A Convergent Approach to Cryptophycin 52 Analogues:  Synthesis and Biological Evaluation of a Novel Series of Fragment A Epoxides and Chlorohydrins

• Published in: Journal of medicinal chemistry 2003-07, Vol.46 (14), p.2985-3007
• Main Authors: Al-awar, Rima S, Ray, James E, Schultz, Richard M, Andis, Sherri L, Kennedy, Joseph H, Moore, Richard E, Liang, Jian, Golakoti, Trimurtulu, Subbaraju, Gottumukkala V, Corbett, Thomas H
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemotherapy; Depsipeptides; Drug Screening Assays, Antitumor; Humans; Lactams - chemical synthesis; Lactams - chemistry; Lactams - pharmacology; Lactones - chemical synthesis; Lactones - chemistry; Lactones - pharmacology; Male; Medical sciences; Mice; Neoplasm Transplantation; Pancreatic Neoplasms - drug therapy; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0203884

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.