SEMINAR: School of Chemistry and Biochemistry Seminar

Urukthaplestatin A (Ustat A) is a novel natural product, consisting of oxazoles and thiazoles inbedded in a macrocycle. It has extraordinary cytotoxicity against cancer cells in the desirable low nanomolar range (average GI50 = 5.6nM). It does not share structural homology with other classes of marketed cancer therapeutics, and it has a different activity profile to compounds with structural similarities indicating a possible novel and unique mechanism of action. We use novel, modular oxazole methodology that generates numerous Ustat A analogs, and specifically we have designed compounds that will explore its structure-activity relationship and mechanism of action. Given the cytotoxicity and the novelty of these molecules, they are ideal starting points for developing new cancer therapies.

Molinski and co-workers discovered Sanguinamide B (San B) from a single species of nudibranch. The San B natural product contains two thiazoles and one oxazole, and is a modified octapeptide macrocycle; unlike other natural products isolated from this sponge, San B contains two proline residues, where these two residues are control the conformation of the macrocycle. The potent cytotoxic and antibiotic properties of other macrolides isolated from this nudibranch species, and the small microgram quantities of the compound that are available from the natural source, make this natural product a very attractive compound to synthesize. We have synthesized and tested San B and numerous analogues against gram +ve, gram –ve bacteria as well as against mammalian cancer cell lines. Not surprisingly, the conformation of these compounds dictates their biological activity.