Design,synthesis and antitumor activities of 4,6-disubstituted pyridopyrimidine compounds
Objective To synthesize 4,6-disubstituted pyrimidines and study their antitumor activities.Methods Reference to the structure-activity relationship of small molecule inhibitors of MNKs kinase and the results of computer virtual docking evaluation,a series of 4,6-disubstituted pyridino[3,2-d]pyrimidines were designed and synthesized.The key intermediate 4,6-dichloropyrimido[3,2-d]pyrimidine(4)was obtained from 6-chloro-2-cyano-3-nitropyridine through reduction,hydrolysis,cyclization and chlorination,and then different anilines were introduced at position 4 by nucleophilic substitution reactions,the target compounds were obtained through Suzuki coupling,acylation and deprotection reactions.Inhibitory activities of the compounds on MNK1 and MNK2 kinases and tumor cell proliferation in vitro were investigated.Results 22 unreported target compounds were obtained.Among them,compounds 12r and 12u had significant inhibitory activities on MNK2,with IC50 values of 0.5 μmol·L-1 and 0.1 μmol·L-1;compound 12u inhibited the proliferation of human colon cancer HCT-116 cells,with a GI50 value of 0.71 μmol·L-1.Conclusions 4,6-disubstituted pyridino[3,2-d]pyrimidines have certain MNK2 inhibitory activity.Compound 12u has the same activity as the lead compound B21,and its inhibitory activity on the proliferation of human colon cancer cells HCT116 is superior to B21.
MNK small molecule inhibitorpyridopyrimidine compoundsanti-tumor
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