Design,Synthesis And Antitumor Activity Studies Of N-9-Position Aromatic Substituted Purine-8-one Derivatives

Purine,which is mainly composed of a pyrimidine ring and an imidazole ring,is an important class of compounds in nature and the most widely distributed nitrogen-containing heterocyclic compound among natural heterocyclic compounds.Purine derivatives can interact with many enzymes or receptors to participate in various life activities,and thus have a wide range of biological activities.Currently,purine derivatives are widely used in the pharmaceutical industry,such as anti-tumor,anti-viral,anti-inflammatory,anti-bacterial,anti-asthma and immune enhancers.Specially,purine derivatives have been used as anti-tumor drugs for a long time.Since the development of thiopurinine antimetabolite,many purine derivatives have been found to have anti-tumor effects.However,the exact targets of several bioactive purine derivatives remain unclear.In this thesis,the role of purine compounds in different fields,especially anti-tumor,will be introduced and discussed.According to previous work of our research group,the substitution of different groups at purine N7 position had little effect on the improvement of anti-tumor activity,whereas the arylamine of C2 contributed to the improvement of anti-tumor activity.Also,the introduction of benzene ring in N9 position showed improved antitumor activity.Therefore,we removed the N7 substituents in the purine-8-one-based structures,and mainly investigated the effects of different substituents at C2 and N9 on antitumor activity.A series of novel N-9-position aromatic substituted purine-8-one derivatives were designed and synthesized and their anti-proliferation activities against tumor cells were investigated.A total of 33 new compounds were synthesized from 2,4-dichloro-5-nitro-pyrimidine by nucleophilic substitution,reduction,cyclization and ammonification.Among them,4 new intermediates and 29 new target compounds were discovered.The structures of all the target compounds were confirmed by 1H NMR,13C NMR and HRMS.The results of anti-proliferation test of tumor cells in vitro showed that some compounds had good anti-proliferation activities.On the basis of structure-activity relationship(SAR)analysis,we found that when isopropyl(8d-12d),dimethylamino(8e-12e)and methanesulfonyl(8f-12f)were introduced to the para-position of C-2 aniline,the activities were lower than that of 8b?12b and 8c?12c.At the same time,although the different substituents of N-9 benzene ring have little effects on the activity,the electron-withdrawing group trifluoromethyl can increase the inhibitory activity to several tumor cells.Furthermore,it was found that the best compound 12c,which was substituted by trifluoromethyl at the N-9 position,exhibit the better anti-proliferation activity than that of the positive control R-Roscovitine.In summary,we reported a series of new purine-8-one-based as potential anti-tumor agents.Compared with the previous results,the anti-tumor activities of different substituted benzene rings at N9 was significantly improved,and the antitumor activities of tumor cells was enhanced by the introduction of trifluoromethyl,an electron-withdrawing group,in the presence of trifluoromethyl group.These findings may serve as a starting point for the future design of new anti-tumor compounds.Since our newly discovered target compounds already exhibit good antitumor activities,future efforts are needed to investigate their anti-tumor mechanism as well as binding target.Meanwhile,further structural modification are also needed in order to find more efficient and selective anti-tumor compounds.