Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt.
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
Bioorg Med Chem. 2021 Jan 1;29:115872. doi: 10.1016/j.bmc.2020.115872. Epub 2020 Nov 12.
Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.
抑制 VEGFR-2 已被确立为治疗癌症的一种治疗策略。因此，设计并合成了 19 种新型喹唑啉-4(3H)-酮衍生物。采用 MTT 法评价了合成化合物对三种人癌细胞系（HepG-2、MCF-7 和 HCT-116）的初步细胞毒性。阿霉素和索拉非尼用作阳性对照。发现五种化合物对所有细胞系均具有有前途的细胞毒性活性。含 2-氯-5-硝基苯基的化合物 16 表现出最强的活性。它对 HepG2、HCT-116 和 MCF-7 细胞的活性分别比阿霉素高约 4.39 倍、5.73 倍和 1.96 倍，比索拉非尼高 3.88 倍、5.59 倍和 1.84 倍。最具活性的细胞毒性剂进一步评估了其在体外对 VEGFR-2 的抑制活性。体外 VEGFR-2 抑制的结果与细胞毒性数据一致。此外，这些化合物在激酶结构域中的分子对接也支持了这一结果。
