Abstract
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 blottingand flow cytometry, respectively. Results: Compounds A1, A5 and A7 containing pyrido[3,2-d]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) atsubnanomolar levelsand had good δ-isoform selectivity. A1, A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in agood 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 thedesignofnovel potent and selective PI3Kδ inhibitors.
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