Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade, 11060, Belgrade, Serbia.
Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
Eur J Med Chem. 2020 Apr 1;191:112119. doi: 10.1016/j.ejmech.2020.112119. Epub 2020 Feb 6.
A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.
一系列早前报道的先导化合物 DVD-445（具有抗癌活性的硫氧还蛋白还原酶抑制剂）的类似物已通过改良的 Ugi 反应合成并进行了研究。七种最有效的化合物（对重组 rTrxR1 酶的 IC 低于 5.00 μM）被检测其对人神经胶质瘤细胞系 U87 及其相应的多药耐药（MDR）细胞系 U87-TxR 中细胞生长和活力、氧化应激诱导和 P 糖蛋白（P-gp）抑制的影响。其中一些先导化合物的表现优于 DVD-445。除了为癌症治疗提供有前途的候选药物外，我们的研究还进一步验证了小亲电 Ugi 迈克尔受体（UMA）化学型作为硫氧还蛋白还原酶有效抑制剂的作用。
