VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents.,Bioorganic & Medicinal Chemistry

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VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.bmc.2020.115328
Eman Y Ahmed ₁ , Nehad A Abdel Latif ₁ , Mohamed F El-Mansy ₂ , Weam S Elserwy ₃ , Omaima M Abdelhafez ₁

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Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their in vitro anticancer activity against MCF-7 breast and PC-3 prostate cancer cell lines and were further assessed for their in vitro VEGFR-2 kinase inhibitory activity. The in vitro cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 4a (IC50 = 1.24 µM) and 3d (IC50 = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC50 = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC50 values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 4a and 3d were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 4a, exhibited significant IC50 of 0.36 µM comparable to staurosporine (IC50; 0.33 µM). Moreover, it was capable of inducing preG1 apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 4a, which demonstrated the ability of the tested compound to interact with the key amino acids in the target VEGFR-2 kinase binding site. Additionally, the ADME parameters and physicochemical properties of compound 4a were examined in silico.

中文翻译：

新合成香豆素衍生物作为抗乳腺癌药物的VEGFR-2抑制作用和分子模型。

分析了二十五个新合成的香豆素支架基衍生物对MCF-7乳腺癌和PC-3前列腺癌细胞系的体外抗癌活性，并对其体外VEGFR-2激酶抑制活性进行了进一步评估。体外细胞毒性研究表明，大多数合成的化合物对MCF-7具有非常有希望的细胞毒性，特别是对MCF-7。化合物4a（IC50 = 1.24 µM）和3d（IC50 = 1.65 µM）表现出优于阳性对照星形孢菌素（IC50 = 8.81 µM）的出色活性。同样，与参考标准相比，大多数化合物具有更高的抗增殖活性，IC50值为2.07至8.68 µM。选择两种细胞毒性衍生物4a和3d以评估其对VEGFR-2激酶的抑制能力。值得注意的是化合物4a的IC50为0.36 µM，与星形孢菌素相当（IC50； 0.33 µM）。此外，它能够诱导preG1凋亡，在G2 / M期阻止细胞生长并激活caspase-9。另一方面，观察到所有化合物对PC-3细胞系的细胞毒性活性均很小。对活性最强的抗VEGFR-2衍生物4a进行了分子对接研究，该试验证明了受试化合物与靶标VEGFR-2激酶结合位点中的关键氨基酸相互作用的能力。另外，在计算机上检查了化合物4a的ADME参数和理化性质。另一方面，观察到所有化合物对PC-3细胞系的细胞毒性活性均很小。对活性最强的抗VEGFR-2衍生物4a进行了分子对接研究，该试验证明了受试化合物与靶标VEGFR-2激酶结合位点中的关键氨基酸相互作用的能力。另外，在计算机上检查了化合物4a的ADME参数和理化性质。另一方面，观察到所有化合物对PC-3细胞系的细胞毒性活性均很小。对活性最强的抗VEGFR-2衍生物4a进行了分子对接研究，该试验证明了受试化合物与靶标VEGFR-2激酶结合位点中的关键氨基酸相互作用的能力。另外，在计算机上检查了化合物4a的ADME参数和理化性质。

更新日期：2020-01-21

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