School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Eur J Med Chem. 2012 Oct;56:10-6. doi: 10.1016/j.ejmech.2012.08.003. Epub 2012 Aug 10.
In order to discuss the structure-activity relationship (SAR) of the thio-benzodiazepine compounds which showed excellent activity against p53-MDM2 protein-protein interaction, we designed and synthesized twenty compounds with electrophilic and nucleophilic groups on the benzene ring. Among them, compounds 8i (K(i) = 91 nM) and 8n (K(i) = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (K(i) = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, compounds 8i and 8n possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation.
为了探讨对 p53-MDM2 蛋白-蛋白相互作用具有优异活性的硫苯并二氮杂䓬化合物的构效关系 (SAR)，我们设计并合成了二十种在苯环上具有亲电和亲核基团的化合物。其中，化合物 8i（K(i) = 91 nM）和 8n（K(i) = 89 nM）与参比药物 Nutlin-3a（K(i) = 121 nM）相比表现出更好的结合活性。此外，通过 MTT 法测定了对 Saos-2、U-2 OS、A549 和 NCI-H1299 细胞系的体外抗肿瘤活性。特别是化合物 8i 和 8n 具有与 Nutlin-3a 相当的优异的生物活性和良好的选择性，是进一步评价的有希望的候选药物。
