Studies On The Synthesis And Bioactivities Of Organoselenium-sugar Derivatives, And Indolo[3, 2-b] Qinoline Glycoside Derivatives

This thesis contains two parts,one is the study on the synthesis and bioactivity of oranoselenium-sugar compounds,and the other part is the study on the synthesis and bioactivity of Indolo[3,2-b]qinoline Glycoside compounds.Focal adhesion kinase(FAK) is a kind of non-receptor tyrosine kinase and it plays an important role in signal transduction pathways in which FAK is a key regulator of survival,proliferation,migration and invasion,processes that are all involved in the development and progression of cancer.Selenium is one of the essential microelements in human body.Selenium have been proved to be able to inhibit the proliferation and migration of tumor cells.Although the mechanism of their action was not clear enough,more attention has been paid to the therapy dosage and the possible toxicity of the exceed dose.It has been found that when modified by carbohydrates,the compounds showed lowered toxicity and side effects,improved bioavailability.According to this,a series of oranoselenium-sugar derivatives were synthesized and their bioactivities were evaluated.1.2-(Chloroseleno)benzoyl chloride and the amino compounds were coupled by ring closing reaction and 34 oranoselenium-sugar compounds were obtained and characterized by NMR and MS.These compounds are(â… ) benzisoselenazolones connected with carbohydrate directly;(â…¡) benzisoselenazolones connected with carbohydrate by amide;(â…¢) benzisoselenazolones connected with carbohydrate by oxygen glycoside.2.Several synthesis routes were designed to get the oranoselenium-sugar compounds (â… ),(â…¡),(â…¢).The side chain sugar which was synthesized firstly coupled with the selenium compound was proved to be an efficient and simple synthetic strategy.It was also found that the active Se-N bond may react with the 1-hydroxyl of saccharide and the catalyst of glycosidation.3.FAK enzyme inhibitory activities of the compounds were also studied.Of which 8 compounds show higher activity against FAK[51(IC₅₀=0.46μM),53(IC₅₀=0.17μM),55(IC₅₀=1.02μM),62(IC₅₀=0.10μM),64(IC₅₀=0.39μM),65(IC₅₀=0.32μM), 71(IC₅₀=0.94μM),72(IC₅₀=1.71μM) resppectively].The primary structure-activity relationships indicated that:1).Selenium is an essential element to the activities of the compounds.2).The bioactivity of the organo-selenium compounds can be improved by carbohydrate units.3).The acetylation of the sugar unit can enhance the activity of organo-selenium sugar compounds.4).The 2 position of benzisoselenazolones connected with rigid groups such as benzene can decrease the activity.Indoloquinoline alkaloids were consisted in a lot of natural products.It is an active component of many medical botanic and has showed multiple physiological activity and pharmacological activity.The modification by carbohydrate can increase its bioactivity and solubility in organic solvent and water.Jusbetonin was the first natural indolo[3,2-b]quinoline alkaloid glycoside which was isolated in 2004 from Justicia betonica and it has quite a unique structure containingβ-D-glucose.However,the synthesis and its bioactivities have not been studied systematically.Herein jusbetonin and indoloquinoline alkaloid glycoside compounds with different sugar moieties were synthesized and their anti-tumor activities were evaluated,this may laid a foundation for the study on SAR and the development of anti-tumor drugs.1.Our retrosynthetic analysis of jusbetonin suggested that indolo[3,2-b]quinolin-one would be a promising intermediate for the total synthesis.And the synthesis of indolo[3,2-b]quinolin-one catalysed by PPA through gradient temperature -elevating was proved to be an efficient method.The new compound 9-hydroxy -10H-indolo[3,2-b]quinoline was synthesized through six steps in 15.4%yield. Glycosylation of 9-hydroxy -10H-indolo[3,2-b]quinoline with different glucose donor show thatα-D- glycopyranosyls bromide was an effective donors when catalyzed by the phase transfer catalyst TBAB.2.Through this method anthranilic acid was used as the starting material,with 8 steps reaction,the target natural compound,jusbetonin were obtained efficiently. The characterization of the compounds by NMR spectra and the result was consistent with the literature.Indoloquinoline alkaloid glycosides 1-(10H-indolo[3,2-b]quinoline-9-yloxy)-β-D-galactoside(38b),1-(10 H-indolo[3,2-b]quinoline-9-yloxy)-β-D-lactoside(38c),1-(11-chloro-10H-indolo [3,2-b]quinoline-9-yloxy)-β-D-glucoside(40a),1-(11-chloro- 10H-indolo[3,2-b] quinoline-9-yloxy)-β-D-galactoside(40b) and 1-(11-chloro-10H-indolo[3,2-b] quinoline-9-yloxy)-β-D-lactoside(40c) were synthesized using the same methods.3.The anti-tumor activity of the compounds has been tested.The results showed that the compounds had moderate proliferation inhibitory activity against MDA-231 cell line at the concentration of 1μM.Of which compounds 1-(10H-indolo[3,2-b] quinoline-9-yloxy)-β-D-lactoside(38c) showed an inhibitory rate of 37.9%.And compound 1-(10H-indolo[3,2-b]quinoline-9-yloxy)-2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl (37a) exhibit proliferation inhibitory activity against HL-60 cell line.