including heart disease, stroke, diabetes, neuropathic pain, neurodegenerative disease, and HIV/AIDS. This design and synthesis driven project encourages creative and collaborative thinking about science and provides a well-rounded training through experiences in the following areas: design and synthesis of complex non-natural products (in this effort one must create the target for synthesis), molecular modeling computer programs, and biological assay techniques (i.e. binding assays, cell-culture and cellular assays, and microscopy).
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Lead References:
- DeChristopher, B. A.; Fan, A. C.; Felsher, D. W.; Wender, P. A. “ ‘Picolog,’ a synthetically-accessible bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo.” Oncotarget, 2012, 3, 58-66.
- Wender, P. A.; Baryza, J. L.; Brenner, S. E.; DeChristopher, B. A.; Loy, B. A.; Schrier, A. J. “Design, synthesis and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity,” Proc. Natl. Acad. Sci. USA, 2011, 108, 6721-6726.
- Wender, P. A.; Schrier, A. J. “Total Synthesis of Bryostatin 9,” J. Am. Chem. Soc., 2011, 133, 9228-9231.
- Wender, P. A.; Loy, B. A.; Schrier, A. J. “Translating nature’s library: the bryostatins and function-oriented synthesis,” Isr. J. Chem., 2011, 51, 453-472.
- Shaha, S. P.; Tomic, J.; Shi, Y.; Pham, T.; Mero, P.; White, D.; He, L.; Baryza, J. L.; Wender, P. A.; Booth, J. W.; Spaner, D. E. “Prolonging Microtubule Dysruption Enhances the Immunogenicity of Chronic Lymphocytic Leukemia Cells,” Clinical & Experimental Immunology, 2009, 158, 186-198.
- Wender, P. A.; Verma, V. A. “The Design, Synthesis, and Evaluation of C7 Diversified Bryostatin Analogs Reveals a Hot Spot for PKC Affinity,” Org. Lett. 2008, 10, 3331.
- Wender, P. A.; DeChristopher, B. A.; Schrier, A. J. “Efficient Synthetic Access to a New Family of Highly Potent Bryostatin Analogues via a Prins-Driven Macrocyclization Strategy,” J. Am. Chem. Soc. 2008, 6658.
- Wender, Paul A.; Baryza, Jeremy L.; Hilinski, Michael K.; Horan, Joshua C.; Kan, Cindy; Verma, Vishal A. “Beyond Natural Products: Synthetic Analogues of Bryostatin 1” in Drug Discovery Research, Ziwei Huang Ed. 2007, 127-162.
- Wender, P. A.; Horan, J. C.; Verma, V. A. "Total Synthesis and Initial Biological Evaluation of New B-Ring-modified Bryostatin Analogs" Org. Lett. 2006, 8, 5299-5302.
- Wender, P. A.; Horan, J. C. "Synthesis and PKC Binding of a New Class of A-Ring Diversifiable Bryostatin Analogues Utilizing a Double Asymmetric Hydrogenation and Cross-Coupling Strategy" Org. Lett. 2006, 8, 4581-4584.
- Wender, P. A.; Verma, V. A. "Design, Synthesis, and Biological Evaluation of a Potent, PKC Selective, B-Ring Analog of Bryostatin" Org. Lett. 2006, 8, 1893-1896.
- Hammond, C.; Shi, Y. H.; Mena, J.; Tomic, J.; Cervi, D.; He, L. W.; Millar, A. E.; DeBenedette, M.; Schuh, A. C.; Baryza, J. L.; et. al. "Effect of Serum and Antioxidants on the Immunogenicity of Protein Kinase C-activated Chronic Lymphocytic Leukemia Cells" J. Immunotherapy 2005, 28, 28-39.
- Wender, P. A.; Hilinski, M.; Mayweg, A. “Late Stage Intermolecular CH Activation for Lead Diversification: A Higly Chemoselective Oxyfunctionalization of the C-9 Position of Potent Bryostatin Analogues” Organic Lett. 2005, 7, 79.
- Baryza, J. L.; Brenner, S. E.; Craske, M. L.; Meyer, T.; Wender, P. A. "Simplified Analogs of Bryostatin with Anticancer Activity Display Greater Potency for Translocation of PKC delta-GFP" Chem. Bio. 2004, 11, 1261-1267.
- Wender, P. A.; Baryza, J. L.; Brenner, S. E.; Clarke, M. O.; Craske, M. L.; Horan, J. C.; Meyer, T. "Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New Bryostatin Analog." Curr. Drug Disc. Tech., 2004; 1, 1-11.
- Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Craske, M.L.; Horan, J.C.; Meyer, T. “Function Oriented Synthesis: The Design, Synthesis, PKC Binding and Translocation Activity of a New Bryostatin Analogue,” Current Drug Discovery Techniques 2003.
- Wender, P.A.; Baryza, J.L.; Brenner, S.E.; Clarke, M.O.; Gamber, G.G.; Horan, J.C.; Jessop, T.C.; Kan, C., Pattabiraman, K.; Williams, T.J. “Inspirations from Nature: New Reactions, New Therapeutic Leads, and New Drug Delivery Systems,” Pure Appl. Chem. 2003, 75, 143.
- Wender, P. A.; Baryza, J.; Bennett, C.; Bi, C.; Brenner, S. E.; Clarke, M.; Horan, J.; Kan, C.; Lacote, E.; Lippa, Nell, P.; Turner, T.“The Practical Synthesis of a Novel and Highly Potent Analog of Bryostatin” J. Am. Chem. Soc.; 2002, 124, 13648.
- "The Rational Design of Potential Chemotherapeutic Agents: Synthesis of Bryostatin Analogues," Med. Res. Rev., 1999, 19, 388.
- "Synthesis of the First Members of a New Class of Biologically Active Bryostatin Analogs," J. Am. Chem. Soc., 1998, 4534.
- "The Design, Computer Analysis, Solution Structure, and Biological Evaluation of the First Totally Synthetic Analogs of Bryostatin 1," Proc. Natl. Acad. Sci. USA , 1998, 6624.
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