Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China.
Yantai Valiant Pharmaceutical Co., Ltd., 60 Taiyuan Road, Dajijia Industrial Park, YEDA Yantai, 264006, PR China.
Eur J Med Chem. 2018 Oct 5;158:493-501. doi: 10.1016/j.ejmech.2018.09.047. Epub 2018 Sep 18.
To explore antitumor agents with potent efficacy and low toxicity, scutellarein derivatives with benzoic acid mustard (10a-c, 11a-c and 13a-c) were designed and synthesized. The antiproliferative activities of the target derivatives against A549, MCF-7 and Bel-7402 cancer cell lines were tested. Compound 10a showed the strongest potency with an IC value of 1.50 μM against MCF-7 cell line, and displayed low toxicity against human liver L-O2 normal cells (IC > 50 μM), showing specificity between normal and malignant cells. The mechanism studies revealed that 10a could induce apoptosis in MCF-7 cells, arrest MCF-7 cell cycle at the G1 phase and cause mitochondrial dysfunction in a concentration-dependant manner. Furthermore, the enhanced expression of the pro-apoptotic proteins caspase-9, caspase-3, Bax and cytochrome c, and the reduced expression of the anti-apoptotic protein Bcl-2 confirmed that 10a induced the intrinsic apoptosis pathway in MCF-7 cells. The potent antiproliferative activity and good selectivity guaranteed 10a a lead compound for the further development into anticancer therapeutics, especially for breast cancer.
为了探索高效低毒的抗肿瘤药物，设计并合成了带有苯甲酸芥（10a-c、11a-c 和 13a-c）的白杨素衍生物。测试了目标衍生物对 A549、MCF-7 和 Bel-7402 癌细胞系的增殖活性。化合物 10a 对 MCF-7 细胞系的抑制活性最强，IC 值为 1.50 μM，对人正常肝细胞 L-O2 的毒性较低（IC > 50 μM），表现出正常细胞与恶性细胞之间的特异性。机制研究表明，10a 能够诱导 MCF-7 细胞凋亡，将 MCF-7 细胞周期阻滞在 G1 期，并以浓度依赖的方式引起线粒体功能障碍。此外，促凋亡蛋白 caspase-9、caspase-3、Bax 和细胞色素 c 的表达增强，以及抗凋亡蛋白 Bcl-2 的表达减少，证实 10a 诱导了 MCF-7 细胞的内在凋亡途径。强大的增殖抑制活性和良好的选择性保证了 10a 成为进一步开发抗癌治疗药物的先导化合物，特别是针对乳腺癌。
