Design, Synthesis And Anticancer Activity Of Pyrimidine Derivatives As Cyclin-dependent Kinase Inhibitors

Cancer has constituted major threat to human health.According to the World Cancer Report 2014,over 14 million people are suffered from cancer,and accounting for 8.2 million deaths in 2012.Deaths from cancer worldwide are projected to continue rising,new cancer cade are expected to rise from 14 million to nearly 22 million annually and lead to 13 million people death every year by 2030.Therefore,cancer has emerged as main threat to public health.A more detail understanding the molecular mechanism and the changes that occur during tumorigenesis as well as the search for a lower toxicity and higher efficiency anticancer agent has become a major task of medical field.Pyrimidine derivatives are an important class of six-membered heterocyclic compounds found in many synthetic and natural occurring products and play a key role in life activities.Pyrimidines have been widely used in medicine and agriculture owing to their possessing a wide spectrum of biological activity,such as antibacterial,insecticide,herbicide,antivirus,antitumor and antiviral activities.In recent years,pyrimidine derivatives which exhibited potent anti-tumor activities have been reported,and some of them have investigated in clinical trials.Although these structurally novel compounds have a common chemical moiety of a pyrimidine ring,there are a variety of mechanisms of their antitumor action.In order to find high activity,low toxicity and excellent anti-tumor effect of new lead compounds,sixty-four pyrimidine derivatives targeting CDK were designed and synthesized.The synthetic methods,anticancer activity,structure-activity relationship and spectral properties were studied,and many of them were found to show excellent antitumor activities.This dissertation may be summarized as follows:1.The research progress of pyrimidine derivatives are summarized in the paper.The review describes in detail their main regularities of the structure-activity relationship,antitumor activity,and biochemical mode of action.2.According to the binding mode of R547 and NU6027 in complex with CDK2,Forty-one 2,4,5-trisubstituted pyrimidine derivatives(?,? and ?)have been designed and synthesized.Total 41 new compounds' structures have been validated by the 1H NMR,ESI-MS and EA.In order to further confirm the structure of the desired compounds ? b and ?1,one single crystals were generated for structure elucidation.These compounds are summarized as follow:? a?? e:N2-substituted aromatic hydrocarbon-N4-(11-(methylsulfonyl)piperidin-4-yl)pyrimidine-2,4-diamine? a?? d:N4-substituted aromatic hydrocarbon-N2-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-2,4-diamine.? e?? m:N2-substituted aromatic hydrocarbon-5-chloro-N4-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-2,4-diamine.?a??g:Ethyl 2-((2-(substituted amino)-5-nitropyrimidin-4-yl)amino)acetate.?h??p:Ethyl 2-(benzyl(2-(substituted amino)-5-nitropyrimidin-4-yl)amino)acetate.?q??w:Methyl 2-(methyl(2-(substituted amino)-5-nitropyrimidin-4-yl)amino)acetate.By the MTT assay,we screen the antitumor activity for most of synthesized compounds on A549,HepG2,MDA-MB-231,and MCF-7 tumor cells,and succeed to find several kinds of lead compounds with excellent activity.The results showed compounds ?d,I e,? i and ?e exhibited pretty high potency against MDA-MB-231 with IC50 values from 1.99 to 15.83 ?mol/L,while 5-fluorouracil is 24.60?mol/L,respectively.Besides,compound I d showed pretty high potency against A549 with IC50 values of 12.78 ?mol/L,when 5-fluorouracil for 35.41 ?mol/L.Compound ?i and ?e also showed pretty high potency against A549 with IC50 values of 32.41 and 35.38 ?mol/L,when 5-fluorouracil for 39.88 ?mol/L.We further screen the cytotoxicity of compounds ?d,? e,?i and ?e on GES-1 cell.The results showed these compounds have lower cytotoxicity with IC50 values from 110.3 ?mol/L to 200 ?pmol/L,when 5-fluorouracil for 95.75 ?mol/L.The compounds ?d,?i and?e extract-induced growth inhibitory effect was associated with an arrest of cell cycle progression in G2/M phase as shown by the cell phase distribution.3.Using compound ?e as the precursor,twenty-three 2,8-disubstituted 7,8-dihydropteridine derivatives(IV)were designed and synthesized.Their structures have been validated by the 1H NMR,ESI-MS and EA.These compounds are summarized as follow:?a??g:2-(substituted amino)-7,8-dihydropteridin-6(5H)-one.?h??p:8-benzyl-2-(substituted amino)-7,8-dihydropteridin-6(5H)-one.?q??w:8-methyl-2-(substituted amino)-7,8-dihydropteridin-6(5H)-one.By the MTT assay,we screen the antitumor activity of ten of synthesized compounds on A549 tumor cell.The results showed some compounds exhibited comparative activity against A549 with 5-fluorouracil.