Iyengar Bhashyam S, Dorr Robert T, Remers William A
Arizona Cancer Center and Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 2004 Jan 1;47(1):218-23. doi: 10.1021/jm030225v.
Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the epsilon-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.
对imexon及相关氰基氮丙啶的作用方式的化学方面进行了研究。尽管存在氮丙啶环，但这些化合物不会使DNA烷基化，也不会与L-赖氨酸的ε-氨基反应。它们很容易与具有生物学重要性的巯基化合物反应，生成的产物源自氮丙啶环的开环、与氰基氮丙啶的氰基相互作用或imexon的亚氨基吡咯烷酮环的开环。imexon及相关氰基氮丙啶与硫醇反应的产物对肿瘤细胞的效力不如其母体化合物。这些结果与生物学研究一致，生物学研究表明细胞毒性机制涉及巯基耗竭，随后是氧化应激导致细胞凋亡。
