title: A convergent approach to cryptophycin 52 analogues: synthesis and biological evaluation of a novel series of fragment a epoxides and chlorohydrins.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Al-awar_Rima_S@Lilly.com
authors.forename: Rima S
authors.initials: RS
authors.lastname: Al-Awar
authors.forename: James E
authors.initials: JE
authors.lastname: Ray
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schultz
authors.forename: Sherri L
authors.initials: SL
authors.lastname: Andis
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Kennedy
authors.forename: Richard E
authors.initials: RE
authors.lastname: Moore
authors.forename: Jian
authors.initials: J
authors.lastname: Liang
authors.forename: Trimurtulu
authors.initials: T
authors.lastname: Golakoti
authors.forename: Gottumukkala V
authors.initials: GV
authors.lastname: Subbaraju
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Corbett
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D007769:Lactams; D007783:Lactones; C114033:cryptophycin 52