Synthesis and biological evaluation of dihydromotuporamine derivatives in cells containing active polyamine transporters

J Med Chem. 2005 Jun 2;48(11):3832-9. doi: 10.1021/jm0491288.

Abstract

Dihydromotuporamine C (4) and its 4,4-triamine analogue (5) were synthesized in good yield using ring-closing metathesis (RCM) methods. Comparison of their biological activities (Ki determinations in L1210 cells and IC50 determinations in L1210, CHO, and CHO-MG cells) revealed that the motuporamine derivatives do not use the polyamine transporter (PAT) for cellular entry. Bioevaluation of a N1-(anthracen-9-ylmethyl)-N1-(ethyl)homospermidine control (7) revealed that the presence of a N1 tertiary amine center imparted a significant reduction in the PAT affinity of the polyamine conjugate and abolished its PAT-targeting selectivity.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anthracenes / chemical synthesis
  • Anthracenes / chemistry
  • Anthracenes / metabolism
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • CHO Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cricetinae
  • Cricetulus
  • Mice
  • Mutation
  • Polyamines / chemical synthesis*
  • Polyamines / chemistry
  • Polyamines / metabolism
  • Spermidine / analogs & derivatives
  • Spermidine / chemical synthesis
  • Spermidine / chemistry
  • Spermidine / metabolism
  • Structure-Activity Relationship

Substances

  • Anthracenes
  • Antineoplastic Agents
  • Carrier Proteins
  • Polyamines
  • Spermidine