A convergent approach to cryptophycin 52 analogues: synthesis and biological evaluation of a novel series of fragment a epoxides and chlorohydrins.
Cryptophycin 52 is a synthetic derivative of Cryptophycin 1, a potent antimicrotubule agent isolated from cyanobacteria. In an effort to increase the potency and water solubility of the molecule, a structure-activity relationship study (SAR) was initiated around the phenyl ring of fragment A. These Cryptophycin 52 analogues were accessed using a Wittig olefination reaction between various triphenylphosphonium salts and a key intermediate aldehyde prepared from Cryptophycin 53. Substitution on the phenyl ring of fragment A was well tolerated, and several of these analogues were equally or more potent than Cryptophycin 52 when evaluated in vitro in the CCRF-CEM leukemia cell line and in vivo against a murine pancreatic adenocarcinoma.
Al-Awar
Rima S
RS
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Al-awar_Rima_S@Lilly.com
Ray
James E
JE
Schultz
Richard M
RM
Andis
Sherri L
SL
Kennedy
Joseph H
JH
Moore
Richard E
RE
Liang
Jian
J
Golakoti
Trimurtulu
T
Subbaraju
Gottumukkala V
GV
Corbett
Thomas H
TH
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; 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; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; C114033:cryptophycin 52