Department of Chemistry, Tsinghua University, Beijing 100084, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, PR China; Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, PR China.
Bioorg Med Chem. 2018 Aug 7;26(14):3958-3966. doi: 10.1016/j.bmc.2018.06.016. Epub 2018 Jun 20.
Multitarget inhibitors design has generated great interest in cancer treatment. Based on the synergistic effects of topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC = 0.90 μM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50 μM. Moreover, compound 8c could interact with DNA and induce U937 apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory anticancer agent.
多靶点抑制剂的设计在癌症治疗中引起了极大的兴趣。基于拓扑异构酶和组蛋白去乙酰化酶抑制剂的协同作用，我们设计并合成了一系列新型吖啶羟肟酸衍生物作为潜在的新型双重拓扑异构酶和组蛋白去乙酰化酶抑制剂。MTT 法实验表明，所有杂交化合物均表现出良好的抗增殖活性，IC 值在低微摩尔范围内，其中化合物 8c 对 U937 的活性最强（IC = 0.90 μM）。此外，化合物 8c 还表现出最佳的组蛋白去乙酰化酶抑制活性，比组蛋白去乙酰化酶抑制剂 SAHA 强几倍。随后的研究表明，所有化合物在 50 μM 时均表现出拓扑异构酶 II 抑制活性。此外，化合物 8c 可以与 DNA 相互作用并诱导 U937 细胞凋亡。本研究为进一步探索双重拓扑异构酶和组蛋白去乙酰化酶抑制剂提供了一系列化合物，化合物 8c 可能成为一种新型的双重拓扑异构酶和组蛋白去乙酰化酶抑制抗癌药物。
