Synthesis And Biological Evaluation Of Anticancer Activity For Novel N-substituted Sophoridine Derivatives

In recent years,with the development of the tumor mechanism in medical research,lots of the tumor associated targets were explained and the structures were determined.These achievements in scientific research promoted the synthesis of anticancer drugs from simplistic cytotoxicity to anti-neoplastic agents with specific targets.The structure of sophoridine is similar to matrine,containing structure of quinolizidine.The only difference between matrine and sophoridine is a chiral carbon atom in the structure of the stereo configuration.Sophoridine is an natural alkaloid with anti-tumor efficacy and has extensive pharmacological activity,especially in antiinflammatory,anti-tumor,antiviral,and anti-arrhythmia research.Furthermore,it has some advantages of simple structure,easy to be modified and so on.However,Sophoridine has some shortcomings such as low bioavailable,insufficient activitity of anti-tumor and anti-inflammatory,resulting in some limitations of clinical application.These factors make scientists to develop some novel sophoridine derivatives with high activity and better bioavailability that has become a research hotspot.In this paper,sophoridine with anti-tumor activity was selected and made as the ligand molecule of target protein.And then on the Molecular Operation Environment(MOE)platform,DNA topo-I was seleted as the target.The molecular docking results showed that the introduction of benzene ring group in sophoridine led the better binding force between derivatives and the target.Consequently,the novel sophoridine derivatives were likely to become better antineoplastic drugs.On the basis of molecular docking,two series of sophoridine derivatives were designed and screened.Considering the results of the combination of compounds and target selection,the structural characteristics of DNA topoisomerase inhibitors and the structure-activity relationship of sophoridine,twenty-eight new sophoridine derivatives were synthesized in this paper and these derivatives have good anti-tumor activity with high selectivity.By 1H NMR,13C NMR,and HRMS,the target compounds were characterized and confirmed.Using the MTT method for the preliminary in vitro,we have finished the tests of four cell lines(A549,CNE2,HepG2 and HEC-1-B)with all synthesized compounds.Most of the derivatives showed the anti-tumor activity in vitro(six compounds,IC50<50?M),In particular,the compound YYW-24 showed a good anti-tumor effect(IC50<20?M).By introducing a benzene ring as a main pharmacophore and reintroduced into a benzene in paraposition on the phenyl ring,on the basis of the original structure the novel sophoridine derivatives improved the anti-tumor activity effectively.Finally,the preliminary structure-chemical analysis and the structure-activity relationship of these sophoridine derivatives were determined.