Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase

Eur J Med Chem. 2015 Dec 1:106:26-33. doi: 10.1016/j.ejmech.2015.10.026. Epub 2015 Oct 19.

Abstract

Efficient one-pot five-component synthetic protocols for highly functionalized tetrahydropyridines (THPs) and their biological evaluation have been illustrated. Synthesis of novel functionalized tetrahydropyridines containing differential substitutions at 2,6-positions has been achieved via a modified MCR. Cytotoxic studies of 23 synthesized compounds have been carried out against three different cell lines, namely A-549, HeLa and HepG2, wherein some compounds have displayed appreciable cytotoxicity. Further, investigation of enzyme inhibition by the synthesized THPs has been carried out against four members of M1 family aminopeptidases. Several compounds have selectively inhibited only one member of this enzyme family i.e., human puromycin sensitive aminopeptidase (hPSA). Among the compounds; 4b, 9b, 9e and 10a demonstrated best inhibition against hPSA.

Keywords: Cytotoxicity; Multicomponent reaction; Puromycin sensitive aminopeptidase and inhibitors; Tetrahydropyridine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyridines
  • Aminopeptidases
  • enkephalin degrading enzyme