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 conv erted to beta-epoxide 6; in three steps, via initial coupling with unprotec ted amino acid 9, followed by deprotection/macrolactamization of acyclic pr ecursor 16, and final oxidation of styrene 7 to install the C7-C8 beta-epox ide. Cryptophycin styrenes 7 and beta-epoxides 6, bearing diverse side chai ns in fragment "B", were evaluated for cytotoxic activity. beta-Epoxides 6, in general, were significantly more potent than the corresponding alpha-ep oxides 17 and styrenes 7. A benzyl side chain was required for potent activ ity, with beta-epoxide 6u, possessing a 3-Cl,4-(dimethylamino)benzyl moiety , as the most potent cytotoxic agent; prepared, with an IC50 = 54 pM, only 2-fold less than that of Cryptophycin-52 (3).