The first goal is the design and development of methodology designed to accomplish a concise synthesis of the troublesome EF ring portion of the potent cytotoxic/anticancer natural product spongistatin 1. Should this approach be successful, the reduction in the synthetic step count for this portion of the molecule from approximately 30 to the proposed 11 steps would result in a much more concise synthesis of the spongistatins, one which would be amenable to a structure-activity study (SAR). The longer-term goal of this proposal is the aforementioned SAR study of the spongistatins wherein the proposed three-dimensional structure will provide the focus for this study, to wit: internal hydroxyl groups, which are hydrogen bonded to each other and are presumed to be important in the three-dimensional structure presentation, will be targeted for methyl ether formation/acylation (role will be H-bond acceptor only), inversion (examining the impact of a change in tertiary structure), inversion and substitution by nitrogen (examining tertiary structure change and atom alteration), and substitution by nitrogen with retention of absolute stereochemistry (examining the effect of the stronger H-bond donor/acceptor properties of the acetamide group). Chemically accessible exposed peripheral hydroxyl groups which might be involved in recognition/binding will be also be targeted for etherification/acylation, inversion, inversion and substitution by nitrogen and retention with replacement with nitrogen. In toto, approximately 45 analogues are envisioned;approximately 12 will be initially targeted, and the biological data garnered will inform on the suitability of the remaining 33.
This work will constitute a much more succinct synthesis of the important natural product spongistatin 1 than has previously been accomplished, and will enable the first meaningful study of the factors responsible for its extraordinary anticancer properties. Spongistatin 1 has been reported to be extremely potent against a broad cross-section of cancers, but low availability from both natural sources and existing syntheses has thus far hampered systematic investigations into its active components and the development of simpler derivatives for use in cancer therapy.