Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs

• DOI: 10.1021/jm701028q
• Publication Date: 2008-02-08T06:00:31Z
• Authors: Jian-Xin Duan; Hailong Jiao; Jacob Kaizerman; Timothy Stanton; James W. Evans; Leslie Lan; Gustavo Lorente; Monica Banica; Don Jung; Jinwei Wang; Huaiyu Ma; Xiaoming Li; Zhijian Yang; Robert M. Hoffman; W. Steve Ammons; Charles P. Hart; Mark Matteucci
• Keywords: Phosphoramidate; Hypoxia

A series of achiral hypoxia-activated prodrugs were synthesized on the basis DNA cross-linking toxin prodrug, ifosfamide. The hypoxia-selective cytotoxicity several compounds was improved over previously reported racemic mixtures chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced toward H460 cells in culture under hypoxia versus their potency aerobic conditions. Compounds further assessed for stability cytochrome P450 metabolism using a liver microsome assay. containing lead compound 3b (TH-302) selectively potent and stable microsomes. It active an vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as monotherapy dramatic efficacy when used combination with gemcitabine, extending survival one eight animals tumor free at day-44. Compound has emerged promising antitumor agent that shows excellent is currently being evaluated clinic.