Design,Synthesis And Anti-tumor Applications Of Diketopyrrolopyrrole-based Water-soluble Conjugated Small Molecules

In recent years,fluorescent probes based on organic conjugated small molecule have attracted widespread interest from researchers in the fields of chemistry,materials science and biology.The discovery of biologically transparent windows and the advancement of near infrared(NIR)technology provide exciting prospect for in vivo fluorescence imaging.The NIR-I region is between 650 and 950 nm,which exhibits significantly increased tissue penetration compared to visible light due to reduced scattering and autofluorescence.Fluorescent probes based on organic conjugated small molecule show the advantages of excellent molar absorptivity,good biocompatibility,low cytotoxicity,and it is easy to adjust their optical properties by changing the structure,so they have great potential in biomedical applications such as in vivo imaging.However,there are still some shortcomings,such as poor water solubility,low fluorescence quantum yield,and the effect of phototherapy needs to be improved.Phototherapy mainly includes photodynamic therapy(PDT)and photothermal therapy(PTT).If PDT is combined with PTT,the heat resistance protein of tumor cells will be damaged,thus enhancing the effect of PTT.At the same time,PTT can improve the permeability of tumor cell membrane and alleviate the hypoxic environment of tumor in PDT.Therefore,PDT and PTT can promote each other and improve the overall therapeutic effect.In this thesis,a series of water-soluble conjugated small molecules,which absorb in NIR region with D-π-A and D-π-A-π configurations,are designed and synthesized using fluorene derivatives as electron donors(D)and diketopyrrolopyrrole(DPP)derivatives as electron acceptors(A).DPP has a good planar conjugated structure and is a good unit for realizing long-wavelength absorption,and it also exhibit high photothermal conversion and active oxygen generation capacity.Fluorene has been demonstrated to have strong light stability and high fluorescence quantum yield,and its structure is easy to be modified.The main research work is as follows:(1)Cationic water-soluble conjugated molecules FD ’and FDF’ are synthesized by Suzuki reaction and quaternization reaction of bromohexyl substituted fluorene derivatives and DPP derivatives.Their structure configurations are D-π-A and D-π-A-π-D,respectively.The NIR absorption and fluorescence emission are realized.The singlet oxygen yield of FD’ is 68%,which is about 20% higher than that of FDF’.This is probably due to the heavy atom effect of bromine atoms on the side of FD’,which improves the ability of inter system crossing.However,the fluorescence quantum efficiency of FDF’ is higher than that of FD’ due to the extended conjugation structure.The two conjugated molecules have good biocompatibility and can be used in photodynamic/photothermalsynergistic therapy guided by NIR fluorescence imaging.In the He La tumor cell phototoxicity test,under the condition of 500 μg/m L,the tumor cell inhibition rate can reach about 75% after 8 min of laser irradiation.(2)In order to further optimize the properties of the materials,two cationic water-soluble conjugated molecules FDO’ and FDOF’ are synthesized by Suzuki reaction and quaternization reaction of alkoxy side chain substituted fluorene derivatives and DPP derivatives.Their structure configurations are D-π-A and D-π-A-π-D,respectively.The side chains doped with oxygen atoms increases the water solubility of conjugated molecules.In addition,n→π* will improve the ability of inter system crossing.Therefore,the singlet oxygen yield of FDO’ and FDOF’ are higher than that of FD’ and FDF’,which are 78.4% and 68.3%,respectively.Moreover,the NIR absorption and fluorescence emission of FDO’ and FDOF’ are red shifted to a certain degree,and good photoacoustic imaging can be realized under 680 nm laser irradiation.FDO’ and FDOF’ can realize photodynamic/photothermal synergistic tumor therapy guided by fluorescence and photoacoustic dual-mode imaging.In the He La tumor cell phototoxicity test,under the condition of 500 μg/m L,the tumor cell inhibition rate can reach about 80% after 8 min of laser irradiation.The phototoxicity is slightly higher than that of FD’ and FDF’.