Design,Synthesis And Bioactivity Evaluation Of Multifunctional Bola-type Nucleoside Derivatives

Bolaamphiphiles is a class of amphiphiles with hydrophilic head groups at both ends of the hydrophobic chain.Thanks to the unique characteristics of bolaamphiphiles,they have attracted wide attention as bioactive entities or as biological materials for gene or drug delivery.1,2,4-triazole nucleoside analogues represented an important family of compounds with potential biological activities,such as antiviral,antimicrobial,antitumor activities etc.Theranostic agents combine the tumor diagnosis or monitoring with the treatment of tumors,which provides an alternative solution for the current cancer treatment and further to realize personalized medicine.In this thesis,we designed and synthesize a series of bola-type 1,2,4-triazole nucleosides with antiproliferative activity against cancer cells as well as bearing fluorescence moiety to have the potential to be imaging agents.The work of this thesis mainly included the following parts:Firstly,a series of bola-type nucleoside derivatives were designed,synthesized and characterized.These compounds have 1,2,4-triazole nucleoside as the polar head group and the ester bond,alkyne group and 1,2,3-triazole were the linker to connect the polar head group and the hydrophobic chain.With the bola-type 1,2,4-triazole nucleoside derivatives in hand,we studied their antiproliferative activity in various cancer cells and screened out several lead compounds.Based on the unique amphiphilic structure of bolaamphiphiles,we next investigated their self-assembly ability to form nanosize self-assemblies.We checked the critical aggregation concentration,hydrated particle size and zeta potential of nano-assemblies formed by these bola compounds.In addition,the morphology and size of the nano-assemblies were investigated by transmission electron microscope.These results suggested that bola-type nucleoside derivatives can form stable spherical nanosize self-assemblies in aqueous solution.As some of our synthesized bola-type nucleosides contained fluorescent group,we studied their fluorescence properties via fluorescence spectra.Further study on the cell uptake showed that the exposure of the cell to the fluorescent derivatives could enhance the fluorescence signal within the cells,indicating the potential of these compounds to be the cell imaging agents.In conclusion,we have designed and synthesized a series of novel bola-type 1,2,4-triazole nucleoside derivatives,which not only exhibit antiproliferative activity against a variety of cancer cells,but also can self-assemble into spherical nanosize self-assemblies in aqueous solution.Also,thanks to bearing the fluorescent group,some of the compounds may have potential application in cell imaging.These bola-type nucleosides therefore can be further developed as candidates for targeted cancer diagnostic and therapeutic reagents.