Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells

J Med Chem. 2005 Jan 27;48(2):483-98. doi: 10.1021/jm040857x.

Abstract

Endothelin-1 (ET-1) is mitogenic and/or antiapoptotic in human cancers, and antagonists to ET-1 receptors are under evaluation for cancer treatment. Inhibition of ET-1 activation by the endothelin-converting enzymes 1(a)(-)(d) (ECE-1(a)(-)(d); EC 3.4.24.71) represents another approach to block the ET-1 effect in cancer. To evaluate this potential, we synthesized and characterized a series of low nanomolar nonpeptidic thiol-containing ECE-1 inhibitors, and evaluated their effect, as well as the effect of inhibitors for the related metalloproteases neprilysin (NEP; EC 3.4.24.11) and angiotensin-converting enzyme (ACE; EC 3.4.15.1), on human glioblastoma cell growth. Only ECE-1 inhibitors inhibited DNA synthesis by human glioblastoma cells. Exogenous addition of ET-1 or bigET-1 to glioblastoma cells did not counterbalance the growth inhibition elicited by ECE-1 inhibitors, suggesting that ECE-1 inhibitors block the proliferation of human glioblastoma cells most likely via a mechanism not involving extracellular production of ET-1. This class of molecules may thus represent novel therapeutic agents for the potential treatment of human cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Carbamates / chemical synthesis
  • Carbamates / chemistry
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Central Nervous System Neoplasms
  • Drug Screening Assays, Antitumor
  • Endothelin-1 / pharmacology
  • Endothelin-Converting Enzymes
  • Glioblastoma
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Metalloendopeptidases
  • Proline / analogs & derivatives
  • Proline / chemical synthesis
  • Proline / chemistry
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemical synthesis*
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / pharmacology

Substances

  • Antineoplastic Agents
  • Carbamates
  • Endothelin-1
  • Hydrazines
  • Pyrimidines
  • Pyrrolidines
  • Sulfhydryl Compounds
  • Proline
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Endothelin-Converting Enzymes