Trisoxazole macrolides from Hexabranchus nudibranchs and other marine invertebrates.

Abstract

Trisoxazole macrolides are cytotoxic and antifungal metabolites initially isolated from the egg-ribbons of the Hexabranchus nudibranch and later found in other marine invertebrates. They possess a characteristic macrolide portion, in which three contiguous oxazole units are integrated, and a side-chain with an N-methyl-vinylformamide terminus. The planar structures of the first members of this group, ulapualides and kabiramide C, were determined by interpretation of spectral data in conjunction with chemical degradation. Following these studies, the structures of approximately 35 congeners have been reported, including mycalolides from a marine sponge Mycale sp. The absolute stereochemistry of mycalolides was determined by chemical methods. Trisoxazole macrolides depolymerize F-actin and form a 1:1 complex with G-actin, thereby exhibiting potent toxicity toward eukaryotic cells. X-ray crystallography established the mode of binding of some of the members to G-actin and their absolute stereochemistry.