Peptide-linked 1,3-dialkyl-3-acyltriazenes: gastrin receptor directed antineoplastic alkylating agents

J Med Chem. 1994 Oct 28;37(22):3812-8. doi: 10.1021/jm00048a016.

Abstract

The gastrin receptor is expressed in various human cancers, such as the adenocarcinoma of the colon. The peptide hormone gastrin and the C-terminal peptides derived from it act as growth factors for these cancers. The hypothesis for the present work was to use the gastrin receptor as a target for appropriately constructed cytotoxic agents. We developed methods to link tetragastrin and pentagastrin by their N-termini to cytotoxic 1-(2-chloroethyl)-3-benzyl-3-succinoyltriazene. These compounds, CBS-4 and CBS-5, respectively, whose complete structures were determined by multinuclear NMR and mass spectrometry, competed effectively with gastrin in an assay using either guinea pig stomach fundus or the rat acinar tumor cell line AR42J as the source of the receptor. CBS-5 was cytotoxic to AR42J cells but was not toxic to A549 human lung cancer cells, which do not express the receptor.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylating Agents / chemistry
  • Alkylating Agents / pharmacology*
  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Sequence Data
  • Peptides / chemistry
  • Rats
  • Receptors, Cholecystokinin / drug effects*
  • Triazenes / chemistry
  • Triazenes / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Alkylating Agents
  • Antineoplastic Agents
  • Peptides
  • Receptors, Cholecystokinin
  • Triazenes