STUDIES ON MACROCYCLIC LACTONE ANTIBIOTICS

XIII. ANTI-TUBULIN ACTIVITY AND CYTOTOXICITY OF RHIZOXIN DERIVATIVES: SYNTHESIS OF A PHOTOAFFINITY DERIVATIVE

Abstract

Chemical modification of the side chain in rhizoxin, a potent antimitotic agent, was attempted in order to study structure-activity relationships and also to devise a probe for photoaffinity labeling of tubulin. An OsO₄/NaIO₄ oxidation gave a nor-rhizoxin 20-al (5) which was converted to 20-ol (6) by a NaBH₃CN reduction. Starting from these two compounds as key intermediates, a series of Wittig reaction products 7-12, and of 20-O-acylates 13-21 were prepared and their anti-tubulin activity and cytotoxicity were determined. An aryl azide derivative 23 was synthesized as a photoaffinity analogue.