新型烟酰胺衍生物作为潜在 VEGFR-2 抑制剂和凋亡诱导剂的抗癌和免疫调节评价：和研究。

Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: and studies.

机构信息

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

Zoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2206-2222. doi: 10.1080/14756366.2022.2110868.

New nicotinamide derivatives , , , and were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound revealed the highest anti-proliferative activities with IC values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC = 9.30 and 7.40 µM). Compound owned promising cytotoxic activities with IC values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC values. Moreover, compound induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds and reduced the levels of TNF- by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.

基于 VEGFR-2 抑制剂的基本特征，我们设计并合成了新的烟酰胺衍生物、、、。与索拉非尼（IC = 9.30 和 7.40 μM）相比，化合物对 HCT-116 和 HepG2 的 IC 值分别为 15.4 和 9.8 μM，显示出最高的抗增殖活性。化合物对相同的细胞系具有有前途的细胞毒性活性，IC 值分别为 15.7 和 15.5 μM。随后，评估了标题化合物的 VEGFR-2 抑制活性，以表现出具有亚微摩尔 IC 值的 VEGFR-2 抑制。此外，化合物在 %G2-M 和 G0-G1 期使细胞周期停滞，并在 HCT-116 中诱导细胞凋亡。与地塞米松（82.4 和 93.1%）相比，化合物和分别将 TNF- 的水平降低了 81.6%和 84.5%，以及将 IL-6 的水平降低了 88.4%和 60.9%。对接、分子动力学模拟、ADMET 和毒性研究都进行了。