): The spongistatins, isolated from the marine sponge Spongia sp. in microscopic quantities, show especially powerful growth inhibitory activity against human melanoma, lung, colon and brain cancers, and have an activity pattern similar to the microtubule-interactive antimitotics. The first representative of this class of macrolides, spongistatin 1, is claimed to be the most extraordinary potent substance presently known against a subset of highly chemoresistant tumor types in the NCI panel of 60 human cancer cell lines. Upon isolation, spongistatin I was obtained in only extremely minimal isolated yield from the whole sponge. Realization of this synthetic project will satisfy the urgent needs for further material of spongistatin 1 for biological testing. Advanced intermediates of spongistatin will be submitted for biological testing in order to find a possible pharmacophore unit. The project plans to achieve a convergent synthesis of spongistatin 1 based mostly on application of boron reagents for the stereocontrolled construction and coupling of smaller fragments containing the A/B, C4D, and E/F ring systems. The primary aim of this proposal is to develop a viable synthetic approach to the spongistatins based on either reagent- or substrate-controlled asymmetric induction. Another goal of the proposed research is confirmation and of the full absolute and relative stereochemistry of spongistatin 1 in the course of its synthesis. Realization of this project will provide a challenging test of current synthetic methodology and further stimulate the development of new methods for supplying sufficient quantities of natural products for biological and pharmaceutical testing. The synthetic approach presented is flexible and will allow synthesis of a variety of analogs of spongistatin for the structure-activity studies. This project will be performed at the Chemistry Department of the University of Michigan under the NCI Howard Temin Award. As a result of this training, the candidate will obtain a high level of expertise in the natural products synthesis that will allow him to start an independent research career in an academic environment.
| Micalizio, G C; Pinchuk, A N; Roush, W R (2000) Synthesis of the C(29)-C(45) bis-pyran subunit (E-F) of spongistatin 1 (Altohyrtin A). J Org Chem 65:8730-6 |
