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: [email protected].
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.