Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs

…, J Kaizerman, T Stanton, JW Evans, L Lan…

Index: Duan, Jian-Xin; Jiao, Hailong; Kaizerman, Jacob; Stanton, Timothy; Evans, James W.; Lan, Leslie; Lorente, Gustavo; Banica, Monica; Jung, Don; Wang, Jinwei; Ma, Huaiyu; Li, Xiaoming; Yang, Zhijian; Hoffman, Robert M.; Ammons, W. Steve; Hart, Charles P.; Matteucci, Mark Journal of Medicinal Chemistry, 2008 , vol. 51, # 8 p. 2412 - 2420

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Citation Number: 137

Abstract

A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under ...