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

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

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Global Pharmaceutical R & D, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101, USA.

Erratum in

  • J Med Chem 2002 Oct 24;45(22):4946.


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.

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