Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(-)-Zampanolide Analogs.

Abstract

We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (-)-zampanolide (ZMP). These analogs were derived from 13-desmethylene-(-)-zampanolide (DM-ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67%-95% yield) and a stereoselective aza-aldol reaction with an (S)-BINOL-derived sorbamide transfer complex, to establish the C(20) stereocenter (24%-71% yield). As the sole exception, for the 5-desmethyl macrocycle, ring-closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. Compared to DM-ZMP, all modifications led to reduced cellular activity and lowered microtubule-binding affinity, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC50's for cancer cell growth inhibition varied between 5 nM and 133 nM, compared to 1 nM to 12 nM for DM-ZMP. Reduction of the enone double bond led to a several hundred-fold loss in growth inhibition. The cellular potency of 2,3-dihydro-13-desmethylene zampanolide, as the most potent analog identified, remained within a 9-fold range of that of DM-ZMP.