Ultrasound-assisted Huisgen-Click Reaction Application Of Chrysin's Modification And Their Interaction With Protein

N-heterocyclic drugs account for a large proportion of currently clinical used drugs and more than half of top 200 global pharmaceutical drugs contains the N-heterocyclic structure.1,2,3-triazoles, as a member of N-heterocycles, bear various biological activities such as anti-HIV, anti-microbial, anti-allergic, and selectiveβ3 adrenergic receptor agonist. Recently,1,2,3-triazole moiety, as an important pharmacophore, was widely introduced in to peptides, DNA, RNA and carbohydrates and so on. And the modifications showed good results. Chrysin, an important naturally occurring flavonoid, bears multiple biological activities, such as anti-viral, antibacterial, antioxidant, anticancer activities. However, the activity of chrysin decreased due to its poor absorption in the intestine. Copper(I)-catalyzed 1, 3-dipolar Huisgen cycloaddition (CuAAC) reaction of azides and terminal alkynes gained much attention because it is an mild, high yield, good regioselectivity method and greatly used in synthesis and structural modification of durgs.In the work describe in this chapter 1, the recently development and applications of Huisgen-Click reaction, the structure modifications of chrysin were reviewed. In the following chapters,1,2,3-triazole moiety was firstly coupled with chrysin by an optimized ultrasound-assisted Huisgen-Click reaction and a series of chrysin derivatives linked with 1,2,3-trizaole moiety were synthesized. The non-covalent interaction between those chrysin derivatives and BSA was studied by fluorescence spectroscopy and UV absorption spectroscopy.1,The reaction between propargyl phenyl ether and ethyl 2-azidoacetate was selected as a model reaction for investigating the influence of ultrasound on the rate and yield of cycloaddition with different catalysts, solvents, base and ligand. The reaction condition was optimized through a series of experiments. The results are as follows:(1) Ultrasound irradiation not only acceletates the cycloadditon rate but also improves the product yield. Water is the better solvent than other tested solvents. Cu(OAc)2 is better than other tested Cu(II) salts in the catalyst system where Cu(I) ion is generated in situ; (2) Thirty two 1,4-disubstituted triazole derivatives were synthesized under the optimized condition, twenty of which are new compounds. Their structures were confirmed by IR, ESI MS and NMR. (3) The influence of ultrasound on the regioselectivity of the reaction was studied. The structure of 1,4-disubstituted triazole derivative was confirmed by 2D NMR such as HMBC, COSY, NOE.2,A series of chrysin derivatives linked with 1,2,3-triazoles were synthesized using the CuAAC reaction under optimized conditions. The 1,3-dipolar cycloaddition reaction can be successfully carried out using CuSO4/sodium ascorbate as the catalyst,t-BuOH-H2O (1:1 v/v) as the solvent under the help of ultrasound at room temperature. Structures of the novel 14 compounds were determined by NMR, ESI MS, IR and elemental analysis. All the 1H,13C chemical shifts of the compound were assigned using 2D NMR techniques, including DEPT,1H-1H COSY,13C-1H HSQC,13C-1H HMBC.3,The interaction of five novel chrysin derivatives with Bovine Serum Albumin, Lysozyme were studied using fluorescence spectroscopy and UV absorption spectroscopy. The result showed that small molecules are able to couse fluorescent of proteins quench, and the quenching process is static quenching. Electrostatic and hydrophobic forces are mainly involved in the initial interaction. Binding constant between 2-5-1 and BSA is as 5.5 times as that between chrysin and BSA, which indicates that the introduced 1,2,3-triazole enhanced the interaction between the small molecules with BSA.