Design,Synthesis And Biological Evaluation Of PROTACs For Degradation Of Galectin-3

Galectin-3 is the only chimeric member of the Galectins family defined as a protein family based on conserved ?-galactoside-binding sites found within their characteristic carbohydrate recognition domains(CRDs).Galectin-3 distributing in mammalian tissues widely exhibites important physiological functions.Over expression of Galectin-3 in related cells is able to promote various diseases process.For example,Galectin-3 promotes tumor metastasis and protects tumor cells from anoikis.Reducing the expression of Galectin-3 or blocking its biological effects through gene knockout,gene editing or RNA interference can achieve the treatment of related diseases,so Galectin-3 is a new target for treatment of related diseases.In recent years,the development of Galectin-3 inhibitors has made a great progress.However,small molecule inhibitors that bind to single domain of Galectin-3 do not affect other domain-mediated effects because of its chimeric structure.On the other hand,current Galectin-3 small molecule inhibitors show poor selectivity and remain to be further developed.PROTACs is a recently developed small molecule drug design strategy based on the mechanism of intracellular ubiquitination protein degradation.In this strategy,target protein was induced to ubiquitinate with E3 ubiquitin ligase,and then was degraded,which achieve the "knock out" of target proteins after the translation.The core of this strategy is the proteolysis targeting chimeras molecules(PROTACs molecules)consisting of three parts,which include target protein ligand,E3 enzyme ligand,and the linker connecting the first two.In this thesis,application of PROTACs technology to achieve the clearance of over-expressed Galectin-3 in cells and block its adverse biological effects was described.We designed and synthesized PROTACs molecules that are able to induce Galectin-3 to be degraded by the ubiquitin proteasome system.18 molecules were synthesized in this thesis and were subjected to extracellular inhibitory activities by fluorescence polarization assay.The results showed that compounds 9-11 retained the inhibitory activity against Galectin-3,while the inhibitory activities of the remained compounds reduced in varying degrees.