Chiral resolution and pharmacological characterization of the enantiomers of the Hsp90 inhibitor 2-amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8- dihydro-6H-quinazolin-5-one oxime

Raffaella Amici, Chiara Bigogno, Roberto Boggio, Andrea Colombo, Stephen M. Courtney, Roberto Dal Zuffo, Giulio Dondio, Fulvia Fusar, Stefania Gagliardi, Saverio Minucci, Marco Molteni, Christian A G N Montalbetti, Annalisa Mortoni, Mario Varasi, Stefania Vultaggio, Ciro Mercurio

Research output: Contribution to journalArticle

Abstract

Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2-Amino-7-[4-fluoro-2-(3- pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime is a racemic Hsp90 inhibitor that targets the N-terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models. Problem resolved: A chemical method to resolve the enantiomers of 2-amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5- one oxime, a Hsp90 inhibitor targeting the N-terminal adenosine triphosphatase site, and the characterization of their inhibitor activity on Hsp90, along with the consequent antiproliferative effect on cancer cells is explored. Pharmacokinetic properties and antitumor activity are also evaluated.

Original languageEnglish
Pages (from-to)1574-1585
Number of pages12
JournalChemMedChem
Volume9
Issue number7
DOIs
Publication statusPublished - 2014

Keywords

  • antitumor agents
  • chiral resolution
  • enantiomers
  • Hsp90
  • oximes

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Fingerprint Dive into the research topics of 'Chiral resolution and pharmacological characterization of the enantiomers of the Hsp90 inhibitor 2-amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8- dihydro-6H-quinazolin-5-one oxime'. Together they form a unique fingerprint.

  • Cite this

    Amici, R., Bigogno, C., Boggio, R., Colombo, A., Courtney, S. M., Dal Zuffo, R., Dondio, G., Fusar, F., Gagliardi, S., Minucci, S., Molteni, M., Montalbetti, C. A. G. N., Mortoni, A., Varasi, M., Vultaggio, S., & Mercurio, C. (2014). Chiral resolution and pharmacological characterization of the enantiomers of the Hsp90 inhibitor 2-amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8- dihydro-6H-quinazolin-5-one oxime. ChemMedChem, 9(7), 1574-1585. https://doi.org/10.1002/cmdc.201400037