Synthesis And Activity Of Bis (Indolyl) Methane And Sulfur (Selenium) Tegafur Derivatives Catalyzed By Dinuclear Titanium Complex

Objective:Among all kinds of diseases,malignant tumor is a kind of disease that seriously threatens human life and health.Its morbidity and mortality are on the rise year by year.The mortality rate caused by cancer ranks is second compared to cardiovascular and cerebrovascular diseases.Therefore,the synthesis of anti-tumor drugs with high biological activity and low toxicity has become the focus of scientists.In general,organometallic Lewis acid catalyst plays an important role in drug synthesis.However,most metal Lewis acid catalysts for the synthesis of bioactive molecules or drug molecules suffer from certain drawbacks,e.g.,the use of air or moisture-sensitive catalysts,weak acidity,low yield,requiring strict anhydrous conditions,heavy environmental pollution,difficult to reuse.Thus,the development of an air-stable and strong acidity catalyst for the synthesis of bioactive molecules with anti-tumor activity has important application value.Research purpose:1.In order to solve the problems of the current metallic Lewis acid,such as air or moisture-sensitivity and weak acidity,the coordination between the salophen Schiff base ligand containing heteroatom(N,0)and titanium was used to increase the air stability of the complex.Then the perfluorooctane(butane)sulfonate anion with strong electron-withdrawing ability was introduced on titanium to increase the acidity of the complex,and novel schiff base titanium perfluoroalkyl sulfonate complexes with strong air stability were synthesized.The physical properties such as thermal stability,solubility,electrical conductivity and acidity were studied.2.Titanium(Ⅳ)salophen perfluorooctanesulfonate as a Lewis catalyst was used for the synthesis of bis(indolyl)methane derivatives with bioactivity via the Friedel-Crafts alkylation of aldehyde/ketone with indoles,and the reusability of catalyst was studied.CCK-8 assay was used to detect the growth inhibitory activity of bis(indolyl)methanes derivatives on cancer cells(colon cancer cell HCT-116 and gastric cancer cell SGC-7901).The mechanism of antitumor activity of bis(indolyl)methanes derivatives in vitro was also preliminarily determined.3.Titanium(Ⅳ)salophen perfluorobutanesulfonate was used to catalyze the reaction of diaryl disulfide(selenium)ether and bromoalkane to synthesize asymmetric sulfur(selenium)ether in the presence of zinc power.Furthermore,A series of novel aryl(N3-tegafluoroalkyl)thio-and selenoethers derivatives was efficiently synthesized by the reaction of tegafluoroalkyl sulfonate with diaryl disulfides or diselenides under titanium(Ⅳ)salophen perfluorobutanesulfonate/zinc catalytic system.The antitumor activity of the target compounds on colon cancer cell HCT116 and gastric cancer cell SGC-7901 in vitro was tested by CCK-8 assay.The mechanism of antitumor activity of tegafur derivatives in vitro was preliminarily verified.Methods:1.Two novel Titanium(Ⅳ)salophen perfluorooctane(butane)sulfonate complexes were successfully synthesized by the reaction of Salophen schiff base Titanium dichlorides with silver perfluorooctane(butane)sulfonate.Their structures were confirmed by techniques such as 1H NMR,19F NMR,IR and HRMS.The thermal stability of the complexes was measured by thermogravimetric analysis(TG-DSC),the molar conductivity of the two complexes was measured by conductometer,and the acidities of the complexes were detected by fluorescence method and Hammett indicator method.2.Two novel Titanium(Ⅳ)salophen perfluorooctane(butane)sulfonate complexes were used to catalyze the synthesis of bis(indolyl)methane derivatives,asymmetric sulfur(selenium)ether and organic sulfur(selenium)tegafur derivatives,respectively.The structures of the target compounds were confirmed by 1H NMR,13C NMR,and mass spectrometry.CCK-8 method was used to test the antitumor activity of the target compounds against cancer cells(colon cancer cell HCT116 and gastric cancer cell SGC-7901)in vitro,and biomolecules with high antitumor activity were screened out.The antitumor activity mechanism of the target compound was preliminarily verified by staining HCT116 cells with DAPI and flow cytometric assay.human embryonic kidney cells(HEK 293)were