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，合成了包含萘基和吡啶基接头的两个新系列化合物，生物测定显示 5-((6-(2-(5-(2-氯苯基)-3-(4-氟苯基)-4,5 -dihydro-1H-pyrazol-1-yl)-2-oxoethoxy)naphthalene-2-yl)methylene)thiazolidine-2,4-dione ( 14b ) 作为最有效的血管内皮生长因子受体 2 (VEGFR) 双重抑制剂-2) 和组蛋白脱乙酰酶 4 (HDAC4)。发现化合物13b、14b、17f和21f可稳定 HDAC4；其中，吡啶基连接器刀具有比萘基连接器更高的稳定效果。此外，与其他化合物相比，13b和14b对 VEGFR-2 的抑制活性最好。化合物14b体外和体内生物学评估证明最有效。它通过抑制内皮细胞增殖、迁移、管形成并抑制生长中的鸡绒毛尿囊膜 (CAM) 中新的毛细血管形成来显示出抗血管生成的潜力。与其他 HDAC 同种型相比，它显示出对 HDAC4 的选择性和效力。化合物14b (25 mg/kg, ip)对人结直肠腺癌 (HT-29)的体内动物异种移植模型也显示出卓越的抗肿瘤功效。蛋白质印迹也证实了14b的作用机制。