Structure-activity relationships within a family of selectively cytotoxic macrolide natural products

[GRAPHICS] We describe a semi-synthetic deglycosylated derivative of apoptolidin that retains considerable activity against the mitochondrial ATPase but has grea tly reduced cellular cytotoxicity. We also demonstrate that a related antif ungal natural product, cytovaricin, inhibits the same molecular target. Str uctural comparison of these macrolides provides insights into their conserv ed features that are presumably important for biological activity and ident ifies promising avenues at the interface of organic synthesis and biosynthe sis for the generation of new selective cytotoxic agents.