Synthesis Of 3-quaternary Carbon Oxindole Fused 3-spirooxindole Compounds And Bioactivities Studies

This thesis is divided into two parts.Part 1: Synthesis of 3-quaternary car bon oxindole fused 3-spirooxindole compounds and bioactivities studies;Part 2:Synthesis of 3-quaternary carbon oxindole derivatives.The first part consists of two sections,synthesis of 3-quaternary carbon ox indole fused 3-spirooxindole compounds and their vitro antitumor activities.A s imple and efficient method for synthesis of 3-quaternary carbon oxindole fused3-spirooxindoles was first found,knoevenagel condensation/Michael/cyclization o ccurs with N-methyl-2-indolone and orthophthalaldehyde catalyzed by piperi dine.After the separation of the intermediates,and then proceed to the methyla tion reaction.Through this route,a large number of 3-quaternary carbon oxindo le fused 3-spirooxindole compounds can be obtained with different substituents.The yield of the reaction is better,and the yield of two step reaction is up to73%,non enantioselective dr>20:1.A total of 39 target compounds were obtain ed,the structures were characterized by 1H-NMR,13C-NMR and HR-ESI-MS.Human leukemia cells(K562),human lung cancer cells(A549)and human prostate cancer cells(PC-3)were screened for antitumor activity in vitro by M TT,results indicated that most of the compounds have good vitro antitumor act ivities.The inhibitory activity of compound 5c(IC50= 9.7 μM),5p(IC50 = 21.9 μM),5x(IC50 = 21.04 μM),5y(IC50 = 21.04 μM),5b’(IC50 = 8.8 μM),5i’(IC50 = 7.4 μM)on human Leukemia cell line(K562)was better than that o f positive control cisplatin(IC50 = 25.4 μM);The inhibitory activity of compou nd 5b’(IC50 = 24.4 μM),5i’(IC50 = 18.1 μM)on human lung adenocarcinomac ell line(A549)was better than positive control cisplatin(IC50= 24.7μM);The i nhibitory activity of compound 5i’(IC50 = 17.7 μM),5j’(IC50 = 21.4 μM)onh uman prostate cancer cell line(PC-3)was better than positive control cisplatin(IC50 = 23.1 μM).The second part of the work mainly includes three aspects:(1)Efficient S ynthesis of novel quaternary 3-substituted aminomethyl qxindole compounds;(2)Synthesis novel 3-amino-α-hydroxy-β-ester-3-quaternary carbon oxindole compou nds;(3)Synthesis of oxindole fused β-Ionone compounds and their bioactivities study.(1)11 novel quaternary 3-aminomethyl oxindole compounds,yield at 68%-98%,were efficiently synthesized by Mannich reaction of 3-substituted oxindole s with imine precursors,using TBAB as the phase transfer catalyst.The structu res were characterized by 1H-NMR,13C-NMR and HR-ESI-MS.(2)21 novel 3-amino-α-hydroxy-β-ester-3-quaternary carbon oxindole comp ounds,yield at 63%-97%,were synthesized by Aldol reaction from aldehyde es ter with substituted 3-amidexindoles,using DABCO as catalyst and CH2Cl2 as solvent.The structures werecharacterized by 1H-NMR,13C-NMR and HR-ESI-M S.(3)17 oxindole fused β-ionone compounds,the yield up to 96%,were eff iciently synthesized by aldol reaction of oxindole with β-ionone,using diethyla mine as catalyst,CH3 OH as solvent.The structures were characterized by 1H-N MR,13C-NMR and HR-ESI-MS.Their in vitro antitumor activities of compoun ds against human leukemia cell line(K562)were investigated by MTT assay.The results showed that 4 compounds had good inhibitory activities.The inhibi tory activity of compounds YJZ-9(IC50= 21.0 μM),YJZ-10(IC50= 26.4 μM),YJZ-12(IC50= 28.7 μM),YJZ-21(IC50= 28.0 μM)on human Leukemia cell li ne(K562)was better than positive control cisplatin(IC50 = 30.0 μM)...