Design, synthesis, and evaluation of azepine-based cryptophycin mimetics

Amos B. Smith, Young Shin Cho, George Pettit, Ralph Hirschmann

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Cryptophycins, depsipeptides isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins.

Original languageEnglish (US)
Pages (from-to)6991-7009
Number of pages19
JournalTetrahedron
Volume59
Issue number35
DOIs
Publication statusPublished - Aug 25 2003

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Keywords

  • Cryptophycin
  • Microtubule
  • Non-peptide peptidomimetics

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

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