Microwave-Assisted Synthesis Of Functional Carbohydrate Conjugates;Synthesis And Application Of Water-Soluble Triazologlycosyl Fluorescence Probes

Carbohydrate is one of the three nutriments in organism attending many parts of metabolism. Recently, varieties of interdisciplines related with carbohydrate have being rapidly developed including glycochemistry, glycobiology, glycoimmunology and glycomics. It would be critical for regulation in life process to use carbohydrate molecules as carrier or probe through studying structure and function of carbohydrate and molecular interactions combining chemical approaches and biological approaches and proving up the mechanism of carbohydrate in life process, and then,. This thesis is based on exploring of application of monosaccharide on both of drugs of carbohydrate as skeleton and sugar probe, it could be divided into two parts:Part1Protein Tyrosine Phosphatase (PTP) is an important regulator of signal transduction which control growth, differentiation and metabolism of cells by regulating tyrosine phosphorylation level. Varieties of diseases including diabets, obesity, cancer and osteoporosis may happen because of improper regulating. PTP1B and CDC25B are two important members in PTP family who have been potential therapeutic targets of type2diabets, obesity and cancer. Development of smaller molecular inhibitors with high catalytic activity, higher bioavailability and high selectivity has been positive strategy of drug discovery.In this part, two series of compounds of triazole-linked functional glycosyl have been constructed on the basis of monosaccharide as skeleton combining with both modularized specific’Click’(Cu-catalyzed cycloaddition reactions between azides and alkynes) and microwave-assisted synthesis, a set of activity data obtained by selecting bioactivity of enzyme targets in PTP family of some target compound and reasonable activity analysis resulting from structure-activity relationship gained through computer-assisted docking all contributing to reference of following research and structural modification:1. The1st series of glycosyl amino acid derivatives were generated by’click’chemistry between C1-propargyl benzyl sugar and azido natural amino acid. The synthesized glycosyl triazoloamino acid derivatives all have inhibition activity of PTP IB and CDC25B with micro-mole level and show specified selectivity of homologous PTP.27has the best PTP1B inhibitory effect (IC50=5.1μM),while28shows better CDC25B inhibitory effect (IC50= 3.9μM).16compounds among them have not yet been reported in the literature so far.2. The2nd series of glycosyl salicylic acid derivatives was generated by’click’reactions between C1-propargyl acetyl sugar and azido polar(hydroxy)benzoates. IC50value to PTP1B of41was36.6μM demonstrating4-time inhibitory activity of other homologous PTP(IC50>160μM).51(50.5μM,98.4%inhibition rate) shows better selectivity comparing with it’s epimer54(35.3%inhibition rate).21compounds among them have not yet been reported in the literature.Part2Fluorescence probe technique is widely used in detecting heavy metal ions, toxic gases and organic contaminants and is applied in detecting aquatic environmental, iron and smaller molecules in creatures more and more. Carbohydrate has been usually used as structural skeleton when generating water-soluble and biological fluorescence probe molecule because of it’s unique stereochemical structure, flexible bioavailability and strong water solubility.In this part, monosaccharide was used as key skeleton to synthesize a series of fluorescent recovering bis-triazolocoumarin glycosyl conjugates by microwave-assisted dual click chemistry between C2,3-or4,6-bis-propargyl1-methoxy glucose, galactose and mannose with fluorescence quenched3-azido coumarin derivative with high conversion and yield. Then, benzyl dropped84and85which have good water-solubility were initially tested by UV and fluorescence in pure water resulting in some significative conclusions providing basic data for further optical test, and it would be used to detect ion-selecting in aquatic environmental; on the other side, galactose-based aminoxy peptide analog fluorescence probe molecule was successfully designed and some preliminary results were presented.16compounds among them have not yet been reported in the literature.