Polyamine sulfonamides with NMDA antagonist properties are potent calmodulin antagonists and cytotoxic agents

Int J Biochem Cell Biol. 1998 Mar;30(3):393-406. doi: 10.1016/s1357-2725(97)00150-7.

Abstract

N1-Dansylspermine and related sulfonamides of the natural polyamines are very potent blockers of NMDA-type glutamate receptors. They exhibit pharmacological properties which were not predicted from the constituents of the conjugates. Cytotoxicity and calmodulin antagonism of N1-dansylspermine were especially impressive. Calmodulin antagonism implies that N1-dansylspermine prevents induction of ornithine decarboxylase and inhibits its own active uptake via the polyamine transport system. Structure-activity considerations demonstrated that an aromatic character of the substituent is not required; amide bond formation with an aliphatic sulfonic acid is sufficient to transform spermine into a highly toxic calmodulin antagonist. Cytotoxicity and calmodulin antagonism are properties which are intrinsic to spermine, but they are observed only at very high concentrations. Amide bond formation at N1 with a lipophilic residue appears to 'amplify' these normally latent properties. The use of polyamine conjugates structurally related to the amides described in this work for targeting tumours may be marred by their calmodulin antagonism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • Amine Oxidase (Copper-Containing)*
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Biological Transport, Active / drug effects
  • Calmodulin / antagonists & inhibitors*
  • Calmodulin / metabolism
  • Cattle
  • Dansyl Compounds / chemistry
  • Dansyl Compounds / metabolism
  • Dansyl Compounds / pharmacology*
  • In Vitro Techniques
  • Leukemia L1210
  • Mice
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism
  • Polyamines / chemistry
  • Polyamines / metabolism
  • Polyamines / pharmacology*
  • Putrescine / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Spermine / analogs & derivatives*
  • Spermine / chemistry
  • Spermine / metabolism
  • Spermine / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology

Substances

  • Antineoplastic Agents
  • Calmodulin
  • Dansyl Compounds
  • N(1)-dansylspermine
  • Polyamines
  • Receptors, N-Methyl-D-Aspartate
  • Sulfonamides
  • Spermine
  • Amine Oxidase (Copper-Containing)
  • Oxidoreductases Acting on CH-NH Group Donors
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Putrescine