Department of Pharmaceutical Chemistry, Bharati Vidyapeeth's College of Pharmacy, Navi Mumbai, India.
School of Health Sciences, Health Campus Universiti Sains 16150 Kubang Kerian, Kelantan, Malaysia.
Bioorg Chem. 2021 Nov;116:105350. doi: 10.1016/j.bioorg.2021.105350. Epub 2021 Sep 11.
In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.
在本研究中，合成了两个包含萘基和吡啶基连接体的新型系列化合物，生物测定结果表明，5-((6-(2-(5-(2-氯苯基)-3-(4-氟苯基)-4,5-二氢-1H-吡唑-1-基)-2-氧代乙氧基)萘-2-基)亚甲基)噻唑烷-2,4-二酮（14b）是血管内皮生长因子受体-2（VEGFR-2）和组蛋白去乙酰化酶 4（HDAC4）的双重抑制剂。发现化合物 13b、14b、17f 和 21f 可稳定 HDAC4；其中，吡啶基连接体比萘基连接体具有更高的稳定效果。此外，13b 和 14b 对 VEGFR-2 的抑制活性优于其他化合物。与其他化合物相比，化合物 14b 的体外和体内生物学评估显示出最佳的抑制活性。它通过抑制内皮细胞增殖、迁移、管形成来显示出抗血管生成潜力，并且还抑制了正在生长的鸡胚绒毛尿囊膜（CAM）中的新毛细血管形成。与其他 HDAC 同工酶相比，它对 HDAC4 具有选择性和效力。化合物 14b（25mg/kg，ip）在人结直肠腺癌（HT-29）的体内动物异种移植模型中也表现出优异的抗肿瘤疗效。14b 的作用机制也通过 Western blot 得到了证实。
