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

• Published in: ChemMedChem 2014-07, Vol.9 (7), p.1574-1585
• Main 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
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; antitumor agents; Binding Sites; Cell Line, Tumor; chiral resolution; enantiomers; Female; HCT116 Cells; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Mice; Mice, Nude; Microsomes - metabolism; Molecular Docking Simulation; Neoplasms - drug therapy; oximes; Oximes - chemistry; Oximes - pharmacology; Oximes - therapeutic use; Protein Binding - drug effects; Protein Structure, Tertiary; Quinazolinones - chemistry; Stereoisomerism; Xenograft Model Antitumor Assays
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201400037

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.