Derivatives of Pyrazolo[1,5-a][1,3,5]Triazines as Enzyme Inhibitors with Potential Therapeutic Value

Abstract

Thymidine phosphorylase (TP) is an enzyme that promotes tumour growth and metastasis thus is an attractive druggable target. The goal of this project was to develop new TP inhibitors based on the pyrazolo[1,5-a][1,3,5]triazine scaffold. A total of 90 compounds containing the pyrazolo[1,5-a][1,3,5]triazine scaffold were synthesized. The most potent compound of the 1,3-dihydro-pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one series showed an IC50 value of 40nM, and it was 800 times more potent than the lead compound 7DX. It was found to be a non-competitive inhibitor, indicating that it might interact at an allosteric site. The most potent compound of the 2-(5-chloro-1,3-dihydropyrimidin-2,4-dioxo-6-ylmethylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one series showed an IC50 value of 0.36?M. It was found to be a mixed-type inhibitor, indicating that it might interact at both the substrate site and the allosteric site. In addition, a total of 9 compounds showed suppressive effects on the expression of the angiogenic factor MMP-9, thus they might possess antiangiogenesis potential.