Dragovich Peter S, Broccatelli Fabio, Chen Jinhua, Fan Peter, Le Hoa, Mao Weiguang, Pillow Thomas H, Polson Andrew G, Wai John, Xu Zijin, Yao Hui, Zhang Donglu
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2017 Dec 1;27(23):5300-5304. doi: 10.1016/j.bmcl.2017.10.023. Epub 2017 Oct 13.
The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1H-imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions.
评估了各种含吡咯并苯二氮卓（PBD）的细胞毒性化合物作为缺氧激活前药的功能。这些分子以掩盖细胞毒性活性所需的反应性亚胺部分的方式，掺入了1-甲基-2-硝基-1H-咪唑缺氧激活触发基团（存在于临床评估的化合物TH-302中）。在常氧和缺氧条件下，将前药与细胞色素P450还原酶一起孵育，结果显示，其中一些（但不是全部）是该酶的有效底物。在这些实验中，源自PBD单体的前药在低氧条件下迅速转化为母体细胞毒性化合物，而相关的PBD二聚体则不会。给定前药作为有效细胞色素P450还原酶底物的功能能力，与在常氧和缺氧条件下该化合物对NCI460细胞的细胞毒性效力之比相关。
