Widdison Wayne C, Wilhelm Sharon D, Cavanagh Emily E, Whiteman Kathleen R, Leece Barbara A, Kovtun Yelena, Goldmacher Victor S, Xie Hongsheng, Steeves Rita M, Lutz Robert J, Zhao Robert, Wang Lintao, Blättler Walter A, Chari Ravi V J
ImmunoGen, Inc., 128 Sidney Street, Cambridge, Massachusetts 02139, USA.
J Med Chem. 2006 Jul 13;49(14):4392-408. doi: 10.1021/jm060319f.
Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.
美登素是一种具有高度细胞毒性的天然产物，由于其具有不可接受的全身毒性，在人类临床试验中作为抗癌药物失败。美登素强大的细胞杀伤能力可用于靶向递送方法，以选择性地破坏癌细胞。合成了一系列带有二硫键或硫醇取代基的新型美登素类化合物。改变了酯侧链的链长以及带有硫醇取代基的碳原子上的空间位阻程度。发现其中几种美登素类化合物在体外比美登素更具活性。使用单克隆抗体对这些美登素类化合物进行靶向递送，在体外导致靶向细胞的高效、特异性杀伤，并在体内具有显著的抗肿瘤活性。
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