SYNTHESIS OF SELECTIVELY CYTOTOXIC MARINE MACROLIDES

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DESCRIPTION: The long-term objective of this research is to discover leads for the development of new anticancer and AIDS-antiviral drugs or chemicals that can serve as molecular probes in mechanistic studies of these diseases. To achieve this objective, the isolation, characterization, and biological evaluation of active compounds from selectively cytotoxic extracts of marine and terrestrial organisms is carried out. A new sponge metabolite, displaying both a unique structure and human tumor cytotoxicity profile, was recently characterized as part of this program. Further biological evaluation has not been possible because of the small amount of sample available. This proposal deals with the investigation of possible synthetic routes to this compound and its congeners in order to more fully evaluate their potential as new drug leads. The synthetic plan is a convergent one involving three fragments, one of which carries all three of the stereogenic centers. One of these centers is provided by malic acid and the remaining two are introduced stereoselectively in an Evans aldol reaction. Two of the synthons are joined by means of a modified Wittig-Horner reaction followed by macrolactonization. The introduction of the third fragment, a rather labile unsaturated amide moiety, is done at the end of the synthesis. One possible and direct method to accomplish this involves the addition of an organometallic reagent to an isocyanate. A second, but longer route utilizes more standard amide chemistry and a selenoxide elimination reaction to generate the key double bond. The synthesis of several congeners in which some of the unsaturation is removed and/or rings replace acyclic moieties, is also planned in order to make structure-activity studies possible.