Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Eur J Med Chem. 2017 Oct 20;139:242-249. doi: 10.1016/j.ejmech.2017.05.065. Epub 2017 Jun 1.
A series of 3,6-diaryl-1H-pyrazolo[5,1-c][1,2,4]triazoles (I) and 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (II) as antitubulin agents were designed, synthesized and bioevaluated. Compounds (II) 4a, 4d, 4f, 4j, 4l and 4n showed potent antiproliferative activity at sub-micromolar or nanomolar concentrations against SGC-7901, A549 and HT-1080 cell lines, indicating that the bioisosteric replacement of the carbonyl group and B-ring of SMART and ABI with a 5,5-fused-heterocycle scaffold successfully maintained potent antiproliferative activity. Compound 4f exhibited the most excellent antiproliferative activity against the three cancer cell lines (IC = 0.022-0.029 μM). Consistent with its potent antiproliferative activity, 4f also displayed excellent antitubulin activity (IC = 0.77 μM). Furthermore, compound 4f could dramatically affect cell morphology and microtubule networking, while cell cycle studies demonstrated that 4f significantly induced SGC-7901 cells arrest in G2/M phase. In addition, molecular docking studies supported the biological assay data and suggested that 4f may be a potential antitubulin agent.
设计、合成并评价了一系列作为抗微管蛋白试剂的 3,6-二芳基-1H-吡唑并[5,1-c][1,2,4]三唑（I）和 3,6-二芳基-[1,2,4]三唑并[3,4-b][1,3,4]噻二唑（II）。化合物（II）4a、4d、4f、4j、4l 和 4n 在亚微米或纳米浓度下对 SGC-7901、A549 和 HT-1080 细胞系表现出有效的抗增殖活性，表明 SMART 和 ABI 的羰基和 B 环与 5,5-稠合杂环支架的生物等排取代成功地保持了有效的抗增殖活性。化合物 4f 对三种癌细胞系表现出最优异的抗增殖活性（IC=0.022-0.029μM）。与它的强抗增殖活性一致，4f 还表现出优异的抗微管蛋白活性（IC=0.77μM）。此外，化合物 4f 可以显著影响细胞形态和微管网络，而细胞周期研究表明，4f 可显著诱导 SGC-7901 细胞停滞在 G2/M 期。此外，分子对接研究支持了生物测定数据，并表明 4f 可能是一种潜在的抗微管蛋白试剂。
