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

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.