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

被引：194

作者：

Duan, Jian-Xin ^{[1
]}

Jiao, Hailong ^{[1
]}

Kaizerman, Jacob ^{[1
]}

Stanton, Timothy ^{[1
]}

Evans, James W. ^{[1
]}

Lan, Leslie ^{[1
]}

Lorente, Gustavo ^{[1
]}

Banica, Monica ^{[1
]}

Jung, Don ^{[1
]}

Wang, Jinwei ^{[2
]}

Ma, Huaiyu ^{[2
]}

Li, Xiaoming ^{[2
]}

Yang, Zhijian ^{[2
]}

Hoffman, Robert M. ^{[2
]}

Ammons, W. Steve ^{[1
]}

Hart, Charles P. ^{[1
]}

Matteucci, Mark ^{[1
]}

机构：

[1] Threshold Pharmaceut, Redwood City, CA 94063 USA

[2] AntiCanc Inc, San Diego, CA 92111 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 08期

关键词：

D O I：

10.1021/jm701028q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 phosphorami date 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.

引用

页码：2412 / 2420

页数：9

共 46 条

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