抄録
Pyripyropene A (PPPA, 1), isolated from the culture broth of Aspergillus fumigatus FO-1289, was found to strongly and selectively inhibit the isozyme of acyl-CoA:cholesterol acyltransferase 2 (ACAT2; IC_<50> >80 1.1M for ACAT1 vs. 70 nM for ACAT2). Moreover, 1 is orally active in mouse models of atherosclerosis. To assist the development of new cholesterol-lowering or anti-atherosclerotic agents, we investigated the structure-activity relationship of 1. Benzoyl and benzoyl 1,11-benzylidene acetal derivatives with different substituents at the 7-position were synthesized from natural 1 in two-to-three steps. Some of the derivatives strongly inhibited ACAT2 with picomolar IC50 values and exhibited higher isozyme selectivity than 1. We achieved a stereocontrolled total synthesis of pyripyropene A (1). Key features of the synthetic strategy included an intramolecular Ti(III)-mediated radical cyclization for construction of the A-ring, stereoselective 13-epoxide formation/Peterson olefmation for preparation of the functional groups on the B-ring, and stereoselective intramolecular cyclization for C-ring formation. The total synthesis provided 1 in 5.3 % overall yield in 17 steps. Extension of this chemistry to the synthesis of structural analogs of 1 for evaluation of the structure-activity relationship is currently under way and will be reported in due course.
