Synthesis and biological activities of the tris-oxazole macrolactone analogs of mycalolides

Abstract

Mycalolides are tris-oxazole macrolides isolated from the marine sponge Mycale sp., which shows cytotoxic, antifungal, and actin-depolymerizing activities. To develop an efficient synthetic route of mycalolides and to evaluate its functional mechanism of biological activities, tris-oxazole macrolactone analogs of mycalolides were synthesized through the use of ring-closing metathesis (RCM). The presence/absence of protecting groups at C3, solvent polarity, and reaction temperature significantly affected the stereoselectivity of RCM (E/Z=2.5/1.0-1.0/2.5). The 19E- and 19Z-stereoisomers both exhibited moderate cytotoxicity against tumor cells, but neither showed significant actin-depolymerizing properties or antimycotic activity against pathogenic fungi. Thus, both the side-chain (actin-binding) moiety and the macrolactone moiety were suggested to be essential for the potent biological activities of the parent molecules. © 2012 Elsevier Ltd. All rights reserved.