Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR-2 Inhibitors

Title:Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR-2 Inhibitors

Volume: 24 Issue: 6

Author(s): Jingwei Liang, Xinyang Li, Su Yang, Xin He, Mingyang Wang and Fanhao Meng*

Affiliation:

• School of Pharmacy, China Medical University, Liaoning 110122, Shenyang,China

Keywords: VEGFR-2 inhibitor, uracil, virtual screening, Acyl aromatic hydrazine, cancer angiogenesis, ATP-competitive inhibitors.

Abstract: Backgound: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp- Phe-Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention.

Methods: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. Results: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50=0.029 µM).

Conclusion: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure-based virtual screening method for drug discovery.

Cite this article as:

Liang Jingwei, Li Xinyang , Yang Su , He Xin, Wang Mingyang and Meng Fanhao*, Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR-2 Inhibitors, Current Pharmaceutical Design 2018; 24 (6) . https://dx.doi.org/10.2174/1381612824666180130123430