作为 VEGFR-2 抑制剂的新型 2-oxo-2-phenylethoxy 和苄氧基二芳基脲杂化物：设计、合成和抗癌评估,Archiv der Pharmazie

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作为 VEGFR-2 抑制剂的新型 2-oxo-2-phenylethoxy 和苄氧基二芳基脲杂化物：设计、合成和抗癌评估
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2022-11-18 , DOI: 10.1002/ardp.202200341
Iman A Y Ghannam ₁ , Ahmed M El Kerdawy _{2,

3} , Marwa M Mounier ₄ , Mahmoud T Abo-Elfadl _{5,

6} , Islam H Ali ₁

Affiliation

合成了两个系列的二芳基脲衍生物，6a-k和7a-n。所有新合成的化合物都通过 SRB 测定法针对 NCI（美国）癌细胞系进行了测试。对氯间三氟甲基苯基衍生物6e–g和7e–g显示出最强的细胞毒活性，GI ₅₀值范围为 1.2–15.9 µM 。此外，7g对氟苄氧基二芳基脲衍生物在 MTT 测定中显示出对八种癌细胞系最有效的细胞毒性，IC ₅₀值低于 5 µM。化合物6a–k和7a–n测试了它们的血管内皮生长因子受体 2 (VEGFR-2) 激酶抑制活性。发现对氯间三氟甲基二芳基脲苄氧基衍生物7e –i和对甲氧基二芳基脲苄氧基衍生物7k、7l和7n是苄氧基系列7中作为 VEGFR-2 抑制剂最具活性的化合物，具有IC ₅₀范围为 0.09–4.15 µM。在 2-oxo-2-phenylethoxy 系列6中，化合物6e–g和6i的 IC ₅₀值分别为 0.94、0.54、2.71 和 4.81 µM。此外，化合物7e和7g诱导细胞凋亡，导致细胞周期停滞在G2/M期。此外，7g在 A-375 细胞中显示出抗迁移作用，并在免疫组织荧光研究中抑制 VEGFR-2 表达。还进行了 VEGFR-2 的分子对接模拟以及 ADME 特性预测。

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Novel 2-oxo-2-phenylethoxy and benzyloxy diaryl urea hybrids as VEGFR-2 inhibitors: Design, synthesis, and anticancer evaluation

Two series of diaryl urea derivatives, 6a–k and 7a–n, were synthesized. All the newly synthesized compounds were tested against the NCI (US) cancer cell lines via SRB assay. The p-chloro-m-trifluoromethyl phenyl derivatives 6e–g and 7e–g showed the most potent cytotoxic activity with a GI₅₀ value range of 1.2–15.9 µM. Furthermore, the p-fluorobenzyloxy diaryl urea derivative 7g revealed the most potent cytotoxicity against eight cancer cell lines in the MTT assay with IC₅₀ values below 5 µM. Compounds 6a–k and 7a–n were tested for their vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibitory activities. The p-chloro-m-trifluoromethyl diaryl urea benzyloxy derivatives 7e–i and the p-methoxydiaryl urea benzyloxy derivatives 7k, 7l, and 7n were found to be the most active compounds as VEGFR-2 inhibitors in the benzyloxy series 7, with an IC₅₀ range of 0.09–4.15 µM. In the 2-oxo-2-phenylethoxy series 6, compounds 6e–g and 6i were reported with IC₅₀ values of 0.94, 0.54, 2.71, and 4.81 µM, respectively. Moreover, compounds 7e and 7g induced apoptosis, causing cell cycle arrest in the G2/M phase. In addition, 7g showed an antimigratory effect in A-375 cells and inhibited the VEGFR-2 expression in an immunohistofluorescence study. Molecular docking simulations on VEGFR-2 as well as ADME properties prediction were also performed.

更新日期：2022-11-18

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