Design,Synthesis And Anticancer Evaluation Of 6,9-Disubstituted Purine Hydroxamate Derivatives

Purine is a substance that exists in the human body,purine nucleotides is the main form,it plays a very important role in energy supply,metabolic regulation and coenzyme.DNA and RNA are composed of purine and pyrimidine,they are very important in the process of life.Purine derivatives have satisfactory result in clinical treatment including cancer,AIDS and other aspects.Histone deacetylase is a kind of protease,which plays an important role in the structural modification and regulate gene expression.intracellular histone acetylation levels is increased by histone deacetylase inhibitors,improve the gene expressionlevel and inhibiting tumor cell proliferation.induced cell cycle arrest,autophagy,apoptosis,and differentiation.it has been proved to huge potential on cancer therapy.Due to hydroxamic acids derivatives have excellent inhibitory activity on HDAC.In recent years,it have been paid much attention by researchers.This paper main study to the following several aspects:Firstly,The synthesis methods and biological activities of purine derivatives are reviewed in this paper,which provided a reference for the development and screening of purine hydroxamic acids derivatives.Secondly,the start material of 6-Chloropurine design a reasonable route and synthetise different purine hydroxamic acids derivatives.The synthesis route is6-chloropurine reacted with fatty amine and aromatic amines in n-butanol at 90℃in the presence of triethylamine to give 6-fat amine purines derivatives and6-arylaminopurine derivatives.Using ethanol as solvent,sodium alkoxide as acid-binding agent,by O-alkylation synthesis of purine derivatives.The purine derivatives soluble in DMF,K₂CO₃as acid binding agent,reaction at room temperature,by replacing the N9 position on the synthesis of active ester intermediates.Finally,using methanol as solvent,sodium methoxide as acid binding agent,reacting with hydroxylamine and the synthesis the target compounds 6,9substituted purine hydroxamic acid derivatives.Thirdly,in the paper use Computer aided drug design for the target compounds,using Autodock software study to target compound and HDAC8 of the molecular recognition,docking results are analyzed and discussed.Fourly,the study of target compounds in vitro biological activity.By comparing the target compounds with positive control drug HDAC inhibitory activity and antitumor activity of cell proliferation.The target compounds were investigated for their in vitro HDAC inhibitory activities and anti-proliferative activities.Results indicated that 3f,3g,5f,5g,compounds could effectively inhibit HDAC and possess obvious anti-proliferative activity against tumor cells.3f(IC₅₀=1.40±0.18μM),3g(IC₅₀=0.92±0.14μM),5f(IC₅₀=1.34±0.15μM),5g(IC₅₀=1.99±0.17μM).Among them,target compounds 3g,exhibited excellent inhibitory effect ompared with SAHA(IC₅₀=1.21±0.12μM).Compound 3l(IC₅₀=14.64±1.20μM)exhibited better anti-proliferative activity against A549 cells.Compound 5g(IC₅₀=11.10±0.58μM)on K562 cell inhibitory activity is higher than the positive control drug HU(IC₅₀=19.86±0.36μM).Combined 5F on SGC-7901 cells,A549 cells,K562 cell exhibited more excellently inhibitory activity than the positive control drug 5-FU and HU.These compounds will be selected as new lead compounds to further develop more potent HDAC and cancer cells inhibitors in the future.