Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Eur J Med Chem. 2017 Jul 28;135:270-281. doi: 10.1016/j.ejmech.2017.03.020. Epub 2017 Apr 21.
To explore novel antitumor agents with high efficiency and low toxicity, a series of NO-donating scutellarin derivatives (14-17) were synthesized and the antiproliferative activities against MCF-7, HCT-116, PC-3 and HepG2 cancer cell lines were assessed. Among them, compound 14b was the strongest with IC values of 2.96 μM, 7.25 μM, 0.09 μM and 0.50 μM, respectively, and displayed low toxicity against normal human liver L-O2 cells with an IC of 47.96 μM, showing good selectivity between normal and malignant liver cells. Moreover, NO releasing ability of the derivatives has been studied. Mechanism studies of the most promising compounds 14b and 15a were carried out. The results indicated that 14b and 15a could induce apoptosis, cell cycle arrest at the S phase and led to mitochondrial dysfunction in the HepG2 and PC-3 cell lines, respectively. Furthermore, Human Apoptosis Protein Array kit assay demonstrated that 14b could induce apoptosis through down-regulating the levels of procaspase-3 and inhibiting the expression of survivin, c-IAP1, HSP27, HSP60, HSP70, HO-1/HMOX1/HSP32 and HO-2/HMOX2 in HepG2 cell line. These results guaranteed compound 14b to be a drug candidate against liver cancer for further investigation.
为了探索高效低毒的新型抗肿瘤药物，我们合成了一系列具有 NO 供体的黄芩素衍生物（14-17），并评估了它们对 MCF-7、HCT-116、PC-3 和 HepG2 癌细胞系的增殖抑制活性。其中，化合物 14b 活性最强，对 MCF-7、HCT-116、PC-3 和 HepG2 的 IC 值分别为 2.96 μM、7.25 μM、0.09 μM 和 0.50 μM，对正常人类肝细胞 L-O2 的 IC 值为 47.96 μM，显示出对正常和恶性肝细胞的良好选择性。此外，还研究了衍生物的 NO 释放能力。对最有前途的化合物 14b 和 15a 进行了机制研究。结果表明，14b 和 15a 可以诱导 HepG2 和 PC-3 细胞系中的细胞凋亡、细胞周期停滞在 S 期，并导致线粒体功能障碍。此外，人细胞凋亡蛋白阵列试剂盒检测表明，14b 可以通过下调 caspase-3 的水平和抑制 survivin、c-IAP1、HSP27、HSP60、HSP70、HO-1/HMOX1/HSP32 和 HO-2/HMOX2 的表达来诱导 HepG2 细胞系中的细胞凋亡。这些结果保证了化合物 14b 是进一步研究肝癌的候选药物。
