Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II

Eur J Med Chem. 2014 May 6:78:294-303. doi: 10.1016/j.ejmech.2014.03.063. Epub 2014 Mar 21.

Abstract

In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.

Keywords: Antiangiogenesis; Breast cancer; Mixed-type inhibition; Pyrazolo[1,5-a][1,3,5]triazine; Thymidine phosphorylase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Matrix Metalloproteinase 9 / biosynthesis
  • Models, Molecular
  • Molecular Structure
  • Neovascularization, Pathologic / drug therapy*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Sulfur Compounds / chemical synthesis
  • Sulfur Compounds / chemistry
  • Sulfur Compounds / pharmacology*
  • Thymidine Phosphorylase / antagonists & inhibitors*
  • Thymidine Phosphorylase / metabolism
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Vascular Endothelial Growth Factor A / biosynthesis

Substances

  • Angiogenesis Inhibitors
  • Enzyme Inhibitors
  • Pyrazoles
  • Sulfur Compounds
  • Triazines
  • Vascular Endothelial Growth Factor A
  • Thymidine Phosphorylase
  • Matrix Metalloproteinase 9