Design, synthesis and biological evaluation of VEGFR-2/HDAC dual inhibitors as multitargeted antitumor agents based on fruquintinib and vorinostat

Yali Gao; Fei Li; Xin Ni; Siwang Yang; Han Liu; Xingye Wu; Jieqing Liu; Junjie Ma

doi:10.1039/d3ra05542f

Design, synthesis and biological evaluation of VEGFR-2/HDAC dual inhibitors as multitargeted antitumor agents based on fruquintinib and vorinostat

RSC Adv. 2023 Sep 27;13(41):28462-28480. doi: 10.1039/d3ra05542f. eCollection 2023 Sep 26.

Authors

Yali Gao¹, Fei Li^{2

3}, Xin Ni², Siwang Yang², Han Liu², Xingye Wu², Jieqing Liu², Junjie Ma²

Affiliations

¹ Pharmacy Department, The Second Affiliated Hospital of Fujian Medical University Quanzhou 362000 PR China 106204660@qq.com.
² School of Medicine, Huaqiao University Quanzhou 362000 PR China liujieqing@hqu.edu.cn majunjie3612@hqu.edu.cn.
³ Sinopharm Dongfeng General Hospital, Hubei University of Medicine Shiyan 442008 Hubei PR China.

Abstract

Herein, a series of 4-(benzofuran-6-yloxy)quinazoline derivatives as VEGFR-2/HDAC dual inhibitors were designed and synthesized based on fruquintinib and vorinostat. Among them, compound 13 exhibited potent inhibitory activity against VEGFR-2 and HDAC1 with IC₅₀ values of 57.83 nM and 9.82 nM, and displayed moderate to significant antiproliferative activity against MCF-7, A549, HeLa and HUVEC. The cellular mechanism studies revealed that compound 13 arrested the cell cycle at the S and G2 phases, and induced significant apoptosis in HeLa cells. Tube formation assay in HUVECs demonstrated that 13 had a significant anti-angiogenic effect. Additionally, a molecular docking study supported the initial design strategy. These results highlighted that 13 was a valuable VEGFR-2/HDAC dual inhibitor and deserved further study for cancer therapy.