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

Autor: Richard M. Schultz, Joseph H. Kennedy, Rima S. Al-Awar, Gottumukkala V. Subbaraju, Jian Liang, Thomas H. Corbett, Richard E. Moore, James E. Ray, Sherri L. Andis, Trimurtulu Golakoti
Rok vydání: 2003
Předmět:
Zdroj: Journal of Medicinal Chemistry. 46:2985-3007
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm0203884
Popis: 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.
Databáze: OpenAIRE