Asymmetric Synthesis Of 3,2’-pyrrolidinyl Spirooxindoles And Preliminary Study On Anti-tumor Activities

Objective: The spirooxindole skeleton is widely present in natural products and biologically active compounds.The skeleton has a wide range of biological activities,especially in anti-tumor activity.The pyrrolidone skeleton is the structural feature of a large number of natural products and bioactive drugs.Therefore,the development of an effective method that can simultaneously introduce indole oxide and pyrrolidine into the same compound skeleton can provide novel compounds for the research of anti-tumor drugs.Methods:(1)Using isatin,methane iodide and hydroxylamine hydrochloride as starting materials and N,N-dimethylformamide as reaction solvent,3-isothiocyanato oxindole compounds were obtained by four-step reaction.(2)Using benzylamine,ethyl acrylate and benzaldehyde as starting materials and anhydrous ethanol as reaction solvent,2,3-dicarbonyl pyrrolidine compounds were obtained by two-step reaction.(3)Using indoles 3-isothiocyanyl oxide as derivatives and 2,3-dioxypyrrolidone to synthesis a family of compounds of chiral spirooxindoles via the asymmetric Michael addition reaction.(4)The synthesized 3,2’-pyrrolidinyl spirooxindoles were tested for anti-tumor activity by MTT assay,and its structure-activity relationship was discussed.Results:(1)Eleven 3-isothiocyanato oxindoles were obtained from isatin by four steps of reaction.(2)With benzylamine as the starting material,21 2,3-dicarbonyl pyrrolidine compounds were obtained after two steps of reaction.(3)The optimal conditions for the reaction system of 3-isothiocyanyl oxide as derivatives and 2,3-dioxypyrrolidone in the synthesis of chiral version:3-isothiocyanato oxindole as derivatives(0.1 mmol),2,3-dioxypyrrolidone(0.12 mmol),reaction temperature 20 ℃,catalyst equivalent(10 mol %),dichloromethane(2 m L).Synthesis of 33 trifluoromethyl-containing3,2’-pyrrolidinyl spirooxindoles under optimal conditions yielded excellent yields(>85%)and diastereoselectivity(>99:1 dr)and enantioselectivity(>94%).(4)In the anti-tumor activity test,five different cancer cells including lung cancer A549,lung cancer H460,prostate cancer DU145,bladder cancer T24 and gastric cancer SCG7901 were selected to investigate the synthesis of24 new 3,2’-pyrrolidinyl spirooxindoles.The activity of 3,2’-pyrrolidinyl spirooxindoles confirmed that the reaction products of this system have a certain anti-tumor activity and have a certain inhibitory effect on all five cells.Conclusion: Using isatin as the starting material,3-isothiocyanato oxindole was synthesized through four steps,and benzylamine as the starting material,2,3-dicarbonyl pyrrolidine compounds were obtained through two steps.The optimum reaction conditions of 2,3-dioxypyrrolidone and 3-isothiocyanide indole with chiral catalyst were determined by conditional screening,and3,2’-pyrrolidinyl spirooxindoles were synthesized under the optimal conditions.The antitumor activity of the synthesized compounds was tested by MTT assay,and the antitumor activity of the synthesized compounds was confirmed.The structure-activity relationship was also discussed.To provide available compounds for further activity study.