Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents,Journal of Enzyme inhibition and Medicinal Chemistry

当前位置： X-MOL 学术 › J. Enzyme Inhib. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents
Journal of Enzyme inhibition and Medicinal Chemistry ( IF 5.6 ) Pub Date : 2021-06-21 , DOI: 10.1080/14756366.2021.1937618
Ahmed M Shawky _{1,

2} , Nashwa A Ibrahim _{3,

4} , Ashraf N Abdalla _{5,

6} , Mohammed A S Abourehab _{7,

8} , Ahmed M Gouda _{3,

4}

Affiliation

Abstract

In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a–e showed higher cytotoxicity than their corresponding Schiff bases 15a–e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC₅₀ in the range of 0.52–6.26 μM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC₅₀=0.155–17.08 μM). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG₁ and G₂/M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents.

Highlights
Two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized.
Compounds 16a,b,d displayed the highest cytotoxicity against the three cancer cell lines.
Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds 16a,b,d.
Compounds 16a,b,d exhibited weak to moderate inhibition of tubulin-polymerization.
Compounds 16a,b,d induced preG₁ and G₂/M cell cycle arrest and early apoptosis in MCF-7 cells.
Docking studies revealed high binding affinities for compounds 16a,b towards tubulin and CDK-2.

中文翻译：

带有 3,4,5-三甲氧基苯基部分的新型吡咯嗪：作为潜在多靶点细胞毒性剂的设计、合成、分子对接和生物学评估

摘要

在本研究中，设计、合成了两个新系列的带有 3,4,5-三甲氧基苯基部分的吡咯嗪，并评估了它们的细胞毒活性。苯甲酰胺衍生物16a-e显示出比其相应的希夫碱15a-e更高的细胞毒性。化合物16a、b、d也抑制 MCF-7/ADR 细胞的生长，IC ₅₀范围为 0.52–6.26 μM。有趣的是，新化合物对正常 MRC-5 细胞的细胞毒性较小（IC ₅₀ = 0.155–17.08 μM）。机理研究揭示了化合物16a , b , d的能力抑制微管蛋白聚合和多种致癌激酶。此外，化合物16a、b、d在MCF-7细胞中诱导preG ₁和G ₂ /M细胞周期停滞和早期凋亡。与共结晶配体相比，化合物16a、b、d进入微管蛋白、CDK-2 和 EGFR 蛋白中的活性位点的分子对接分析显示出更高的结合亲和力。这些初步结果表明，化合物16a、b、d可以作为有前景的先导化合物，用于未来开发新的强效抗癌剂。