selected to investigate the toxicity of tegafur derivativesResults:1.The results of IR,1HNMR,19FNMR,HRMS studies indicated that two complexes were μ-oxo-bridged binuclear structures,the structural formulas were[{Ti(salophen)H2O}2O][OSO2C8F17]2(1a)and[{Ti(salophen)H2O}2O][O SO 2C4F9]2,respectively.Complexes 1a and 1b were thermally stable up to 220℃ and 200℃,respectively.The results of solubility and conductivity showed two complexes had good solubility in CH3OH,THF,acetone,CH3CN,but they are not soluble in some hydrophobic solvents such as CH2Cl2,toluene and n-hexane.The molar conductivity(A)of 1a and 1b were 136 μScm-1 and 126 μS·cm-1,(CH3CN as testing solvent),respectively.In addition,the fluorescence maximum(λmax)of complex 1a was 504 nm,Hammett indicator method showed the acid strength of both complexes was 0.8<Ho≤ 3.3.2.Titanium(Ⅳ)salophen perfluorooctanesulfonate complex could catalyze the Friedel-crafts reaction of aldehyde/ketone with indoles for the synthesis of bis(indolyl)methane derivatives.Twenty-four target compounds were synthesized with yields of 85%-99%.Moreover,it can be reused five times with minimal changes in catalytic efficiency.The antitumor activities of six bis(indolyl)methane derivatives were tested,and most of the compounds showed more than 50%inhibition against colon cancer cell HCT116 and gastric cancer cell SGC-7901.The chromatin concentration of HCT116 cells incubated by bis(indolyl)methane derivatives was observed in DAPI staining experiment.3.Titanium(Ⅳ)salophen perfluorobutanesulfonate could catalyze the reaction of diaryl disulfide(selenium)ether and bromoalkane to synthesize asymmetric sulfur(selenium)ether in the presence of zinc power.11 target compounds were synthesized with yields of 85%-94%.Moreover,twenty-five novel aryl(N3-tegafluoroalkyl)thio-and selenoethers derivatives were efficiently synthesized by the reaction of tegafluoroalkyl sulfonate with diaryl disulfides or diselenides with yields of 81%-95%under titanium(Ⅳ)salophen perfluorobutanesulfonate/zinc catalytic system.Antitumor activity tests(HCT116 and SGC-7901)of the synthetic organic sulfur(selenium)tegafur derivatives showed that the organic sulfur(selenium)tegafur derivatives had obvious inhibitory effect on both cancer cells.DAPI staining of HCT116 cells showed that chromatin concentration could be observed.Annexin V-FITC/PI staining and flow cytometry were used to quantitatively detect the apoptosis of HCT116 cells induced by tegafur derivatives containing triazole groups 11k.The results showed that compound 11k could induce the apoptosis of HCT116 cells in a concentration-dependent manner.The inhibitory rates of organic sulfur(selenium)tegafur derivatives on human embryonic kidney cells(HEK 293)were lower than that of tegafur derivative(200μg/mL).Conclusion:1.In this paper,we have successfully synthesized two binuclear titanium(Ⅳ)salophen perfluorooctane(butanes)sulfonate complexes.These two complexes showed good air-stability,high thermostability,good solubility and strong acidity.2.Titanium(Ⅳ)salophen perfluorooctanesulfonate complex 1a showed highly catalytic efficiency for the synthesis of bis(indolyl)methane derivatives by the reaction of aldehyde/ketone with indoles.Furthermore,it can be reused five times.These derivatives had good inhibitory effect on colon cancer cell HCT116 and gastric cancer cell SGC-7901.Moreover,HCT116 cells staining experiments(DAPI)indicated the growth inhibition was associated with the induction of apoptosis.3.Titanium(Ⅳ)salophen perfluorobutanesulfonate showed highly catalytic efficiency for the reaction of diaryl disulfide(selenium)ether and bromoalkane or tegafluoroalkyl sulfonate to synthesize asymmetric sulfur(selenium)ether or aryl(N3-tegafluoroalkyl)thio-and selenoethers derivatives in the presence of zinc power.Due to the introduction of alkyl and sulfur-containing or selenium-containing groups,most of the target compounds exhibited higher inhibitory effects on colon cancer cells HCT116 and gastric cancer cells SGC-7901 than tegafur.Cell staining and flow cytometric assay confirmed that tegafur derivatives could induce apoptosis and inhibit cell growth.The toxicities of organic sulfur(selenium)tegafur derivatives on human embryonic kidney cells(HEK 293)were less than that of tegafur(200 μg/m L).