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. Issue 7 (17th April 2014)

• Record Type: Journal Article
• Authors: Amici, Raffaella; Bigogno, Chiara; Boggio, Roberto; Colombo, Andrea; Courtney, Stephen M.; Dal Zuffo, Roberto; Dondio, Giulio; Fusar, Fulvia; Gagliardi, Stefania; Minucci, Saverio; Molteni, Marco; Montalbetti, Christian A. G. N.; Mortoni, Annalisa; Varasi, Mario; Vultaggio, Stefania; Mercurio, Ciro
• Is Part Of: ChemMedChem. Volume 9:Issue 7(2014:Jul.)
• Page Start: 1574
• Page End: 1585
• Publication Date: 2014-04-17
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201400037
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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‐6<italic>H</italic>‐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 (<italic>S</italic>) 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.</p> </abstract>