HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Synthesis of reblastatin, autolytimycin, and non-benzoquinone analogues: potent inhibitors of heat shock protein 90.

Abstract
A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (approximately 25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (approximately 100 nM).
AuthorsIwona E Wrona, Alexander Gozman, Tony Taldone, Gabriela Chiosis, James S Panek
JournalThe Journal of organic chemistry (J Org Chem) Vol. 75 Issue 9 Pg. 2820-35 (May 07 2010) ISSN: 1520-6904 [Electronic] United States
PMID20392070 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Phenols
  • Quinones
  • autolytimycin
  • reblastatin
  • quinone
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Benzoquinones (chemistry)
  • Cell Line, Tumor
  • HSP90 Heat-Shock Proteins (antagonists & inhibitors)
  • Humans
  • Lactams, Macrocyclic (chemical synthesis, chemistry, pharmacology)
  • Molecular Structure
  • Phenols (chemical synthesis)
  • Quinones (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: