Synthesis And Bio-active Study Of Pyrimidine Derivatives

Pyrimidine is often applied as a main structure in medicinal development.There are many kinds of drugs that contain the structure of pyrimidine,including anticancer,antibacterial,antihypertensive,immune drugs and so on.In chapter two,according to the previous work of our group,the position and number of methyl groups on pyrazolo[4,3-d]pyrimidine were changed to explore the influence of methyl groups on the inhibition rate of BTK of these compounds.Seven1-methyl,2-methyl pyrazolo[4,3-d]pyrimidine derivatives were designed and synthesized.In vitro kinase assay indicated that the compounds without 3-methyl group showed different inhibition rate against BTK.1-methylpyrazolo[4,3-d]pyrimidine derivatives exhibited even higher levels of immune activity and BTK kinase inhibition than 2-methylpyrazolo[4,3-d]pyrimidine derivatives.Compound 11a-3 showed the most potent inhibition(Con A IC₅₀=0.34?M,LPS IC₅₀=0.1?M,BTK IC₅₀=7.69n M).Unfortunately,this series of compounds exhibited poor selectivity against BTK compared to Ibrutinib.In chapter three,5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine was used as the main structure and connected with reactive warheads(sulfonyl fluoride,ethylene sulfonyl and dichlorotazine)that can covalently bind with lysine residues.Three tetrahydropyridine[4,3-d]pyrimidine derivatives were designed and synthesized,in an attempt to explore the influence of different warheads on the inhibition rate of these compounds against PI3K?and the reactivity of warheads with cysteine and lysine.The results indicated that 3-22(dichlorotazine warhead)had mild reactivity with lysine residue(t_1/2=5 h).However,in vitro kinase assay indicated that the series of compounds had slight inhibitory effect against PI3K?.