ヒストン脱アセチル化酵素阻害物質スピルコスタチンAの合成研究

Spiruchostatin A (1), isolated from a culture broth of Pseudomonas sp., has been shown to be a potent histone deacetylase (HDAC) inhibitor. HDAC inhibitors can suppress the growth of human tumor xenografts, this natural product, therefore, is expected to be a promising candidate for novel molecular-targeted anticancer agents. We envisioned that 1 would be synthesized through twofold macrolactam/macrolactone cyclization of the fully elaborated acyclic disulfide 2. The key segments 3 and 4, required for the preparation of the advanced key intermediate 2, were initially synthesized, and the two segments were subsequently subjected to the critical cross S-S coupling reaction to produce the desired key intermediate 11 (synthetically equivalent to 2). Upon deprotection of the N-Boc and the methyl ester groups in 11, the crucial cyclization formation was achieved using PyBOP to provide the desired macrolactam 16, a potential key precursor for 1. Further investigations concerning the transformation of 16 to the target molecule 1 were also described