Arepalli Sateesh Kumar, Park Byeongwoo, Lee Kiho, Jo Hyunji, Jun Kyu-Yeon, Kwon Youngjoo, Kang Jong-Soon, Jung Jae-Kyung, Lee Heesoon
College of Pharmacy, Chungbuk National University, Chungbuk 28160, Republic of Korea.
College of Pharmacy, Korea University, Sejong 30019, Republic of Korea.
Bioorg Med Chem. 2017 Oct 15;25(20):5586-5597. doi: 10.1016/j.bmc.2017.08.030. Epub 2017 Aug 22.
A novel series of twenty 1,3-diphenylbenzo[f][1,7]benzonaphthyrdine derivatives were designed and synthesized through intermolecular imino Diels-Alder reaction. Their in vitro cytotoxic activities were evaluated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Majority of synthesized compounds exhibited significant cytotoxic activities against all tested human cancer cell lines. Among them 4l, 4m, and 4o derivatives exhibited most promising cytotoxic activities. Furthermore these compounds were evaluated against human Topoisomerase IIα inhibition. Interestingly, the compound 4l exhibited 1.3 and 1.2 times more potent human Topoisomerase IIα inhibition than the reference drug etoposide in both 100µM and 20µM concentrations respectively. Molecular docking studies for the compound 4l have also been executed by Sybyl X-2.1 in which it reveals the binding site of the compound 4l with topo IIα DNA cleavage site where etoposide was situated. The benzo[f][1,7]naphthyridine ring was stacked between the DNA bases of the cleavage site.
通过分子间亚氨基狄尔斯-阿尔德反应设计并合成了一系列新型的20种1,3-二苯基苯并[f][1,7]苯并萘啶衍生物。评估了它们对六种人类癌细胞系（NCIH23、HCT15、NUGC-3、ACHN、PC-3和MDA-MB-231）的体外细胞毒性活性。大多数合成化合物对所有测试的人类癌细胞系都表现出显著的细胞毒性活性。其中4l、4m和4o衍生物表现出最有前景的细胞毒性活性。此外，还评估了这些化合物对人拓扑异构酶IIα的抑制作用。有趣的是，化合物4l在100µM和20µM浓度下对人拓扑异构酶IIα的抑制作用分别比参考药物依托泊苷强1.3倍和1.2倍。还通过Sybyl X-2.1对化合物4l进行了分子对接研究，结果显示化合物4l与拓扑异构酶IIα DNA切割位点（依托泊苷所在位置）的结合位点。苯并[f][1,7]萘啶环堆积在切割位点的DNA碱基之间。
