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苯并恶唑衍生物作为新型 VEGFR-2 抑制剂和凋亡诱导剂的设计、合成、研究及抗增殖活性评价

Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, studies, and antiproliferative evaluation.

机构信息

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2063-2077. doi: 10.1080/14756366.2022.2103552.

DOI:10.1080/14756366.2022.2103552
PMID:35875937
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9327782/
Abstract

In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds (, , , , and ) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member IC = 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively had the most promising VEGFR-2 inhibitory activity (IC = 97.38 nM). A further biological evaluation revealed that compound could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound could induce apoptosis in HepG2 cells by 35.13%. likely, compound exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that exhibited interactions with the key amino acids in a similar way to sorafenib.

摘要

在这项研究中，设计、合成了一组新型苯并恶唑衍生物，并将其作为潜在的 VEGFR-2 抑制剂进行了生物评价。五种化合物（、、、、和）对 HepG2 和 MCF-7 细胞系表现出高的生长抑制活性，进一步研究了它们对 VEGFR-2 的抑制活性。最有效的抗增殖成员对 HepG2 和 MCF-7 的抑制活性分别为 IC = 10.50 μM 和 15.21 μM，对 VEGFR-2 具有最有前途的抑制活性（IC = 97.38 nM）。进一步的生物学评价表明，化合物可以主要将 HepG2 细胞生长停滞在 Pre-G1 和 G1 期。此外，化合物可以通过 35.13%诱导 HepG2 细胞凋亡。可能的是，化合物表现出 caspase-3 水平（2.98 倍）和 BAX（3.40 倍）的显著升高，以及 Bcl-2 水平（2.12 倍）的显著降低。最后，对接研究表明，化合物以类似于索拉非尼的方式与关键氨基酸相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50b3/9327782/a04cd444906d/IENZ_A_2103552_F0010_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50b3/9327782/0d5dacdbedeb/IENZ_A_2103552_SCH0001_B.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50b3/9327782/b08c6c30385c/IENZ_A_2103552_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/50b3/9327782/17c4cb30580c/IENZ_A_2103552_F0003_C.jpg
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