Discovery of novel flavonoid derivatives targeting VEGFR2 and tubulin with potent anticancer efficacy

Xiang He; Yijiao Peng; Renbo Liu; Weixi Yuan; Pengju Ye; Zhe Wang; Chengxiao Fu; Zhizhong Xie; Xiaoyan Yang; Xiaoyong Lei; LiLi Wang; Bo Yang; Guotao Tang; Xiangping Deng

doi:10.1016/j.bioorg.2025.108713

Discovery of novel flavonoid derivatives targeting VEGFR2 and tubulin with potent anticancer efficacy

Bioorg Chem. 2025 Jun 30:163:108713. doi: 10.1016/j.bioorg.2025.108713. Online ahead of print.

Authors

Xiang He¹, Yijiao Peng¹, Renbo Liu¹, Weixi Yuan¹, Pengju Ye¹, Zhe Wang², Chengxiao Fu¹, Zhizhong Xie¹, Xiaoyan Yang¹, Xiaoyong Lei³, LiLi Wang¹, Bo Yang⁴, Guotao Tang⁵, Xiangping Deng⁶

Affiliations

¹ The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
² The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
³ The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China; Department of Pharmacy, Xiangnan University, Chenzhou 423000, Hunan, China.
⁴ The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: ybnhfy@126.com.
⁵ The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: tgtzq@163.com.
⁶ The First Affiliated Hospital, Department of Pharmacy, Institute of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China. Electronic address: dengxpusc@163.com.

PMID: 40609278
DOI: 10.1016/j.bioorg.2025.108713

Abstract

The clinical efficacy of VEGFR inhibitors and tubulin inhibitors as monotherapies is restricted by adverse reactions and resistance. We reported a classic pharmacophore hybridization strategy to develop dual VEGFR2/tubulin inhibitors that simultaneously inhibited tumor angiogenesis and tubulin assembly. A series of novel flavonoid derivatives containing N, N'-diethylurea group and trimethoxyphenyl were designed and synthesized. Among them, compound 6r demonstrated excellent antitumor activity in vitro and in vivo. Mechanistic studies revealed that 6r exerted antitumor activity by inhibiting VEGFR2 and tubulin in the micromolar range. Further studies showed that 6r inhibited angiogenesis in the CAM model. Additionally, 6r also demonstrated moderate PK profiles with broad tissue distribution characteristics and good safety. Notably, 6r inhibited tumor growth in the HGC-27 xenograft model. All the reported results suggested that 6r may be a potent anticancer candidate and merited further investigation.

Keywords: Anticancer; Dual-target inhibitor; Flavonoid derivatives; Tubulin; VEGFR2.