Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region.
Structure modification of the beta-alanine region (fragment C) of the potent antimitotic agent cryptophycin was investigated. This includes: (1) introduction of substituents at the previously unsubstituted C7 position of the macrolide ring and (2) replacement of the (2R)-3-amino-2-methyl-propanoic acid (beta-alanine) with various (1)-amino acids to give the corresponding 15-membered unnatural cryptophycin analogs.
Shih
C
C
Lilly Research Laboratories, Indianapolis, IN 46285, USA.
Gossett
L S
LS
Gruber
J M
JM
Grossman
C S
CS
Andis
S L
SL
Schultz
R M
RM
Worzalla
J F
JF
Corbett
T H
TH
Metz
J T
JT
D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D015091:beta-Alanine / Q000737:chemistry*