Potent, orally active heterocycle-based combretastatin A-4 analogues: synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation

J Med Chem. 2002 Apr 11;45(8):1697-711. doi: 10.1021/jm010523x.


The synthesis and structure-activity relationship study of a series of compounds with heterocycles in place of the cis double bond in combretastatin A-4 (CA-4) are described. Substituted tosylmethyl isocyanides were found to be the key intermediates in construction of the heterocycles. Cytotoxicities of the heterocycle-based CA-4 analogues were evaluated against NCI-H460 and HCT-15 cancer cell lines. 3-Amino-4-methoxyphenyl and N-methyl-indol-5-yl were the best replacements for the 3-hydroxy-4-methoxyphenyl in CA-4. 4,5-Disubstituted imidazole was found to be the best for the replacement of the cis double bond in CA-4. Medicinal chemistry efforts led to the discovery of compounds 24h and 25f that were found to be 32 and 82% bioavailable, respectively, in rat. Evaluation of 24h and 25f against murine M5076 reticulum sarcoma in mice revealed that both compounds were orally efficacious with an increase in life span of 38.5 and 40.5%, respectively.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Biopolymers
  • Cell Division / drug effects
  • Dogs
  • Drug Screening Assays, Antitumor
  • Haplorhini
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Lymphoma, Large B-Cell, Diffuse / drug therapy
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Rats
  • Stilbenes / chemistry*
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Tubulin / chemistry
  • Tumor Cells, Cultured


  • 1-methyl-4-(3,4,5-trimethoxyphenyl)-5-(3,4-bis(2-(methylamino)ethyl)phenyl)imidazole
  • 1-methyl-4-(3,4,5-trimethoxyphenyl)-5-(3-amino-4-methoxyphenyl)imidazole
  • Antineoplastic Agents
  • Biopolymers
  • Imidazoles
  • Stilbenes
  • Tubulin
  • fosbretabulin