前药
谷胱甘肽
化学
机制(生物学)
毒性
药理学
生物化学
计算生物学
酶
生物
医学
有机化学
认识论
哲学
作者
Xinyu Zhang,Adnan A. Elfarra
标识
DOI:10.1080/17460441.2018.1508207
摘要
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target selectivity should improve drug safety. Areas covered: The authors examined the hypothesis that new prodrug designs based upon mechanisms of kidney-selective toxicity of trichloroethylene would reduce systemic toxicity and improve selectivity to kidney and tumor cells. Two approaches specifically were investigated. The first approach was based upon bioactivation of trichloroethylene-cysteine S-conjugate by renal cysteine S-conjugate β-lyases. The prodrugs obtained were kidney-selective but exhibited low turnover rates. The second approach was based on the toxic mechanism of trichloroethylene-cysteine S-conjugate sulfoxide, a Michael acceptor that undergoes rapid addition-elimination reactions with biological thiols. Expert opinion: Glutathione-dependent Michael addition-elimination reactions appear to be an excellent strategy to design highly efficient anticancer drugs. Targeting glutathione could be a promising approach for the development of anticancer prodrugs because cancer cells usually upregulate glutathione biosynthesis and/or glutathione S-transferases expression.
科研通智能强力驱动
Strongly Powered by AbleSci AI