Synthesis Of Antitumor Compounds By Electrochemical Sulfonation And Indole Dearylation

In the past decade,oxidative cross coupling of R¹-H/R²-H?CDC?has become one of the most direct methods to construct new chemical bonds.This reaction method is one of the most atom economical methods in organic synthesis because it does not need the substrate pre-functionalization and greatly shortens the synthesis steps.However,the loss of hydrogen during the coupling process to synthesize new chemical bonds often requires external driving forces,that is,metal catalysts and stoichiometric oxidants.The use of these oxidants and catalysts not only cause shortcomings such as reaction peroxidation,formation of by-products,and unfriendliness to the environment,but also may lead to metal residue in the final product,limiting their application in medicinal chemistry.Electrochemistry has always been considered as an environmentally friendly synthetic tool.In recent years,the research results show that electrochemical anodization and cathodic proton reduction have become a promising method to realize cross coupling of R¹-H/R²-H.In this thesis,we mainly studied the electrochemical mediated sulfonylation and indole dearylation.Using electricity instead of traditional oxidant,a series of compounds with pharmacological activities were synthesized rapidly and efficiently without metal and oxidant,and their antitumor activities were studied.The specific research contents are as follows:?1?Thiosulfonates are an important class of compounds,which have a wide range of biological activities,such as anti-microbial,anti-fungal,insecticidal,anti-tumor and anti-virus.Herein,we have developed a metal free,oxidant free,green and sustainable method to synthesize asymmetric thiosulfonates.Under mild electrochemical conditions,a series of asymmetric thiosulfonates were synthesized by cross dehydrogenation coupling reaction of thiophenol and sulfonylhydrazine.Free radical capture experiments and cyclic voltammetry showed that the reaction was carried out through the free radical pathway.This reaction has the advantages of wide substrate applicability,good functional group tolerance,and high atomic economy.Moreover,the industrial application potentiality of the reaction is illustrated by the successful gram-level reaction.?2?The indole skeleton is widely present in various natural products.Due to its special chemical and biological properties,it is considered to be the"dominant skeleton"in medicine.At present,a large number of literatures have reported the effective synthesis methods of indole.However,most of these methods need equivalent metal catalysts or excessive oxidants.Under mild electrochemical conditions,we have studied the selective sulfonation and hydrazinylation of indole by sulfonylhydrazine and synthesized a series of sulfonylhydrazinylindoles.The structures of these compounds were determined by X-single crystal diffraction,and the reaction mechanism was determined by control experiments and cyclic voltammetry.The reaction does not require metal catalyst and additional oxidant,and the by-products are hydrogen and nitrogen.Compared with the traditional synthesis methods,it is more green and environmentally friendly,and the raw materials are cheap and easy to obtain,the operation is simple.?3?Alkynyl sulfone is an important kind of organic sulfone compounds.It not only has good pharmacological activity,but also is an important intermediate in the synthesis of many natural products.At present,there is no report on the synthesis of acetylsulfones from terminal alkynes.Herein,we have developed a mild electrochemical method for the synthesis of alkynyl sulfones.Under mild electrochemical conditions,a series of alkynsulfones were synthesized with tetrabutylammonium iodide as electrolyte and sulfonylhydrazine as sulfonation agent.The results of EPR experiment,cyclic voltammetry and control experiment revealed that the reaction might exist two reaction mechanisms.The method does not require pre-functionalization of the substrate,has high atom economy,mild reaction conditions,simple operation,and does not require an oxidant and a metal catalyst.?4?The selective introduction of fluorinated substituents into organic molecules is particularly important in synthetic chemistry,because it can change the electronic distribution and lipophilicity of the whole molecule,which is conducive to new applications in the fields of medicine,pesticide and material science.Therefore,under mild electrochemical conditions,we synthesized a series of dearylated hexafluoroisopropoxyindoles by the reaction of indole with hexafluoroisopropanol and the introduction of two hexafluoroisopropoxy groups on the indole skeleton.The structure of the compounds was characterized by X-ray single crystal diffraction,and the reaction mechanism was studied by control experiment and cyclic voltammetry.In addition,the coupling reaction between aniline and hexafluoroisopropanol was realized under the condition.?5?We used MTT method to screen the antitumor activities of the synthesized compounds in vitro.The results showed that most of the compounds had good inhibitory activities on tumor cells.The IC₅₀ values of thiosulfonate compounds 3ac and 3ag on MGC-803 and T-24 were all below 10?M.The antitumor activity of sulfonylhydrazide indole compound 3ae?was significantly higher than that of its indole raw material.In addition,most of the IC₅₀ values of the alkynyl sulfone compounds on tumor cells were below 20?M.Hexafluoroisopropoxyindole compound 2i???has good inhibitory activity on T-24 and HeLa cells.Further studies on antitumor mechanism showed that thiosulfonate compound 3ag could block T-24cell cycle in G2/M phase,inhibit the balance of tubulin polymerization and induce cell apoptosis,thus inhibiting cell migration.