Journal of medicinal chemistry · 2006
Semisynthetic maytansine analogues for the targeted treatment of cancer.
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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
Аннотация
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.