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).
Patel
V F
VF
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. patel@kinetixpharm.com
Andis
S L
SL
Kennedy
J H
JH
Ray
J E
JE
Schultz
R M
RM
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047630:Depsipeptides; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009904:Optical Rotation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000577:Amides; D000970:Antineoplastic Agents; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; C120312:cyclo(2,2-dimethylalanyl-2-hydroxy-4-(methylpentanoyl)-5-hydroxy-6-(3-phenyloxiranyl)-2-heptenoyl-3-chloro-4-(dimethylamino)phenylalanyl); C114033:cryptophycin 52