Ghorab Mostafa M, Ragab Fatma A, Heiba Helmy I, El-Gazzar Marwa G, El-Gazzar Mostafa G M
Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City, P.O. Box 29, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Bioorg Med Chem Lett. 2018 May 15;28(9):1464-1470. doi: 10.1016/j.bmcl.2018.03.089. Epub 2018 Mar 31.
In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10-13b as most active anticancer agents with IC equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 µM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib.
在本研究中，基于II型VEGFR2抑制剂的一般药效学特征，设计并合成了一系列新型的硫脲基苯磺酰胺衍生物，这些衍生物带有间位或对位取向的烯胺酮连接基，并具有末端线性或取代的芳环或杂芳环系统5-16a,b。对合成的化合物进行体外抗HEPG2肝癌细胞活性评估，确定化合物5b、6b和10-13b为活性最强的抗癌剂，其IC值分别为0.12、0.29、0.58、0.44、0.42和0.66 μM。对这些化合物体外抑制VEGFR2激酶的能力进行了评估。结果表明，它们对VEGFR2具有高度有效的剂量依赖性抑制作用，IC值在纳摩尔范围内（分别为33、57、210、37、37和纳摩尔220）。研究了最有前景的化合物的放射增敏能力，结果表明，与合成化合物联合使用后，辐射的细胞杀伤作用增强，IC值降低了近50%。对最有效的化合物进行了分子对接，以预测它们在VEGFR2活性位点内可能的结合模式，结果显示它们与索拉非尼具有相似的结合亲和力。
