Discovery of novel anti-angiogenesis agents. Part 6: Multi-targeted RTK inhibitors

  • Eur J Med Chem. 2017 Feb 15:127:275-285. doi: 10.1016/j.ejmech.2016.12.059.
Lin Zhang  1 ,  Yuanyuan Shan  2 ,  Chuansheng Li  1 ,  Ying Sun  1 ,  Ping Su  1 ,  Jinfeng Wang  1 ,  Lisha Li  1 ,  Xiaoyan Pan  1 ,  Jie Zhang  3
Affiliations
  • 1. School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China.
  • 2. Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, PR China.
  • 3. School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province, 710061, PR China. Electronic address: [email protected].
PMID: 28068599 DOI: 10.1016/j.ejmech.2016.12.059
Abstract

Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, TIE-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/TIE-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, TIE-2, and EphB4. The representative compound (18a) displayed both potent multi-targeted RTK inhibition and considerable antiproliferative activities against human umbilical vein endothelial cells (EA.hy926). These results will contribute to the discovery of novel muti-targeted anti-angiogenesis agents.

Keywords
Anti-angiogenesis agents; Diaryl malonamide; Diaryl thiourea; Multi-targeted; RTK inhibitors.