Fluorescent Purine Nucleosides Analogues:Synthesis And Properties

Objective : Nucleosides are basic components of nucleic acids(DNA or RNA).Nucleoside derivatives are widely used in drug research and development,molecular probes designed,cancer mechanism and so on.It is also used as anti-viral and antitumor reagent.The base and sugar moieties of nucleoside molecules can be chemically modified.The modification on C-8 position of the base moiety is one of the important ways to synthesize the new purine nucleoside derivatives.At present,there are few reports on the modification of the C8 position of 2-amino-2'-deoxyadenosine and 2'-deoxyisoguanosine.Our study intends to modify the 8 position of 2-amino-2'-deoxyadenosine and 2'-deoxyisoguanosine to obtain novel purine nucleosides with antitumor activity and fluorescence.Methods:1 Preparation of Compounds Halogenated purine nucleoside is an important intermediate of base modification.First,8-bromo-2-amino-2'-deoxyadenosine was synthesized by adding bromine drop-wise to a solution of 2-amino-2'-deoxyadenosine and sodium acetate in acetic acid.Then,8-bromo-2-amino-2'-deoxyadenosine was dissolved in DMF,and Pd(PPh3)2Cl2 / Cu I(1:2),Et3N(3 eq)and alkynes were added.The reaction was heated by microwave irradiation assistant to synthesize 8-alkynylated 2-amino-2'-deoxyadenosine nucleoside derivatives.In the same way,a series of 8-substituted adenosine derivatives were synthesized using 8-bromoadenisine as precursor.8-alkynylated 2-amino-2'-deoxyadenosine nucleoside were transformed to 8-alkynylated-2'-deoxyisoguanosine derivatives by heating at 50oC for 4.5 hours with Na NO2 and Ac OH in a H2O/THF(1:1)mixture solution.2 Study on Fluorescence Properties Fluorescence spectrum of 8-alkynylated 2-amino-2'-deoxyadenosine and 2'-deoxyisoguanosine were measured in water.The effects of solvent polarity(dioxane and methanol)and different p H(1.5-12)on the fluorescence spectrum of 8-alkynylated2'-deoxyisoguanosine also were investigated.3 Determination of the p Ka value of the compound The p Ka values of 8-alkynylated-2'-deoxyisoguanosine were measured by ultraviolet spectrophotometric titration method.4 Anti-tumor activity test The anti-tumor activities of 2-amino-2'-deoxyisoguanosine,2'-deoxyisoguanosine and adenosine derivatives on Prism human multiple myeloma cells were evaluated by CCK-8 method.The GI50 were calculated.Results: 8-bromo-2-amino-2'-deoxyadenosine,8-bromo-adenosine and 8-alkylnated2-amino-2'-deoxyadenosine and 2'-deoxyisoguanosine derivatives were obtained in 52-95% yield;the The structure of all new compounds were identified by 1H-NMR,13 CNMR and high resolution mass spectrum.compounds 2a-c and 3a-c were found to be fluorescent.The fluorescence wavelength and intensity of 3a-c were changed in different solution and p H;The compounds 2a,2c,4,4a,4b,4c had the effect on inhibiting the proliferation of MM.1S.The GI50 is 24.28,21.11,7.87,13.78,10.08,7.10,respectively.Conclusions : A series of new fluorescent 8-alkylnated 2-amino-2'-deoxyadenosine and 2'-deoxyisoguanosine derivatives were obtained with satisfied yields.The 8-alkylnated 2'-deoxyisoguanosine derivatives were sensitive to the environment and might be used as fluorescence probes.Some 8-alkylnated 2-amino-2'-deoxyadenosine and 2-amino-2'-deoxyadenosine derivatives could inhibit the tumor cell.