Synthesis and JAK2 inhibitory activities of 4-phenyl-pyrrolo[2, 3-d] pyrimidine derivatives / 中国药科大学学报

A series of 4-phenyl-pyrrolo[2,3-d] pyrimidine derivatives were synthesized through modifying the structure of the lead compound ruxolitinib by molecular hybridization strategy.It was synthesized from pyrimidine-4,6-diol by Vilsmeier-Haack reaction,SNAr reaction,cyclized,dehydration,Suzuki coupling and finally acylated to give 12 new compounds(12a-121).All structures of the synthesized compounds were confirmed by 1H NMR,13C NMR,and HRMS analysis.The biological activities were evaluated in vitro.Their JAK2 inhibitory activities were studied using JAK2 enzymatic and TF1-GMCSF cellular assays.The results indicated that compounds 12b,12e and 12h showed moderate activity.The anti-tumor activities were studied against JAK2-independent A549 cell line by the MTT assay.Results showed that the tide compounds exhibited potent antiproliferative effect on A549,especially compound 12c(IC50 =0.12 μmol/L),suggesting that this series compounds might be promising anti-tumor agents for futher investigation.

Design, synthesis and bioactivities of 4-(3-sulfonylbenzene) amino-6-formylpyrrole2,3-d pyrimidine derivatives / 中国药科大学学报

Taking JAK2 inhibitor baricitinib and fedratinib as the lead compounds,to design the novel 4-(3-sulfonylbenzene) amino-6-formylpyrrole[2,3-d] pyrimidine JAK2 inhibitors nucleus using the molecular hybrid drug design principle.17 target compounds were synthesized by derivatization of sulfonyl and formyl groups respectively.We used JAK2 kinase and GM-CSF-induced TF-1 cells to measure the activities of compounds.The results showed that most compounds had JAK2 inhibitory activities.Among them,compound 31 had excellent inhibitory activity on JAK2 kinase (IC50 =0.009 μmol/L) and GM-CSF-induced TF-1 cells (IC50 =0.136 μmol/L),which proved that the compound had potential research and development value.