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BRYOSTATIN

    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 enhances learning and extends memory in animal models. 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 and preclude 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 and opportunities, 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 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 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.  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, and neurodegenerative diseases. 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). (More on this project) (References)

     

    Lead References:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  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.
  12. 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.
  13. 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.
  14. "The Rational Design of Potential Chemotherapeutic Agents:  Synthesis of Bryostatin Analogues," Med. Res. Rev., 1999, 19, 388.
  15. "Synthesis of the First Members of a New Class of Biologically Active Bryostatin Analogs," J. Am. Chem. Soc., 1998, 4534.
  16. "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.

 

    LAULIMALIDE

    Laulimalide: This marine derived natural product represents an exceptional lead for treating cancer and a formidable synthetic and drug design problem.  Importantly, while having some aspects of its mode of action in common with taxol, it exhibits activity against taxol-resistant cancer.  In 2002 we reported a concise and flexible total synthesis. More recently we have been engaged in the synthesis and biological evaluation of analogues. These designed analogues exhibit laulimalide-like activity (see PNAS cover story) but are designed to circumvent the parent compound's instability. Continuing efforts involve design and synthesis of simplified laulimalide analogues and elucidation of structure-activity relationships (SAR), as needed to advance this therapeutic opportunity.

    (Image at right illustrates the physiological effects of laulimalide analogue on the mitotic spindle during cell division.)

    Lead references:

  1. Wender, P. A.; Hegde, S. G.; Hubbard, R. D.; Zhang, L.; “Total Synthesis of (-)-Laulimalide,” J. Am. Chem. Soc.; 2002; 4956-4957.
  2. Wender, P. A.; Hegde, S. G.; Hubbard, R.D.; Zhang, L.; Mooberry, S. L. “Synthesis and Biological Evaluation of (-)-Laulimalide Analogues,” Org. Lett.; 2003, 5; 3507.
  3. Mooberry, SL; Randall-Hlubek, DA; Leal, RM; Hegde, SG; Hubbard, RD; Zhang, L; Wender, PA “Microtubule-stabilizing agents based on designed laulimalide analogues” PNAS, 2004, 101, 8803.
  4. Wender, P. A.; Hilinski, M. K.; Soldermann, N.; Mooberry, S. L. "Total Synthesis and Biological Evaluation of 11-Desmethyllaulimalide, a Highly Potent Simplified Laulimalide Analogue" Org. Lett. 2006, 8, 1507-1510.
  5. Wender, P. A.; Hilinski, M. K.; Skaanderup, P. R.; Soldermann, N. G.; Mooberry, S. L. "Pharmacophore Mapping in the Laulimalide Series: Total Synthesis of a Vinylogue for Late-Stage Metathesis Diversification Strategy" Org. Lett. 2006, 8, 4105-4108.

    APOPTOLIDIN

    Apoptolidin: In 1997, Seto reported the structure of apoptolidin A, which was isolated from Nocardiopsis sp. in a screening program designed to identify new compounds that selectively induce apoptosis in E1A transformed cells. Apoptolidin A was subsequently shown to be among the top 0.1% most selective agents tested in the NCI's 60 human cancer cell line panel out of the more than 37,000 compounds analyzed. The ability of apoptolidin A to induce apoptosis potently and with remarkable selectively makes it an exciting lead compound for the treatment of cancer, an arena of medicine in which selectivity of therapeutic function is still a major unmet challenge. Our research goals include use of synthetic chemistry to learn more about the chemistry of apoptolidin and its derivatives, and to use that synthetic expertise to study the mode of action of these molecules (in collaboration with several research groups).  Furthermore, knowledge of mode of action and synthetic expertise can be combined towards the design of superior agents for treatment of human disease.

    apop

     

    Lead References:

    CYATHANE DITERPENE SYNTHESIS

     

    Synthetic Approaches

    Mechanistic Rationale

    GNIDIMACRIN & KIRKININE

    Gnidimacrin: Long an unidentified constituent of folk remedies, gnidimacrin (shown below) was only recently found to have selective activity against a variety of cancer cell lines (stomach, non-small cell lung and leukemias) with sub-nanomolar (0.35 nM) IC50 values. Of special therapeutic relevancy, gnidimacrin’s anticancer activity has also been shown in animal cancer models in which significant life extensions and even cures have been reported. Gnidimacrin appears to work through a novel mode of action that might involve selective modulation of a PKC isozyme. Unfortunately, isolation yields of gnidimacrin are approximately 0.0005%, making its supply from natural sources very limited. The main goal of this project is to achieve the total synthesis of gnidimacrin, and gnidimacrin–like compounds which can be used to study its biological activity and develop improved therapeutic agents. Gnidimacrin itself is a formidable synthetic challenge that is beyond the current capabilities of synthesis, thus representing an opportunity to advance the frontiers of synthetic chemistry. Ideally, a synthetic route toward this target would allow for the rapid generation of analogues that can provide information on gnidimacrin's unique mode of action and thus inspire the design of superior anticancer leads.

     

    Phorbol

     

    Kirkinine: Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are devastating neuronal disorders.  As of 2003, 4.5 million Americans were suffering from Alzheimer’s disease (AD), and the annual costs related to AD add up to over 100 billion dollars in the US alone. Kirkinine is a daphnane diterpenoid isolated in low yield (0.00002 %) from the roots of Synaptolepis kirkii, a medicinal plant in Africa. Kirkinine has a very complex molecular architecture featuring a highly oxygenated tricyclic ring system, an orthoester side chain, and an epoxide, as well as eleven stereogenic centers. This densely functionalized structure presents challenging problems in synthesis. More importantly, it is kirkinine's remarkable neurotrophic (protecting nerve cells) activity that makes it a very attractive synthetic target.  Kirkinine effectively promotes neuronal survival against serum deprivation in nanomolar concentrations. As a result, kirkinine and its analogs present very promising therapeutic opportunities against neurodegenerative diseases such as Alzheimer’s. 

     

    Lead references:

  1. Wender, P. A.; D'Angelo, N.; Elitzin, V. I.; Ernst, M.; Jackson-Ugueto, E. E.; Kowalski, J. A.; McKendry, S.; Rehfeuter, M.; Sun, R.; Voigtlaender, D. “Function-Oriented Synthesis: Studies Aimed at the Synthesis and Mode of Action of 1-Alkyldaphnane Analogues ” Org. Lett. 2007, 1829-1832.
  2. Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.; Kan, C.; Kee, J. M.; Ohmura, H. "Studies on Oxidopyrylium [5+2] Cycloadditions: Toward a General Synthetic Route to the C12-Hydroxy Daphnetoxins" Org. Lett. 2006, 8, 5373-5376.
  3. Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. "The First Synthesis of a Daphnane Diterpene: The Enantiocontrolled Total Synthesis of (+)-Resiniferatoxin" J. Am. Chem. Soc. 1997, 119, 12976-12977.
  4. Wender, P. A.; Rice, K. D.; Schnute, M. E. "The First Formal Asymmetric Synthesis of Phorbol" J. Am. Chem. Soc. 1997, 7611-7612.

 

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