一些新合成的三取代咪唑啉酮作为 VEGFR-2 抑制剂的启示

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-05-29 DOI:10.1021/acsmedchemlett.4c00095

Manar R. Mohamed, Walaa R. Mahmoud*, Rana H. Refaey*, Riham F. George and Hanan H. Georgey,

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引用次数: 0

摘要

研究人员合成了两个系列的十个新的 1,2,4-三取代咪唑啉-5-酮，并针对 MCF-7 乳腺癌细胞系和 A549 肺癌细胞系进行了筛选，以测试其潜在的体外抗癌活性。结果表明，与 A549 细胞株相比，受试化合物对 MCF-7 细胞株具有优先活性。最有希望的十种化合物（3a、3c、3f、3g、3h、3i、3j、6a、6f 和 6i）接受了 VEGFR-2 酶抑制活性测试，以进一步探索其作用机制。与索拉非尼（Sorafenib）和舒尼替尼（Sunitinib）的 IC50 值分别为 0.06 和 0.12 μM 相比，所测试的化合物在 0.07 至 0.36 μM 的微摩尔浓度范围内表现出明显的酶抑制作用。研究人员进一步评估了最有希望的候选药物 3j 的细胞周期阶段、凋亡诱导能力、抗增殖活性以及抑制内皮细胞迁移的潜力，并通过细胞划痕试验进行了分析。此外，研究人员还进行了硅学研究，以确定和检测结合位点的稳定性。

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Insight on Some Newly Synthesized Trisubstituted Imidazolinones as VEGFR-2 Inhibitors

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (3a, 3c, 3f, 3g, 3h, 3i, 3j, 6a, 6f, and 6i) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 μM, compared with Sorafenib and Sunitinib with IC₅₀ values of 0.06 and 0.12 μM, respectively. The most promising candidate, 3j, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.