Design,synthesis and antitumor activity evaluation of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives as PIM/MNK dual inhibitors
With compound 21o as the lead,a series of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives with PIM/MNK dual inhibitory activity were designed through molecular docking technique.Using 4,6-dichloropyrido[3,2-d]pyrimidine as the starting material,the target compounds 10a-10n were obtained via nucleophilic substitution reaction,followed with Suzuki coupling reaction.Moreover,the scaffold hopping strategy was used to design the isoindolinone derivatives 11a-11g with more restricted conformation.The kinase inhibitory activity of target compounds was assayed by HTRF method,and the results indicated that some compounds displayed potent PIM and MNK dual inhibitory activity.The antiproliferation activity of target compounds against PC-3 and HCT-116 cell lines was measured using MTT assay.The result demonstrated that compound 11f displayed better antiproliferation activity than compound 21 o and SGI-1776,which worthed further research.
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