Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Nahda University, Beni-suef, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka, 2014, Saudi Arabia.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka, 2014, Saudi Arabia.
Eur J Med Chem. 2018 Aug 5;156:774-789. doi: 10.1016/j.ejmech.2018.07.024. Epub 2018 Jul 10.
A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for their antiproliferative activities against NCI 60 cell line. Compounds 10 (a, c), 11 (a-d), and 14 (a-e) were selected for evaluation at single concentration of 10 μM towards panel of sixty cancer cell lines. Some of nitric oxide (NO) donating triazole/oxime hybrids 11a-d showed antiproliferative activity better than their corresponding ketones. On the other hand, the thiazolo [3,2-b][1,2,4]-triazoles 14a-e showed remarkable antiproliferative activities against the same cell lines. Compound 14d was selected for five dose testing against the full panel of 60 human tumor cell lines. Compound 14d showed high selectivity against renal subpanel with selectivity ratio of 6.99 at GI level. Compounds 11a-d, 10a-d and 14a-e were tested against four cell lines using MTT assay then compounds of the least IC were evaluated against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compound 14d showed promising EGFR inhibitory activity of cancer cell proliferation and were also observed to be moderate BRAF and tubulin inhibitors. Moreover, cell cycle analysis and apoptosis assay were finished for compounds 14d and 14f. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.
一系列带有 1,2,4-三唑骨架的新型化合物被制备出来，并评估了它们对 NCI 60 细胞系的抗增殖活性。化合物 10（a，c）、11（a-d）和 14（a-e）被选择在 10 μM 的单一浓度下针对 60 种癌细胞系进行评估。一些含有一氧化氮（NO）的三唑/肟类混合物 11a-d 比它们相应的酮类表现出更好的抗增殖活性。另一方面，噻唑并[3,2-b][1,2,4]-三唑 14a-e 对相同的细胞系表现出显著的抗增殖活性。化合物 14d 被选择进行五个剂量测试，以评估整个 60 个人类肿瘤细胞系面板。化合物 14d 对肾亚系表现出高选择性，GI 水平的选择性比值为 6.99。化合物 11a-d、10a-d 和 14a-e 使用 MTT 测定法针对四种细胞系进行了测试，然后对最少 IC 的化合物针对三种已知的抗癌靶点（包括 EGFR、BRAF 和微管蛋白）进行了评估。结果表明，化合物 14d 对 EGFR 表现出有希望的抑制活性，能够抑制癌细胞的增殖，并且对 BRAF 和微管蛋白也具有中度抑制作用。此外，还对化合物 14d 和 14f 进行了细胞周期分析和凋亡测定。最后进行了分子建模研究，以探索最活性化合物与靶酶的结合模式。
