State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University , Lanzhou 730000, China.
J Med Chem. 2015 Feb 26;58(4):1795-805. doi: 10.1021/jm5016507. Epub 2015 Feb 6.
The selenoprotein thioredoxin reductases (TrxRs) are attractive targets for anticancer drugs development. Xanthohumol (Xn), a naturally occurring polyphenol chalcone from hops, has received increasing attention because of its multiple pharmacological activities. We synthesized Xn and its 43 analogues and discovered that compound 13n displayed the highest cytotoxicity toward HeLa cells (IC50 = 1.4 μM). Structure-activity relationship study indicates that the prenyl group is not necessary for cytotoxicity, and introducing electron-withdrawing group, especially on the meta-position, is favored. In addition, methylation of the phenoxyl groups generally improves the potency. Mechanistic study revealed that 13n selectively inhibits TrxR and induces reactive oxygen species and apoptosis in HeLa cells. Cells overexpressing TrxR are resistant to 13n insult, while knockdown of TrxR sensitizes cells to 13n treatment, highlighting the physiological significance of targeting TrxR by 13n. The clarification of the structural determinants for the potency would guide the design of novel potent molecules for future development.
硒蛋白硫氧还蛋白还原酶（TrxR）是抗癌药物开发的有吸引力的靶点。黄腐酚（Xn）是一种天然存在的来自啤酒花的多酚查尔酮，由于其多种药理学活性而受到越来越多的关注。我们合成了 Xn 及其 43 种类似物，并发现化合物 13n 对 HeLa 细胞显示出最高的细胞毒性（IC50=1.4μM）。构效关系研究表明，对于细胞毒性而言， prenyl 基团不是必需的，并且引入吸电子基团，特别是在间位，是有利的。此外，苯氧基团的甲基化通常会提高活性。机制研究表明，13n 选择性抑制 TrxR 并在 HeLa 细胞中诱导活性氧和细胞凋亡。过表达 TrxR 的细胞对 13n 损伤具有抗性，而 TrxR 的敲低使细胞对 13n 处理敏感，突出了 13n 通过靶向 TrxR 的生理意义。对效力的结构决定因素的阐明将指导用于未来开发的新型有效分子的设计。
