Synthesis And Antiviral Activity Of Purine Deoxyribonucleoside Analogues

Thymine,cytosine,adenine and guanine are natural 2'-deoxynucleobases that exhibit certain activity in inhibiting the synthesis of nucleic acids in tumor cells or viruses,but it is less effective for treating tumors or viral diseases;in addition,with the emergence of new pathogens and the evolution of old pathogens,the host's own immune response is confused,losing the ability to inhibit tumors or viruses.Nucleoside phosphonates are characterized by isosteric,heteropolar and isoelectronics.Under the action of enzymes,they can be converted to corresponding corresponding triphosphonate analogs with strong antiviral or antitumor biological activity.In this paper,we refer to the chemical structure of antiviral drugs such as entecavir and tenofovir levamide,and design and synthesize a series of new nucleoside phosphonate compounds by bioisosteric theory,and antiviral of new compounds.The activity was evaluated and the research contents are as follows:(1)The carbon oxygen double bond of guanine is alkylated to guanine analogue,and the hydroxyl group of the ribose is modified and reacted with guanine analogue,and then substituted with phosphorus oxychloride,and finally with L-alanine.The reaction of p-toluenesulfonates and vitamin B6 esterification derivatives,The branched purine nucleoside phosphonate compound was obtained.Pass antiviral activity test,(3-(((R)-((2R,3R,4R,5R)-5-(2-amino-6-ethoxy-9H-purine-9-group)-4-fluoro-3-hydroxy-4-(methyltetrahydrofuran-2-group)methoxy((((S)-1-isopropyl-1-oxypropane-2-group)amino group)phosphoryl group)-5-(hydroxymethyl)-2-methylpyridine-4-group)methylisobutyrate(7?)shows weak antiviral activity,Cytotoxicity occurs only at 200 ug/ml and therefore has the potential to continue research and needs further development.(2)The uracil is used as a base,the ribose is reacted as a sugar group,and then replaced with phosphorous oxychloride.Finally,L-alanine is added to toluenesulfonate and pyridoxine diacetate to obtain a branched chain.Pyrimidine nucleoside phosphonate target compound,after antiviral activity test,Basically no antiviral activity and showed a certain degree of cytotoxicity.(3)Using phenol as the starting material,(S)-cyclopentyl-2-hydroxy-2-(2-hydroxyphenyl)acetate compounds with two reaction sites are obtained by substitution reaction,hydrolysis reaction,and esterification reaction.The cyclic purine nucleoside phosphonate compound was obtained by substitution and polymerization of phosphorus trichloride and nucleoside analogues.After the antiviral activity test,no activity was found.(4)The carboxyl and amino groups of L-pyroglutamic acid are protected by Bn and Boc,respectively,and then hydrolyzed to give alcohols.The resulting alcohols are sulfonated and etherized,and then reduced to give thiols,which are then reacted with phosphorus trichlorochloride.Cyclic,Finally,it was replaced with nucleoside analogues to obtain heterocyclic purine nucleoside phosphonate compounds.Through antiviral activity test,(2S,4S)-2-(((2R,3R,4R,5R)-5-(2-amino-6-methoxyl-9H-Purine-9-base)-3,4-dihydroxy-4-methyltetrahydrofuran-2-group)-1,3,2-thiazolophoshetero-cy cloheptane-4-carboxylate-2-oxide(20?)showed moderate inhibition,However,at 45?M,strong cytotoxicity occurred,so toxicity needs to be reduced and activity increased,and further research is needed.Through the modification design of three structural fragments of base,glycosyl or phosphonate,a series of nucleoside phosphonate compounds were synthesized and evaluated for antiviral activity.It was found that only 7? and 20? have certain potential value.,laid the foundation for subsequent research.