Novel Cryptophycin Antitumor Agents: Synthesis and Cytotoxicity of Fragment “B” Analogues

A general synthetic approach to novel cryptophycin analogues 6 is described. N-Hydroxysuccinimide active ester 15, a key common intermediate, was converted to beta-epoxide 6 in three steps, via initial coupling with unprotected amino acid 9, followed by deprotection/macrolactamization of acyclic precursor 16, and final oxidation of styrene 7 to install the C7-C8 beta-epoxide. Cryptophycin styrenes 7 and beta-epoxides 6, bearing diverse side chains in fragment "B", were evaluated for cytotoxic activity. beta-Epoxides 6, in general, were significantly more potent than the corresponding alpha-epoxides 17 and styrenes 7. A benzyl side chain was required for potent activity, with beta-epoxide 6u, possessing a 3-Cl,4-(dimethylamino)benzyl moiety, as the most potent cytotoxic agent prepared, with an IC(50) = 54 pM, only 2-fold less than that of Cryptophycin-52 (3).