We will be investigating synthetic methods towards the total synthesis of the newly isolated bromotyrosine derivative, 11-Deoxyfistularin-3 (1). Compound 1 was isolated from the Caribbean sponge Aplysina fisularis (Aplysinellidae), and 1 is cytotoxic against MCF-7 (human breast carcinoma) cells with an LD50 of 17 mug/mL. A possible mechanism of one action against MCF-7 breast carcinoma is through the inhibition of the estrogen receptor enzyme aromatase. We expect to achieve the total synthesis of 1 as well as a number of synthetic analogues through the synthetic plan outlined in this proposal. Our synthetic strategies utilizes a convergent approach that brings three compounds together in a single step. The most challenging synthetic sequence involves the formation of a spirocyclic iisoxazole/cyclohexadienone. A biological collaborator, Dr. Carolyn Howard, will be testing the synthetic analogues of 1 against MCF-7 cells by measuring cell proliferation through performing cell counts and [3H]-Thymidine incorporation. Since the biological activity of 1 is known, 1 will be one of the control compounds used during the cell proliferation studies. The data gathered from these studies will be used to determine IC50 values. If one or more of the synthetic analogues prove to have a lower IC50 concentration than 1, then we will determine which functional group(s) is responsible for the increase in potency. This structure activity relationship data will serve as a tool to direct our analogue syntheses. We also plan to determine if any of the synthetic analogues inhibit the aromatase enzyme.
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