Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mohamed A Mahmoud, Anber F Mohammed, Ola I A Salem, Tahani Mazyad Almutairi, Stefan Bräse, Bahaa G M Youssif
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引用次数: 0

Abstract

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.

新型 1,2,3-三唑/1,2,4-恶二唑混合物作为表皮生长因子受体/表皮生长因子受体-2 双重抑制剂的设计、合成和凋亡抗增殖作用。
作为表皮生长因子受体(EGFR)/表皮生长因子受体(VEGFR)-2 的双重抑制剂,我们开发了一系列新型 1,2,3-三唑/1,2,4-噁二唑混合物(7a-o)。以厄洛替尼为参照药物,对 7a-o 化合物进行了抗增殖剂评估。结果表明,与厄洛替尼(GI50 = 33 nM)相比,大多数受试化合物显示出显著的抗增殖作用,GI50 值在 28 至 104 nM 之间,其中化合物 7i-m 的效力最强。化合物 7h、7i、7j、7k 和 7l 被评估为表皮生长因子受体/表皮生长因子受体-2 双重抑制剂。这些体外实验表明,化合物 7j、7k 和 7l 是强效的抗增殖剂,可作为表皮生长因子受体/表皮生长因子受体-2 的双重抑制剂。对化合物 7j、7k 和 7l 的凋亡潜在活性进行了评估,结果表明,化合物 7j、7k 和 7l 通过激活 caspase-3、8 和 Bax 以及下调抗凋亡的 Bcl-2 来促进细胞凋亡。分子对接模拟显示了最具活性的抗增殖化合物与表皮生长因子受体和血管内皮生长因子受体-2活性位点的结合模式。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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