Synthesis and antitumour activity of trimethylsilylpropyl substituted benzimidazoles

Eur J Med Chem. 2001 Jun;36(6):507-15. doi: 10.1016/s0223-5234(01)01241-7.

Abstract

The quaternisation of N-substituted benzimidazoles by heating with various alkyl, allyl, propargyl and benzyl chlorides and bromides leads to the formation of benzimidazolinium salts. The interaction of N-monosubstituted benzimidazoles with various salts (CuCl2, ZnCl2, CoCl2, PdCl2 and AgNO3) yielded stable solid complexes. Potential cytotoxic activity of synthesised benzimidazolinium salts and benzimidazole metal complexes was tested in vitro on four monolayer tumour cell lines: MG-22A (mouse hepatoma), HT-1080 (human fibrosarcoma), B16 (mouse melanoma), Neuro 2A (mouse neuroblastoma) and normal mouse fibroblast cells. A preliminary analysis of the structure-activity relationship for the benzimidazole derivatives clearly indicates that the character of substituents in the benzimidazole ring has strong influence on the cytotoxic activity. The insertion of the silicon atom into the N-alkyl chain increases the cytotoxic activity of benzimidazolinium salts significantly, which show a very significant potency in vitro against all studied tumour cell lines, being particularly active in experiments with B16 (mouse melanoma). TD50 for the most active compounds are in the range 0.001-0.008 microg x ml(-1). Cytotoxicity of benzimidazole metal complexes (L2MX2) strongly depends on the metal nature. 1-(3-trimethylsilylpropyl)benzimidazole in dose 1 mg x kg(-1) inhibits carcinoma S-180 tumour growth by 62% (on ICR mice).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Cell Division / drug effects
  • Cell Size / drug effects
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mice
  • Neoplasm Transplantation / pathology
  • Sarcoma / drug therapy
  • Sarcoma / pathology
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Benzimidazoles