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: Rima S Al-Awar, James E Ray, Richard M Schultz, Sherri L Andis, Joseph H Kennedy, Richard E Moore, Jian Liang, Trimurtulu Golakoti, Gottumukkala V Subbaraju, Thomas H Corbett
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 14 Pg. 2985-3007 (Jul 03 2003) ISSN: 0022-2623 [Print] United States
• PMID: 12825938 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Depsipeptides
• Lactams
• Lactones
• cryptophycin 52

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Depsipeptides
• Drug Screening Assays, Antitumor
• Humans
• Lactams (chemical synthesis, chemistry, pharmacology)
• Lactones (chemical synthesis, chemistry, pharmacology)
• Male
• Mice
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy)
• Structure-Activity Relationship
• Tumor Cells, Cultured