Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells

Bioorg Med Chem Lett. 2013 Jan 15;23(2):528-31. doi: 10.1016/j.bmcl.2012.11.030. Epub 2012 Nov 21.

Abstract

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis*
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Dinoprostone / antagonists & inhibitors*
  • Dinoprostone / biosynthesis
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Mice
  • Molecular Structure
  • Phthalazines / chemical synthesis*
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Transplantation, Heterologous

Substances

  • 5-aminophthalazine
  • Aminopyridines
  • Antineoplastic Agents
  • Phthalazines
  • Dinoprostone