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

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Duan JX, Jiao H, Kaizerman J, Stanton T, Evans JW, Lan L, Lorente G, Banica M, Jung D, Wang J, Ma H, Li X, Yang Z, Hoffman RM, Ammons WS, Hart CP, Matteucci M

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

J Med Chem. 2008 Apr 24;51(8):2412-20. doi: 10.1021/jm701028q. Epub 2008 Feb 8.

PubMed ID
18257544 [ View in PubMed
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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 hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.

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