Design,Synthesis And Antiproliferative Activity Study On Novel Purin-8-one Derivatives

Purine rings are the most common nitrogen-containing heterocycles in nature.They are found in a variety of marine organisms and plants and is also nucleic acids(RNA and DNA)adenine and guanine core structure.Due to their broad spectrum of biological activity,purines and their derivatives are widely used in the pharmaceutical industry for the treatment of various diseases.Such as anti-asthma drugs,cardiovascular drugs,central nervous system(CNS)stimulants,immune enhancers,antiviral,antifungal and antibacterial,anti-tumor and so on.The focus of this paper is to study the role of purine compounds in anti-tumor.In the aspect of anti-tumor,purine compounds have been studied long ago,such as 6-Mercaptopurine and 6-Thioguanine were used for the treatment of leukemia early.As well as Nelarabine,Clofarabine,Idelalisib and R-roscovitine,all have good anti-tumor activity.In this paper,the applications of purine compounds in anti-tumor were introduced.And a series of purin-8-one compounds were designed and synthesized through the study of structure-activity relationship on the basis of our previous study of purine derivatives.The anti-tumor activity of the synthesized compounds was studied by MTT method.In this study.30 novel target compounds were synthesized.And all the target compounds were confirmed by 1H-NMR,13C-NMR and HRMS.The 2,4-dichloro-5-nitropyrimidine was used as the starting material and reacted with different substituted primary amines to prepare the nitro-pyrimidinamine intermediates.The intermediates were reduced by stannous chloride,followed by condensation and cyclization reaction with phenyl chloroformate to form the purine intermediates.Then the target compounds 5a to 5j could be prepared by subjecting them to an aromatic nucleophilic substitution reaction with different substituted aniline.The target compounds 6a to 6r were prepared by the target compounds 5a to 5j reacting with the halogenated materials.The target compounds 7a and 7b were prepared by removing the Boc-groups under acidic conditions using 5j and 6r as raw materials.In vitro antiproliferative activity experiments showed that a number of compounds exhibited good anti-proliferative activities against Hela at 50 ?mol·L-1.By analyzing the structure-activity relationship,it was found that the activity of the ethyl acetate fragment,the acetone fragment and the acetic acid fragment being introduced at the N7 position of the purin-8-one was poor,and the activity of propyl group,allyl group,propargyl group and benzyl group was remarkable improved.The activity of the compounds were better when the N9 position of the purin-8-one was a cyclohexyl group or a phenyl group,and the activity of the compound is also remarkable improved when the hydroxyl group,Boc-piperazinyl group or piperazinyl group were introduced into the benzene ring.The activity of the compounds 5h,6h,6i and 6j are excellent and the inhibitory activity against Hela,MOLT-4 and K562 tumor cell lines is similar or superior to R-roscovitine.These compounds can be used as lead compounds for further structural optimization and modification to develop the more potential anti-tumor compounds.