Synthesis And Biological Evaluation Of Prazole Compounds Which Modified By Glycosides

As the widespread large class of heterocyclic compounds in the nature, the synthesis and applications of pyrazole compounds are most common. The derivatives have a variety of pharmacological activities in medicine, such as anti-cancer, anti-inflammatory, bactericidal activities. In the field of agricultural products pyrazoles can be used as pesticides, herbicides, acaricides and so on. Furthermore, pyrazoles used as chiral ligand auxiliaries in asymmetric synthesis and analytical reagents in the complexation of transition metal ions are also prevalent. Due to the importance of pyrazoles in organic synthesis and applications, more attention has been paid to this field.Carbohydrate compounds are an essential component of the life. In recent years, as constantly emergence of new discoveries in biology, the research of sugar compounds has become hot spots once again. After modified by sugar, the physical and chemical properties of heterocyclic compounds have changed significantly, such as improving water-solubility and biological activity, more prone to be absorbed and metabolized by celles, further impoved the original application of the compounds. There are still many problems of glucoside synthesis to be solved at the regioselectivity, stereo-selectivity and yield, etc. In general, such reactions need to deal with protection and deprotection of hydroxyl, leading to tedious steps, more by-products and lower yield. Therefore, how to obtain the product by the reaction of free-protected sugar with the substrate via one step is undoubtedly the most ideal synthesis of glycosides.Through modification of the pyrazole compounds by protected sugar and unprotected sugar, we intend to synthesize novel compounds with potent bioactivity and study the bioactivity of the obtained products, finally screen out drugs with the anti-tumor activity.This paper involves the following two parts:First, the synthesis and bioactivity evaluation of pyrazole carbohydrazide glycoside derivatives.1. Synthesis of 3-aryl-l-arylmethyl-lH-pyrazole-5-carbohydrazideβ-glycoside derivatives has been accomplished by the reation of xylose (glucose) with pyrazole carbohydrazide under the condition of acetic acid catalyst. The structure of these compouds was characterized by 1H NMR, IR and HRMS spectral data.2. Based on the obtained 3-aryl-l-arylmethyl-lH-pyrazole-5-Carbohydrazideβ-glycoside derivatives, we studied the bioactivity of them. The results showed that the compounds 3a-h exhibited an inhibitory effect on the proliferation of A549 cells in a time and dose-dependent manner. Among them,3d showed a most potent inhibitory effect on A549 cells growth.3. Based on the bioactivity data, we intend to find out the structure-activity relationship of this class of drugs. The cytotoxic potency was highly dependent, as expected, on the substitution types and patterns on the aryl ring as well as the kind of sugar. The IC50 values of compounds 3a,3d and 3f are lower than that of corresponding compounds without sugar moiety. In addition, compounds with xylose moiety 3a,3d and 3g alter the antitumor effect significantly than that with glucose moiety. Compound 3d with chlorine (at the 4-position of 3-aryl ring) had lower IC50 values. The compounds with a bulkier tert-butylgroup at the 4-position of 1-aryl ring resulted in a significant activity increasing.Second, the synthesis of pyrazole carboxylic acid glycoside derivativesThe method of phase transfer catalysis was applied in this synthesis. By the reaction of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide with pyrazole carboxylic acid, we accomplished a series of glycoside esters. The structure of these compouds was characterized by'H NMR, IR and HRMS spectral data. Theβconfiguration has been confirmed by X-ray through the representative single-crystal structural characterization of the compounds 2g.In conclusion, we synthesized a series of 3-aryl-1-arylmethyl-lH-pyrazole-5-carbohydrazideβ-glycoside derivatives through one step reation, simplifying the operations, improving the yield. Evaluated the biological effects of the compounds, studied the structure-activity relationship of this class of drugs and builded up basis for research and development of novel agents with inhibitory activity against cancer cell growth. Second, a series of pyrazole carboxylic acid glycoside derivatives has been synthesized. Compared to previous studies, the reaction conditions has been further improved. The bioactivity as a potential anti-cancer drug needs to be evaluated.