Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
Bioorg Chem. 2016 Dec;69:7-19. doi: 10.1016/j.bioorg.2016.09.002. Epub 2016 Sep 4.
A series of imidazopyridinyl-1,3,4-oxadiazole conjugates were synthesized and investigated for their cytotoxic activity and some compounds showed promising cytotoxic activity. Compound 8q (NSC: 763639) exhibited notable growth inhibition that satisfies threshold criteria at single dose (10μM) on all human cancer cell lines. This compound was further evaluated at five dose levels (0.01, 0.1, 1, 10 and 100μM) to obtain GI values ranging from 1.30 to 5.64μM. Flow cytometric analysis revealed that compound 8q arrests the A549 cells in sub G1 phase followed by induction of apoptosis which was further confirmed by Annexin-V-FITC, Hoechst nuclear staining, caspase 3 activation, measurement of mitochondrial membrane potential and ROS generation. Topo II mediated DNA relaxation assay results showed that conjugate 8q could significantly inhibit the activity of topo II. Moreover, molecular docking studies also indicated binding to the topoisomerase enzyme (PDBID 1ZXN).
一系列咪唑并[1,2-a]吡啶并[3,4-d]恶二唑类化合物被合成并研究其细胞毒性活性，一些化合物表现出有希望的细胞毒性活性。化合物 8q（NSC：763639）在所有人类癌细胞系中在单剂量（10μM）时显示出显著的生长抑制，满足阈值标准。该化合物在五个剂量水平（0.01、0.1、1、10 和 100μM）下进一步评估，以获得 GI 值范围为 1.30 至 5.64μM。流式细胞术分析显示，化合物 8q 将 A549 细胞阻滞在 sub G1 期，随后诱导细胞凋亡，这进一步通过 Annexin-V-FITC、Hoechst 核染色、caspase 3 激活、线粒体膜电位和 ROS 生成的测量得到证实。拓扑异构酶 II 介导的 DNA 松弛测定结果表明，缀合物 8q 可显著抑制拓扑异构酶 II 的活性。此外，分子对接研究还表明与拓扑异构酶酶（PDBID 1ZXN）结合。
