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
Threshold Pharmaceuticals, 1300 Seaport Boulevard, Suite 500, Redwood City, California 94063, USA.
J Med Chem. 2008 Apr 24;51(8):2412-20. doi: 10.1021/jm701028q. Epub 2008 Feb 8.
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.
基于前药异环磷酰胺的DNA交联毒素，合成了一系列非手性的缺氧激活前药。与先前报道的手性生物还原磷酰胺前药的外消旋混合物相比，几种化合物的缺氧选择性细胞毒性有所提高。通过2-硝基咪唑还原激活的前药在缺氧条件下对培养中的H460细胞的细胞毒性比其在有氧条件下的效力提高了400倍。使用肝微粒体试验进一步评估化合物对细胞色素P450代谢的稳定性。含2-硝基咪唑的先导化合物3b（TH-302）在缺氧条件下具有选择性强效，并且对肝微粒体稳定。它在体内MIA PaCa-2胰腺癌原位异种移植模型中作为单一疗法具有活性，并且与吉西他滨联合使用时显示出显著疗效，在第44天时有八分之一的动物肿瘤消失，延长了生存期。化合物3b已成为一种有前景的抗肿瘤药物，显示出优异的体内疗效，目前正在临床中进行评估。
