Design,Synthesis And Properties Research Of Acridone Derivatives

Fused-heterocycle is a kind of important organic small molecule compounds possessed excellent biological activity and optical activity.Fused-heterocycle include a wide range of heterocyclic compounds,acridone is one of them,acridone derivatives not only has the good biological activity but also excellent optical performance attributed to its rigid plane structure,amount of organic small molecule compounds based acridone skeleton were continuously research and development.The present research in the filed of acridone derivative biological activity are mostly focused on the treatment of leukemia,and in the filed of the optical properties mainly focused on their application.However,the research in other aspects of acridone derivatives were rarely reported.Therefore,based on its reactive sites,a seriels of4-anminoacridone Schiff and N¹⁰-subsituted acridone derivatives were systematically designed and synthesized,The study of their activity focused on others four cell lines except leukemia cell lines,The target and mechanism of action of acridone derivatives were proved by a series of experiments.Meanwhile the structure-activity relationship and regulation of multi-drug resistance were theoretically study in order to provides a solid base for further the design of this kind of compounds.Also two acridone dericatives were designed to identify the metal ions,using the theory to discuss the relationship between structure and performance of two probes,and one of the probe were successfully applied to the cell imaging.The first chapter detailed descibed acridone derivatives'research progress in aspects of its synthesis,biological activity,fluorescent probe.and the research thought and methodology.The Cu-Cu₂O,Cu₂O,Cu I nanoparticles possed different dispersion degree,different morphology,different particle size were prepared by four common copper salts for copper source,their structures were characterized by XRD and SEM,further the application,which catalyzed synthesis of precursor of acridone derivatives,were researched.The results showed that Cu₂O nanoparticles,which occupied spherical structure,good dispersion,uniform particle size distribution prepared by copper acetate has the best catalytic effect.The yield was 82%-96%when the reaction conditions was optimal?Cs₂CO₃ as base,DMF as solvent,the amount of the catalyst is 1.2 mol%,the reaction time is 3h,reaction temperature 110??.Finally two possible mechanisms were presented.25 novel 4-aminoacridone Schiff base were synthezied based on4-anminoacridone,All the final products were screened for their cytotoxicity against several cell lines by the standard MTT assay in vitro.The better activity derivatives were chosen to research topoisomemse inhibition activity through?DNAdecatenation,pBR322 DNA,Atabilization of the cleavage complex and DNA intercalation.4-AAS25 showed a better cytotoxicity against Hela cell lines and inhibition activity on TopoIIa as a Topooison.Three-dimensional contour maps based on highly predictive 3D-QSAR studies were applied to explain the structure-activity relationships of these compounds.And molecular docking were conducted to predict the multidrug resistance modulator?MDR?effects on the ATP binding site and transmembrane binding pocket of P-gp.the carbonyl‘O'of acridone ring of 4-AAS25displayed an essential hydrogen bond with residue Ser-975,which was the primary interaction between 4-AAS25 and P-gp.N¹⁰-substituted acrdione derivatives occupy not only a better antitumor activity,but also the capability to modulate the multidrug resistance,For the existing N¹⁰-substituted acrdione derivatives,they have exhibited a better antitumor activity contained alkoxy groups or halogen atoms.As one of the most common functional group in biologically active molecules,methyl has significantly biological activity.However,for N¹⁰-substituted acridones which acridone rings are substituted by methyl,it is relatively rare in literatures.Based on the above considerations,a series of N10-substituted methyl or halogen acridone derivatives were designed and synthesized.The inhibition activity in vitro and mechanism of action were researched by apply the same approach as the Chapter?.The research result shows:1,NSA17has shown potent antitumor activities against HeLa cells?IC50=0.83?M?,Docking analysis of NSA-10,17,23 show that the derivatives had better MDR,Carbonyl group of its parent form hydrogen bonds with hydroxyl groups on the amino acid residues in oder to reduce the bonding energy and increase the targeted protein binding ability;2?Most of synthsized compounds have good effects on inhibiting Raji cell lines(IC₅₀<10?M),3D-QSAR studies were applied to explain the structure-activity relationships of these compounds in order to provides a solid base for further the design of this kind of compounds;3?these derivatives showed inhibition activity on TopoIIa as a embedded topooison.Two derivatives were designed and synthesized,the experimental result dedicated:designed derivatives could served as fluorescent probe,both had better selectivity,good pH tolerability,strong anti-interference ability,lower detection limit,SNA become weak gradually when Cu²⁺was added,the recognition mechanism of SNA was eatablised through theoretical calculation,so that the system of fluorescence.AAN can recognized Cr³⁺specially,the recognition mechanism of the SNA was also eatablised through theoretical calculation,while AAN had low cytotoxicity and good selectivity,so AAN also has been successfully applied to the detection Cr³⁺in the Hela cell.The last Chapter concluded the full work and and gave study prospect of promising applications on activity and fluroence probe of acridone derivatives.