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Article

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

Supporting Info

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^† and Mark Matteucci*^†

Threshold Pharmaceuticals, 1300 Seaport Boulevard, Suite 500, Redwood City, California 94063, and AntiCancer, Inc., 7917 Ostrow Street, San Diego, California 92111

J. Med. Chem., 2008, 51 (8), pp 2412–2420

DOI: 10.1021/jm701028q

Publication Date (Web): February 8, 2008

* To whom correspondence should be addressed. Telephone: 650-474-8231 . Fax: 650-474-0408. E-mail: jduan@thresholdpharm.com (J.-X.D.); Telephone: 650-474-8225 . Fax: 650-474-0408. E-mail: mmatteucci@thresholdpharm.com (M.M)., †

Threshold Pharmaceuticals.

, ‡

AntiCancer, Inc.

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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