Design,Synthesis And Bioactivity Evaluation Of Bola-type Nucleoside

Nucleoside is composed of ribose and base.Nucleoside analogues are structurally mimics of the natural nucleoside.As an important family of antiviral and anticancer drugs,nucleoside analogues inhibit tumor proliferation or viral infection by specifically interfering with DNA synthesis,RNA transcription or protein synthesis.1,2,4-triazole nucleoside analogues are nucleosides bearing 1,2,4-triazole as nucleobase,which have antibacterial,antitumor and immunomodulatory activities etc.Bolaamphiphiles is a class of amphiphiles with hydrophilic head groups at both ends of the hydrophobic chain.Because of their unique chemical structure,bolaamphiphiles can realize the assembly of different functional aggregates at the interface and in the solution to form self-assembly structures such as micelles,vesicles,nanotubes and fibers etc.Improving the water solubility is an efficient way to ameliorate the pharmacokinetic and drug-like properties of the compounds and glucosylation or glucuronization are considered as important strategy to improve the water solubility.Moreover,as one of the important pharmacophores,the addition of the dimethylamino group to the parent compound have been found to not only provide improved biological activity,but also better physical and chemical properties.Therefore,we have designed three types of novel bola-type1,2,4-triazole ribonucleosides analogues.The first type is the bolaamphiphiles with1,2,4-triazole ribonucleoside as the head groups;the first type compounds are further glycosylated by β-D-glucopyranosyl to produce the second type bola triazole ribonucleosides.The third type analogues are constructed via adding dimethylamino groups to the sugar moiety of the first type ribonucleoside.In the work of this thesis,the above designed bola-type 1,2,4-triazole nucleosides analogues were synthesized and their structures were characterized.Then we investigated the water solubility of these compounds.The results showed that both modifications endowed the improved water solubility of the parent compounds.Based on the unique structure of bolaamphiphiles,we evaluated their self-assembly ability to form nanosize self-assemblies.The results showed that the aggregates form by bola nucleosides displayed Dindal effect in water.Further measurement of their critical aggregation concentration and hydrated particle size proved that these compounds could self-assemble into nanosized aggregates in aqueous solution.Moreover,we evaluated the bioactivity of the synthesized compounds in vitro and screened out the lead compounds with potent anti-proliferation activity against various cancer cells.From the analysis of structure-activity relationship,it was proved that the introduction of dimethylamino groups can greatly improve the antiproliferation activity of the compounds.Meanwhile,the data showed that the hydrophobic chain with appropriate length should play a significant role of the anti-proliferation activity.In conclusion,we designed and synthesized a series of novel bola-type1,2,4-triazole ribonucleosides.These compounds can form into nanosize self-assemblies in aqueous solution.Glycosylation and amination modification provided better water solubility of the original nucleosides and several lead compounds displayed potent anticancer activities.This family of compounds therefore has the potential to be developed as nanodrugs to treat cancers or other life-threaten diseases.