前药
硝基咪唑
化学
缺氧(环境)
吉西他滨
硝基还原酶
药品
药理学
胰腺癌
硝基
体外
硝基化合物
肿瘤缺氧
生物化学
癌症
生物
内科学
有机化学
医学
放射治疗
氧气
烷基
作者
Takashi Tsuji,Honoka Tsunematsu,Masaki Imanishi,Masaya Denda,Koichiro Tsuchiya,Akira Otaka
标识
DOI:10.1016/j.bmcl.2023.129484
摘要
Hypoxia in cancer is important in the development of cancer-selective medicines. Here, a novel hypoxia-responsible dual-prodrug is described. We designed and synthesized 2-nitroimidazole derivatives which spontaneously release both a PYG inhibitor and gemcitabine under hypoxic conditions. One such derivative, a prodrug 9 was found to be stable against chemical and enzymatic hydrolysis, and upon chemical reduction of the nitro group on imidazole, successfully releases both drugs. In an in vitro proliferation assay using human pancreatic cells, compound 9 exhibited significant anti-proliferative effects in hypoxia but fewer effects in normoxia. Consequently, prodrug 9 should be useful for cancer treatment due to its improved cancer selectivity and potential to overcome drug resistance.
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