Arico-Muendel Christopher C, Blanchette Heather, Benjamin Dennis R, Caiazzo Teresa M, Centrella Paolo A, DeLorey Jennifer, Doyle Elisabeth G, Johnson Steven R, Labenski Matthew T, Morgan Barry A, O'Donovan Gary, Sarjeant Amy A, Skinner Steven, Thompson Charles D, Griffin Sarah T, Westlin William, White Kerry F
Praecis Pharmaceuticals, Inc. , 830 Winter Street, Waltham, Massachusetts 02451-1420, United States, and Department of Chemistry, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208, United States.
ACS Med Chem Lett. 2013 Feb 22;4(4):381-6. doi: 10.1021/ml3003633. eCollection 2013 Apr 11.
Semisynthetic analogues of fumagillin, 1, inhibit methionine aminopeptidase-2 (MetAP2) and have entered the clinic for the treatment of cancer. An optimized fumagillin analogue, 3 (PPI-2458), was found to be orally active, despite containing a spiroepoxide function that formed a covalent linkage to the target protein. In aqueous acid, 3 underwent ring-opening addition of water and HCl, leading to four products, 4-7, which were characterized in detail. The chlorohydrin, but not the diol, products inhibited MetAP2 under weakly basic conditions, suggesting reversion to epoxide as a step in the mechanism. In agreement, chlorohydrin 6 was shown to revert rapidly to 3 in rat plasma. In an ex vivo assay, rats treated with purified acid degradants demonstrated inhibition of MetAP2 that correlated with the biochemical activity of the compounds. Taken together, the results indicate that degradation of the parent compound was compensated by the formation of active equivalents leading to a pharmacologically useful level of MetAP2 inhibition.
烟曲霉素的半合成类似物1可抑制甲硫氨酸氨基肽酶-2（MetAP2），并且已进入临床用于癌症治疗。尽管优化后的烟曲霉素类似物3（PPI-2458）含有一个与靶蛋白形成共价连接的螺环氧化物官能团，但它具有口服活性。在酸性水溶液中，3发生水和HCl的开环加成反应，生成四种产物4 - 7，并对其进行了详细表征。氯醇产物而非二醇产物在弱碱性条件下抑制MetAP2，这表明环氧化物的还原是作用机制中的一个步骤。与此一致的是，氯醇6在大鼠血浆中显示能迅速还原为3。在一项体外试验中，用纯化的酸降解产物处理的大鼠表现出MetAP2的抑制作用，且这种抑制作用与化合物的生化活性相关。综合来看，结果表明母体化合物的降解通过活性等效物的形成得到补偿，从而导致MetAP2抑制达到药理学上有用的水平。
