Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Arch Pharm (Weinheim). 2019 Oct;352(10):e1900113. doi: 10.1002/ardp.201900113. Epub 2019 Aug 25.
Novel series of benzoxazoles 4 -16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 was found to be the most potent against HepG2, HCT-116, and MCF-7 with IC = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 , 5 , 6 , 5 , and 6 showed the highest anticancer activities against HepG2 cells with IC of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT-116 cells with IC of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF-7 cells with IC of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 and 6 were further evaluated for their vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition. Compounds 5 and 5 potently inhibited VEGFR-2 at lower IC values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC = 0.1 ± 0.02 µM). Compound 5 potently inhibited VEGFR-2 at low IC value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR-2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
我们设计、合成了一系列新型苯并恶唑衍生物 4-16 ，并评估了它们对 HepG2 、 HCT-116 和 MCF-7 细胞的抗癌活性。HCT-116 细胞对新衍生物的影响最为敏感。特别是化合物 5 对 HepG2 、 HCT-116 和 MCF-7 的抑制活性最强，IC50 值分别为 4.13 ± 0.2、6.93 ± 0.3 和 8.67 ± 0.5 μM。化合物 5 、 5 、 6 、 5 和 6 对 HepG2 细胞的抗癌活性最高，IC50 值分别为 5.93 ± 0.2、6.58 ± 0.4、8.10 ± 0.7、8.75 ± 0.7 和 9.95 ± 0.9 μM；对 HCT-116 细胞的抗癌活性最高，IC50 值分别为 7.14 ± 0.4、9.10 ± 0.8、7.91 ± 0.6、9.52 ± 0.5 和 12.48 ± 1.1 μM；对 MCF-7 细胞的抗癌活性最高，IC50 值分别为 8.93 ± 0.6、10.11 ± 0.9、12.31 ± 1.0、9.95 ± 0.8 和 15.70 ± 1.4 μM，均优于索拉非尼作为参考药物，IC50 值分别为 9.18 ± 0.6、5.47 ± 0.3 和 7.26 ± 0.3 μM。活性最高的化合物 5 和 6 进一步评估了它们对血管内皮生长因子受体-2 （VEGFR-2 ）的抑制作用。化合物 5 和 5 对 VEGFR-2 的抑制作用较强，IC50 值分别为 0.07 ± 0.01 和 0.08 ± 0.01 μM，低于索拉非尼（IC50 值为 0.1 ± 0.02 μM ）。化合物 5 对 VEGFR-2 的抑制作用较强，IC50 值为 0.10 ± 0.02 μM ，与索拉非尼相当。我们的设计基于 VEGFR-2 抑制剂索拉非尼的基本药效团特征。对所有化合物进行了分子对接，以评估它们与 VEGFR-2 活性位点的结合模式和亲和力。
