Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold.

Aim: In our study compounds with pyrido[3,2- d ]pyrimidine and pyrido[3,4- d ]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blotting and flow cytometry, respectively. Results: Compounds A1 , A5 and A7 containing pyrido[3,2- d ]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) at subnanomolar levels and had good δ-isoform selectivity. A1 , A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in a good concentration-dependent manner. A7 induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that A1 , A5 and A7 bound tightly to PI3Kδ through key hydrogen bonding interactions. Conclusion: This study suggests that employing pyrido[3,2- d ]pyrimidine can facilitate the design of novel potent and selective PI3Kδ inhibitors.