Chemical Modification And Biological Activity Study Of Rhein

Rhubarb is an important medicinal material in the traditional Chinese medicine,which has clear heat and purging fire 、cooling blood detoxification、stasis through the pass,dampness and yellow resolving and so on.Rhein is one of the main active ingredients of rhubarb,and its pharmacological effects are extensive,which has antibacterial、 anti-tumor、anti-diabetic nephropathy and anti-inflammatory and other activities.In the antibacterial,anti-tumor disease treatment has aroused widespread attention.Because of the poor water solubility and low bioavailability limit its clinical application in a great extent.Therefore,a serie of rhein derivatives were synthesized by the conversion of anthraquinone nucleus substitutions and carboxyl groups,and the antibacterial activity was preliminary discussed.Hoping to improve the biological activity of rhein and improve its physical and chemical properties,and further provide a theoretical basis for the clinical application of rhein.In this paper,a series of rhein amide derivatives were synthesized by the reaction with amine compounds to modify the carboxyl groups of rhein At the same time,the reaction conditions of amide derivatives were optimized,The best process technology was follows:The reaction yield was 94% in the ratio of Rhein:EDCI: HOBT = 1: 2: 2 for 8 hours with DMF as the optimum reaction solvent.and the reaction products were separated and purified by silica gel column chromatography.On the basis of the synthesis of rhein amide derivatives,the key intermediate 7-hydroxymethyl rhein amide derivatives were synthesized and the reaction conditions of the synthesis of key intermediates were optimized by Orthogonal Experimental Design.The best process technology was follows:With A1: Na₂S₂O₄ = 1: 2,at a temperature of 5 ℃-10 ℃ reaction 6 h and the best yield is 27 %.Following the synthesis of the 7-hydroxymethyl rhein amide derivative,the 7-hydrox-ymethyl rhein amide derivative is replaced with bromine to give the 7-bromomethyl rhein amide derivative,and finally reacted with the amine compound to obtain 12 target products.In this paper,a total of 22 compounds were synthesized.Among them,19 compounds were new compounds.The structures of all the compounds were confirmed by FTIR,¹H-NMR and ¹³C-H-NMR.In this paper,7-aminomethyl rhein derivatives were obtained by 4-step reaction product.The antibacterial activity of rhein was studied by using microtiter plate method for Escherichia coli and Staphylococcus aureus.The result of antibacterial activity experiment shows that rhein derivatives showed different MIC values for different colonies.Among them,1,8-Dihydrox y-2-morpholin-4-ylmethyl-6-（piperidine-1-carbonyl）-anthraquinone（D4）,1,8-Di hydroxy-2-piperidin-1-yl-methyl-6-（pyrrolidine-1-carbonyl）-anthraquinone（D5）and 1,8-Dihydroxy-6-（piperidine-1-carbonyl）-2-pyrrolidin-1-ylmethyl-anthraquino ne（D11）had better antibacterial activity against Escherichia coli than rhein,a nd the antibacterial activity of 1,8-Dihydroxy-2-piperidin-1-yl-methyl-6-（pyrroli dine-1-carbonyl）-anthraquinone（D5）and 1,8-Dihydroxy-6-（piperidine-1-carbo nyl）-2-pyrrolidin-1-ylmethyl-anthraquinone（D11）was the best,and those act ivity is about 8 times that of rhein,even stronger than the positive control dru g kalamycin;And antibacterial activity of 1,8-Dihydroxy-6-（piperidine-1-carbonyl）-2-pyrrolidin-1-ylmethyl-anthraquinone（D3）and 1,8-Dihydroxy-2-piperidin-1-yl-methyl-6-（pyrrolidine-1-carbonyl）-anthraquinone（D5）on Staphylococcus aureus is better than rhein,and rather than the positive control of kalamycin.On the basis of the active screening experiment,the preliminary structure-activity relationship analysis was carried out on the synthesized new compounds.It was found that the 3-position carboxyl group of rhein was amide modified and the 7-position of rhein was replaced,which could enhance the antibacterial activity of rhein.The above results provide some theoretical guidance for the further development and application of rhein.