Synthesis and biological evaluation of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives as novel PI3Kδ inhibitors

An efficient synthesis of novel 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine scaffold has been designed and deveopled. A series of 5-phenylurea derivatives was synthesized using this method. Their cytotoxic activities against breast cancer cell line BT-474 were evaluated by CCK-8 assay. Most of them showed potent anti-proliferative activities, of which compound 20 and 21 exhibited IC50s of 1.565 μmol/L and 1.311 μmol/L, respectively. Furthermore, compound 20 and 21 also showed potent inhibitory activities against PI3Kδ with IC50s of 0.286 μmol/L and 0.452 μmol/L, respectively. These results indicate that these 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives are novel antitumor agents through the inhibition of PI3Kδ.

Graphical abstractAn efficient synthesis of 3-(piperidin-4-yl)isoxazolo[4,5-d]pyrimidine derivatives has been designed and developed. A series of novel PI3Kδ inhibitors with potent antitumor activities have been identified.Figure optionsDownload full-size imageDownload as PowerPoint slide