Synthesis Of Novel Phosphorylated Chrysin Derivatives By1,3-dipolar Cycloaddition Reaction

Chrysin, namely5,7-dihydroxyflavone, which has a variety of physiologicalactivities，is widely distributed in plants. It has a great influence on preventing andtreating diseases such as tumour, cardio-vascular, etc. However, little or no absorptionin the intestine reduces its activity. Even worse, it can rapidly react with commoncarbohydrate, aldehyde and acid and be metabolized finally. To obtain new moreefficient and harmfuless lead compounds, appropriate modifications of chrysin intherapy have been an important research field attracted by scientists around the world.Phosphate ester, as a kind of organic phosphorous fat-soluble compound, is ofgreat significance to life process. Besides, the phosphate ester structure unit arecontained in many endogenous active substances. For example, phosphodiester is avital component of DNA, tripolyphosphate is one of the components of ATP. Besides,both coenzymecell and cell membrane contain phosphate ester structure unit. Theseactive substances play an important role in life processes, such as: energy conversion,genetic expression, etc. Therefore, the phosphate ester groups can be applied to drugmodifications in order to develop new drugs with better activity.1,2,3-Triazoles have been known for over a century, which is a class of nitrogencontaining heterocycles with rich biological activities as well as a fairly largeproportion in the clinical use of drugs. Among the top200global drug sales, morethan half of the structures contain nitrogen hyterocycles. Recently,1,2,3-triazolemoiety has been widely studied among the field of medicine. As an essentialpharmacophore, it has been effectively introduced to modify DNA, peptides,carbohydrates, etc. Moreover,1,2,3-Triazole could connect two pharmacophores toget novel drugs for its attractive linker unit, so it is of great significance to constructfunctional molecules and bioactive molecules.However, according to the survey, little attention has been paid to the synthesisof1,4,5-trisubstituted-1,2,3-triazole and phosphonate scaffolded onto chrysinderivatives. In order to get new compounds with higher biological activity as well as less side effect, we designed a simple and effective method to introduce1,2,3-triazole and phosphate groups onto chrysin by1,3-dipolar cycloaddition.The main contents of this paper are as follows:1. The physiological activities, applications and development of chrysin in recentyears were reviewed.2. Based on the prodrug principle of drug molecules design, thirty novel1,4,5-trisubstituted-1,2,3-triazole and phosphate contained chrysin derivatives were synthe-sized. Each structure was investigated by IR, HR-MS and NMR.3. The optimal reaction conditions were investigated successively usingcyclopropyl alkynyl phosphate and7-(3-azide propoxy)-chrysin as a model reaction.Otherwise, since the existing reaction can’t give single target products, a series ofdifferent reaction conditions were conducted in order to get a better selectivity. Inadditon, this study first developed a selective catalyst system for the1,3-dipolarsystem, which using alkynyl phosphorous and azides as substrate, Pb(AcO)2ascatalyst,2,2-dipyridyl as ligand. Compared to the traditional noble metal catalystsystem-Cp*RuCl(PPh3)2, our catalyst system is more economical.