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设计、合成、体外生物学评估及新型 3-(萘-1-基)-4,5-二氢吡唑类化合物作为具有潜在 EGFR 抑制活性的抗癌剂的分子建模研究。

Design, synthesis, in vitro biological assessment and molecular modeling insights for novel 3-(naphthalen-1-yl)-4,5-dihydropyrazoles as anticancer agents with potential EGFR inhibitory activity.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt.

School of Biotechnology, Badr University in Cairo, Badr City, Cairo, 11829, Egypt.

出版信息

Sci Rep. 2022 Jul 27;12(1):12821. doi: 10.1038/s41598-022-15050-8.

DOI:10.1038/s41598-022-15050-8
PMID:35896557
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9329325/
Abstract

Currently, the humanity is in a fierce battle against various health-related challenges especially those associated with human malignancies. This created the urge to develop potent and selective inhibitors for tumor cells through targeting specific oncogenic proteins possessing crucial roles in cancer progression and survive. In this respect, new series of pyrazole-thiazol-4-one hybrids (9a-p) were synthesized as potential anticancer agents. All the synthesized molecules exhibited potent antiproliferative actions against breast cancer (BC) T-47D and MDA-MB-231 cell lines with IC ranges 3.14-4.92 and 0.62-58.01, respectively. Moreover, the most potent anti-proliferative counterparts 9g and 9k were assessed against EGFR. They displayed nanomolar inhibitory activity, IC 267 ± 12 and 395 ± 17 nM, respectively. Worth noting, both compounds 9g and 9k induced apoptosis in MDA-MB-231 cells, and resulted in a cell cycle arrest at G2/M phase. Furthermore, an in silico analysis including docking and molecular dynamic simulations was performed.

摘要

目前，人类正在与各种与健康相关的挑战，特别是与人类恶性肿瘤相关的挑战进行激烈的斗争。这促使人们通过靶向在癌症进展和存活中具有关键作用的特定致癌蛋白，开发出有效的、选择性的肿瘤细胞抑制剂。在这方面，我们合成了一系列新的吡唑-噻唑-4-酮杂合体（9a-p）作为潜在的抗癌剂。所有合成的分子都表现出对乳腺癌（BC）T-47D 和 MDA-MB-231 细胞系的强大增殖抑制作用，IC 范围分别为 3.14-4.92 和 0.62-58.01。此外，对增殖作用最强的类似物 9g 和 9k 进行了针对 EGFR 的评估。它们显示出纳摩尔的抑制活性，IC 267 ± 12 和 395 ± 17 nM，分别。值得注意的是，两种化合物 9g 和 9k 都能诱导 MDA-MB-231 细胞凋亡，并导致细胞周期在 G2/M 期停滞。此外，还进行了包括对接和分子动力学模拟在内的计算机分析。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d82/9329325/5667475d0855/41598_2022_15050_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d82/9329325/791c01b2cc9d/41598_2022_15050_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d82/9329325/01940a6ed24a/41598_2022_15050_Fig2_HTML.jpg
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