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

Le Wang*, Keith W. Woods, Qun Li, Kenneth J. Barr, Richard W. McCroskey, Steven M. Hannick, Laura Gherke, R. Bruce Credo, Yu Hua Hui, Kennan Marsh, Robert Warner, Jang Y. Lee, Nicolette Zielinski-Mozng, David Frost, Saul H. Rosenberg, Hing L. Sham

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

390 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1697-1711
Number of pages15
JournalJournal of Medicinal Chemistry
Volume45
Issue number8
DOIs
StatePublished - Apr 11 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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