Study On The Design,Synthesis And Antitumor Activity Of 6-Substituted Rhein Derivatives

The effective treatment of cancer is one of the difficult problems that human beings need to solve at present.The main chemical constituents of Rhubarb?Rheum palmatum?,one of the traditional Chinese medicines in China,are rhubarb anthraquinones,which have antimicrobial,antiviral and anti-tumor activities.Among them,rhein,as an effective and marker component of rhubarb,has some reports on its pharmacological activity and derivatization.However,the derivatization of Rhein based on anti-tumor activity is relatively few,and the structure-activity relationship is not deep enough.Based on this,this paper mainly carries out the following three aspects of work:In the first part,a series of 6-alkoxy substituted rhein-amino acid adducts were designed and synthesized on the basis of our previous studies,and the antitumor activity and structure-activity relationship in vitro were studied.11 Novel 6-alkoxy substituted rhein-amino acid adducts?2-7aa²-7ee?were synthesized from emodin by acetylation,oxidation,deacetylation,esterification,etherification,hydrolysis and condensation,and all structures were characterized by ¹H NMR,¹³C NMR and HR-MS.The inhibitory activities of the target compounds on four tumor cells?Hela,MCF-7,HEK-293T and SGC-7901?were investigated by MTT assay.The results show that 2-7ea had certain inhibitory activity and good selectivity on four tumor cells.The inhibitory activity on SGC-7901(IC₅₀=9.78?mol·L^-1)was similar to that of positive control substances?doxorubicin and cisplatin?.In the second part,based on the pharmacological activity of 1,2,3-triazole and its special use in organic synthesis,we designed and synthesized 10 novel 6-triazole substituted Rhein derivatives by click-chemical strategy,using triazole as ligand and introducing aromatic rings at the 6-position of rhein acid.All structures were characterized by ¹H NMR,¹³C NMR and HR-MS.The in vitro inhibitory activities of the target compounds against four kinds of cancer cells?Hela,MCF-7,HEK-293T and SGC-7901?were investigated by MTT method.The results show that the total activity of these compounds was not high,and only the Rhein derivatives substituted by benzyl or 4-methyl benzyl triazole had certain activity.In the third part,aiming at the key steps in the synthesis of 6-triazole Rhein derivatives in the second part,we carried out corresponding methodological studies.A one-pot method for the synthesis of triazole from aryl boric acid,NaN₃ and terminal alkynes catalyzed by copper?II?-pyrrolimide complex?C1^C4?was established which has the characteristics of less catalyst consumption,high yield and wide adaptability.The method was applied to the synthesis of 6-triazole rhein derivatives successfully.However,the yield was relatively low,probably due to the low reaction inertia and solubility of the substrates.