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 |
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Rok vydání: | 2003 |
Předmět: |
Male
Lactams Stereochemistry Antineoplastic Agents Adenocarcinoma Chemical synthesis Cryptophycin 52 Lactones Mice Structure-Activity Relationship Depsipeptides Drug Discovery Tumor Cells Cultured Animals Humans Structure–activity relationship chemistry.chemical_classification Antimicrotubule agent Cyclic peptide Pancreatic Neoplasms chemistry Cryptophycin Wittig reaction Molecular Medicine Drug Screening Assays Antitumor Neoplasm Transplantation Lactone |
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 |
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