Electrochemical Synthesis Of Alkyl Sulfone And Alkoxy Heterocyclic Compounds And Their Antitumor Applications

Objective:Sulfone and heterocyclic skeletons widely exist in natural products and drug molecules,which have superior biological activities and are important structural motifs in clinical drugs and pesticides.Therefore,it is of great significance to develop efficient methods to synthesize sulfone-based compounds and heterocyclic compounds.We plan to synthesize sulfone-based compounds and heterocyclic compounds by mild,green and efficient electrochemical methods.In addition,the antitumor activities of the synthesized compounds were studied in vitro,aiming at finding lead compounds containing sulfone or heterocyclic skeletons with good antitumor activity.Methods:Under electrochemical conditions,oxanthracene was used as C(sp~3)-H bond substrate and sulfonyl hydrazide to form alkyl sulfone compounds.In addition,alkoxy heterocyclic compounds were constructed with vinylaniline and alcohol as substrates,and the reaction mechanism was studied by control experiment and cyclic voltammetry experiment.MTT assay was used to detect the anti-tumor activity of these compounds against T-24(human bladder cancer cells),MGC-803(human gastric cancer cells),He La(human cervical cancer cells),and Hoechst 33342 nucleic acid staining,detection of reactive oxygen species concentration,cell tubulin polymerization balance and scratch assay were used to further study the anti-tumor mechanism of these compounds.Results:20 alkyl sulfones,22 alkoxy benzoxazines and 16 alkoxy indolines were synthesized by electrochemical method.The results of control experiment and cyclic voltammetry showed that these three kinds of reactions all underwent free radical pathway.In vitro antitumor activity experiments showed that most of the synthesized compounds had good antitumor activity,especially alkyl sulfone compound 3af and alkoxy indolines compound 4p’.The study of anti-tumor mechanism showed that compound 4p’can induce the increase of reactive oxygen species concentration in He La cells,thus promoting apoptosis of cells;It can interfere with mitosis of He La cells by inducing tubulin polymerization balance of He La cells;The results of scratch test showed that compound 4p’could effectively inhibit the migration of He La cells.Conclusions:Under electrochemical conditions,new methods for synthesizing alkyl sulfone compounds and alkoxy heterocyclic compounds were developed.The method does not need external oxidants and transition metals,and has the advantages of mild reaction conditions,wide application range of substrates and environmental friendliness.Most of the synthesized compounds have good anti-tumor activity.Further study on the anti-tumor mechanism provides a solid theoretical basis for the future study on the anti-tumor activity of sulfone-containing or heterocyclic skeleton compounds.