Discovery of biphenyl-based VEGFR-2 inhibitors. Part 3: design, synthesis and 3D-QSAR studies

Bioorg Med Chem. 2015 Mar 1;23(5):1044-54. doi: 10.1016/j.bmc.2015.01.006.

Wen Lu ¹, Pengfei Li ², Yuanyuan Shan ³, Ping Su ¹, Jinfeng Wang ¹, Yaling Shi ¹, Jie Zhang ⁴

Affiliations

1 School of Pharmacy, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
2 School of Pharmacy, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China; Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, PR China.
3 Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, PR China.
4 School of Pharmacy, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.

PMID: 25637123 DOI: 10.1016/j.bmc.2015.01.006

Abstract

VEGFR-2 plays an essential role in angiogenesis and is a central target for Anticancer drug discovery. In order to develop novel VEGFR-2 inhibitors, we designed and synthesized 33 biphenyl amides based on our previously reported lead compound. The biological results indicated that four compounds (18b, 20e, 20h and 20j) are potent VEGFR-2 inhibitors which are comparable to positive control. Compound 18b displayed the most potent VEGFR-2 inhibition with IC50 value of 2.02nM. Moreover, it exhibited promising antiproliferative activity against MCF-7 and SMMC-7721 cells with IC50 values of 1.47μM and 5.98μM, respectively. Molecular docking and 3D-QSAR studies were also carried out. The results indicated that these biphenyl amides could serve as promising leads for further optimization as novel VEGFR-2 inhibitors.

Keywords

3D-QSAR; Amide; Anticancer; Biphenyl; VEGFR-2 inhibitors.

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