Anticancer Activity Research In Vitro And Quantitative Structure-activity Relationship Analysis Of Purine Derivatives

Purine antitumor drugs could inhibit the survival and replication of tumor cell by inhibiting the synthesis of folic acid,purine,and leading to tumor cell death eventually.Purine ring was modified on different 2,6,9 derivatives,which indicated that it could be accepted various compounds.Study on the 2,6,9-trisubstituted purine derivatives and purine hydroxamic acid derivatives,which were used as target compounds to screen through its activity in vitro,secondly,the two compounds were researched by quantitative studies.Select the SGC-7901 cells and A549 cells,K562 cells and Hep G2 cells as model,and determine the 50 purine derivatives and 26 purine hydroxamic acid derivatives by the MTT method,subsequently,calculate the IC₅₀on the tumor cell inhibitory concentration.Target compounds with 2,6,9-trisubstituted purine derivatives and purine hydroxamic acid derivatives,and its IC₅₀(μmol?L^-1)was transferred to p IC_50,which was used as experimental data and quantitative structure-activity relationship.Based on the OPLS method,2D-QSAR was established and obtained QSAR equation;and in view of the Cerius2 in the software of Discovery Studio 4.5,3D-QSAR was created.Finally,the relationship of compounds and tumor cell activity were analyzed by this model.1)The antitumor activity was compared to 2,6,9-trisubstituted purine derivatives with SAHA.In our study,3m,3h,4g,5a have good antitumor activity,which shown that the IC₅₀was 9.26μM,25.12μM,1.54μM and 3.49μM,respectively.Compound 4g not only has stronger antitumor activity in K562 cells,but also Hep G2 cells to.The antiproliferative activity of certain compounds are better than 5-fluorouracil（5-FU）and hydroxyurea（HU）,such as 3m,4o,3f and so on,especially,compound 3m showed broad spectrum antitumor activityIn this paper,purine hydroxamic acid derivatives as the target compounds were investigated via its biological activity in vitro,by comparing the resistance of tumor cell proliferation of target compounds and SAHA.Compound 8k(IC₅₀=4.85±0.47μM)is higher than the SAHA(IC₅₀=1.21±0.12μM);the inhibitory activity of compound 8j(IC₅₀=11.10±0.58μM)on K562 cells is higher than the HU(IC₅₀=19.86±0.36μM);the inhibited activity of compound 8i on SGC-7901 cells,A549 cells and K562 cells is higher than the 5-FU and HU.Finally,all of above compounds were further studied by QSAR.2)Based on the 2D-QSAR model,which was established by 2,6,9-trisubstituted purine derivatives compounds,and four models were set up according to the correlation coefficient r²and coefficient of cross-validation q².Among them,Hep G2cell model（r²=0.833,q²=0.726）was better in all cell models.Similarly,in the3D-QSAR model,A549 cell model（r²=0.995,q²=0.552）also was preferable in cell patterns.In summary,all of patterns have research significance and predictive ability,especially in the activity research.Based on the 2D-QSAR model,which was established by purine hydroxamic acid derivatives,and four models were found according to the correlation coefficient r²and coefficient of cross-validation q².Among them,A549 cell model（r²=0.767,q²=0.726）was better in all cell models.Similarly,in the 3D-QSAR model,two patterns were obtained,A549（r²=0.887,q²=0.506）and K562（r²=0.905,q²=0.654）had stronger activity in this model.In a word,the established model was predictable to antitumor activity.Study on the activity assessment of 2,6,9-trisubstituted purine derivatives and purine hydroxamic acid derivatives in vitro,and construct 2D and 3D quantitative structure-activity relationship model,which lay a foundation for further study of purine derivatives.