Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) is critically involved in cancer angiogenesis. Blocking of VEGFR-2 signaling pathway proved effective suppression of tumor growth. Accordingly, two series of new triazoloquinoxaline-based derivatives were designed and synthesized as VEGFR-2 inhibitors. All in vitro cytotoxic activities of the synthesized compounds were evaluated against two human cancer cell lines (MCF-7 and HepG2). To confirm the potential mechanism of cytotoxicity, enzymatic assays against VEGFR-2 were estimated for all the target compounds. The results of VEGFR-2 inhibitory activity and cytotoxicity were in high correlation. Compound 22a exhibited the highest cytotoxic effect with IC₅₀ values of 6.2 and 4.9 μM against MCF-7 and HepG2, respectively, comparing to sorafenib (IC₅₀ = 3.53 and 2.18 μM). Such derivative showed the best VEGFR-2 inhibitory activity with an IC₅₀ value of 3.9 nM, which is very close to that of sorafenib (IC₅₀ = 3.13 nM). Moreover, compounds 22b, 23b, and 23e exhibited strong cytotoxic activity with IC₅₀ values ranging from 11.7 to 15.3 μM. Also, these compounds showed promising VEGFR-2 inhibition with IC₅₀ values of 4.2, 5.7, and 4.7 nM, respectively. In silico docking, ADMET, and toxicity studies were carried out for the synthesized compounds. The results revealed that some compounds have a good binding mode against VEGFR-2 and a high level of drug-likeness.

Graphic abstract

中文翻译：

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新的[1,2,4]三唑并[4,3-a]喹喔啉衍生物作为靶向VEGFR-2激酶的抗癌剂的设计、合成和分子对接

摘要

血管内皮生长因子受体 2 (VEGFR-2) 与癌症血管生成密切相关。阻断VEGFR-2信号通路证明有效抑制肿瘤生长。因此，设计并合成了两个系列的新型三唑并喹喔啉衍生物作为 VEGFR-2 抑制剂。合成化合物的所有体外细胞毒活性均针对两种人类癌细胞系（MCF-7 和 HepG2）进行了评估。为了确认细胞毒性的潜在机制，针对所有目标化合物估计了针对 VEGFR-2 的酶促测定。VEGFR-2抑制活性与细胞毒性结果呈高度相关性。化合物22a表现出最高的细胞毒作用，IC ₅₀与索拉非尼相比，MCF-7 和 HepG2 的值分别为 6.2 和 4.9 μM（IC ₅₀  = 3.53 和 2.18 μM）。该衍生物显示出最好的VEGFR-2抑制活性，IC ₅₀值为3.9 nM，与索拉非尼(IC ₅₀  = 3.13 nM)非常接近。此外，化合物22b、23b和23e表现出强细胞毒活性，IC ₅₀值范围为 11.7 至 15.3 μM。此外，这些化合物显示出有希望的 VEGFR-2 抑制作用，IC ₅₀值分别为 4.2、5.7 和 4.7 nM。对合成的化合物进行了计算机对接、ADMET 和毒性研究。结果表明，一些化合物对VEGFR-2具有良好的结合模式和高水平的药物相似性。

图形摘要