Design,Synthesis And Anticancer Evaluation Of C6,N9 Disubstituted Purine Hydroxamate Derivatives

Tumor is one of the largest causes of deaths in the world,which isa very threat to human’s life.Researchers have always been devoted themselves to discover safe and effective anti-tumor drugs.Therefore,purine compounds’and hydroxmaic acid compounds’good biological activity in terms of anti-tumor become the focus of scholars studies.This thesis mainly studies in the several aspects followed:Firstly,research progress and anti-tumor mechanism of purine derivatives and hydroxmaic acid compounds are reviewed in this paper,which will provide a reference for the research of purine hydroxamic acids derivatives.Secondly,we designed tworeasonable routes for synthesis of purine hydroxamic acid derivatives by using 2,6-dichloro purine and 6-chloro purine as materials.The first synthetic route is 2,6-dichloro purineand different fatty amineproduct 6-fat amino substituent purine derivatives via N-alkylation reaction at purine C-6.Then,the active ester intermediates were synthesized by substitution of N9 with the corresponding ester.At the end,the ester intermediates react with oxammonium hydrochloride to form synthesis 9-substituent of purine hydroxamic acid derivatives.The second synthetic route,which is materialed by 6-chloropurine or 2,6-dichloro purineandtwo different amines,issubstituted by different diamine at purine C-6.Then it reacted with aniline to synthesize 2,6-disubstituted purine derivatives under the effect of TEA.And then reacted with 4-nitro phenyl chloroformate to form active ester,at the end the ester intermediates reacted with oxammonium hydrochloride to form synthesis 6-substituent of purine hydroxamic acid derivatives.The other is6-dichloro purine is substituted for 6-substituent of purine hydroxamic acid derivatives only at purine C-6 with the second methods.Atotal of 15 compounds were synthesizedand identified their structures via IR、MS、¹H-NMR and ¹³C-NMR methods.Thirdly,I use Computer software Autodock to dock target compound drugs and HDAC8 in molecular level,and analyze and discuss it according to the results of docking target compounds with the active site of HDAC of metalion Zn²⁺、hydrogen bond interaction and hydrophobicinteractionand etc.Fourly,the target compounds were investigated for their anti-proliferative activities.By comparing the antitumor activity of the target compounds and the positive control drugs,some compounds with better activity were screened out.The inhibitory activity of the target compound 5d(IC₅₀=16.62±2.31 M)and 12c(IC₅₀=45.35±0.21 M)on SGC-7901 cells were higher than that of the positive control drug 5-FU(IC₅₀=50.38±1.21 M).5d(IC₅₀=8.21±0.62 M)had good inhibitory activity on K562 cells,which was about 3 times higher than that of the positive control drug HU(IC₅₀=23.11±0.14 M).The target compounds 4d(IC₅₀=1.77±0.32μM),5d(IC₅₀=1.74±0.32μM)and 5f(IC₅₀=1.91±0.14μM)were close to the positive control drug SAHA(IC₅₀=1.35±0.09μM).