| Objective:Sophoridine is a kind of a monomer alkaloids,which was extracted from the traditional medicine herb Sophora alopecuroides L.The basic structure is composed of two fused trivalent nitrogen atom of the double piperidine rings.It is white or light yellow crystals,its molecular formula is C5H24N2O and relative molecular mass is 248.37,its melting point is 108～112℃.The injection of hydrochloride Sophoridine was the first anti-cancer drug which contains Quinolone structure and was approved for marketing in domestic and foreign.Clinically,it has a significant effect on malignant trophoblastic tumor,it also has a certain effect on malignant lymphoma and gastrointestinal tumors.Sophoridine has some advantages,such as simple structure,safety and minor side effects.The purpose of this experiment is based on a lot of the literature and research at home and abroad,a new type of structure Sophoridine derivatives were designed and synthesized,these derivatives were screened for biological activity.In order to get a good anti-tumor activity of the compound,while providing valuable information for the design and development of new drugs.Methods:Based on a large number of the literature and research of domestic and foreign,since Sophoridine containing lactam structure,its hydrolysis product sophoridine acid has equal anti-tumor activity to Sophoridine and more modified groups.Therefore,Sophoridine acid was used as a lead compound in this experiment,Meanwhile,a number of compounds of nitrogen mustard was designed and synthesized,such as mechlorethamine hydrochloride,chlorambucil benzyl alcohol,benzoic acid nitrogen mustard,nitrogen mustard between methoxybenzoate,aniline mustard.Using the split structure principle,a series of Sophoridine derivatives was synthesized.The first route is protecting Sophoridine acid carboxyl,then connected with 12-N of Sophoridine acid using amide bond.A series of nitrogen mustard-type series Sophoridine ester compounds were synthesized,they were did structural characterization and texted antitumor activity to get a better activity derivatives.The second route is protecting Sophoridine acid 12-N and using benzyl protecting,then connected with mustard compounds.A series of benzyl Sophoridine acid derivatives were synthesized,they were did structural characterization and texted antitumor activity to get a better activity derivatives.Results:During the first stage of the experiment,20 kinds Sophoridine ester derivatives were synthesized,including 10 kinds of nitrogen mustard-type Sophoridine ester derivatives and 10 kinds of non-nitrogen mustard-type Sophoridine ester derivatives.Their structures were confirmed by element analysis,1H-NMR and MS.Antitumor activity in vitro showed that compound 14e was weaker than Melphalan.The second stage successfully designed and synthesized three kinds of benzyl Sophoridine acid acid derivatives,they were not reported in the literature,and confirmed by element analysis,1H-NMR and MS.Antitumor activity in vitro showed that compound 22 was equal to Melphalan.Conclusion:Through a large number of literature of domestic and foreign,we found more research on pharmacological effects,and less study of structure modification of Sophoridine.In this experiment,Sophoridine was used as raw materials,and 23 kinds Sophoridine derivatives was successfully designed and synthesized based on the principle of structural split.MTT assay was used to test anti-cancer activity of HepG2 cells in vitro.The anti-tumor activity of compound 22 in vitro is equal to Melphalan,The anti-tumor activity of the compound 14e is slightly weaker than Melphalan;The increasing activity of Sophoridine acid ester was associated with R group,the bigger R group,the more multi-branched,the stronger the anti-tumor activity;Introduction of nitrogen mustard compounds can effectively enhance sophoridine antitumor activity;Benzyl nitrogen mustard-type structure Sophoridine acid derivatives have the best anti-tumor activity.So,nitrogen mustard group and the introduction of the R groups enhanced anti-tumor activity,maybe due to the synergy results of both groups and sophoridine.The specific reasons need for further investigation. |
