The development and application of organic synthesis methods is a powerful enabling approach to medicinal chemistry. Our lab combines the methods of organic synthesis and transition metal catalysis to explore structure activity relationships of small organic molecules. For example, vitamin E and analogs have shown promise in both the treatment and prevention of cancer.^1,2 We are developing a library of totally synthetic vitamin E analogs for testing against prostate cancer cell lines. Current methods for obtaining vitamin E analogs rely on making derivatives of naturally occurring (?)-D-(R,R,R)-tocopherol.³ Our abilities as synthetic organic chemists allow us to make more structurally diverse vitamin E analogs since we can build the molecule from much simpler starting materials, and are thus limited only by our imagination which we use in conjunction with existing knowledge on the structure-activity relationship profile of vitamin E and the feedback from Dr. Clement Ip, our biological collaborator at Roswell Park Cancer Institute in Buffalo, NY.

Palladium(II) catalyzed cyclization of the known phenolic precursor (X = OAc) using new protocol being developed by our labs will provide a chlorinated chroman (see scheme below). Suzuki cross-coupling of the alkylchloride with a variety of alkylboranes using the conditions developed by Fu⁴ followed by exchange of the phenolic acetate for a succinate (X = COCH2CH2CO2H), an important pharmacaphore for this class of molecules, should provide a variety of vitamin E analogs for testing at Roswell Park. REU students who work on this project will learn aspects of transition metal catalysis, organic synthesis and medicinal chemistry and will interact with faculty and graduate student mentors at both UB and Roswell Park.

References

1. Zu, K. and C. Ip (2003). "Synergy between Selenium and Vitamin E Apoptosis Induction is Associated with Activation of Distinctive Initiator Caspases in Human Prostate Cancer Cells." Cancer Research 63:6988-6995.
2. Kline, K. K.A.Lawson, W.P. Yu and B.G. Sanders (2003). "Vitamin E and Breast Cancer Prevention: Current Status and Future Potential." J. Mammary Gland Bio. And Neoplasia 8(1):91-102.
3. Berringer, M., J.H. Ey Tina, B.A. Salvatore and J. Neuzil (2003). "Vitamin E. Analogues as Inducers of Apoptosis: Structure-function Relation." B. J. Cancer 88:1948-1955.
4. Kirchhoff, J.H., C. Dai and G.C. Fu (2002). "A Method for Palladium-Catalyzed Cross-Couplings of Simple Alkyl Chlorides: Suzuki Reactions Catalyzed by [Pd2(dba)3)]/PCy3." Angew. Chem. Int. Ed. Engl. 41:1945-1947.