Design,Synthesis And Application Of Cyclobutanone-based Chromophores

Cyclobutanone and its derivatives can be used as electron acceptor?A?,which can be employed to construct donor-receptor-donor?D-A-D?and donor-receptor-receptor?D-A-A?type chromophores.Among them,squaric acid?3,4-dihydroxy-3-cyclobutenedione?is a special cyclobutanone derivative with strong electron attraction.After further chemical modification,chromophore compounds containing cyclobutanone or its derivatives exhibit good optical properties,such as higher fluorescence quantum yield,high molar extinction coefficient,and longer absorption and emission wavelengths.These properties make the chromophore compounds containing cyclobutanone useful in the fields of imaging and biological detection.In this thesis,three chromophore compounds containing cyclobutanone were designed and prepared,and their applications in fluorescence imaging and detection were discussed.Firstly,an imaging agent and photosensitizer?PS?based on cyclobutanone and a prodrug compound were designed and prepared.The structure of the compounds was confirmed by NMR and MS.Furthermore,PS and prodrug were encapsulated with unsaturated phospholipid to form Lip-Pro-Stm,and thus a liposome nanoprodrug system with a particle size of about 90nm was obtained.Under the excitation of appropriate excitation light,PS in the nanoprodrug system would produce singlet oxygen and red fluorescence;the singlet oxygen produced can disintegrate the nanoprodrug system and release the active drug?chlorambucil?,the active drug can cause cancer cell apoptosis,singlet oxygen can further promote cancer cell apoptosis;while the red fluorescence can be used for the imaging of drug delivery process.Secondly,a near infrared fluorescent probe?NIR-SQ-NO₂?containing cyclobutanone was designed and prepared,which can detect glutathione.Due to the strong electron absorption of nitro group in the molecule,the probe would exhibit photoinduced electron transfer effect,which would cause fluorescence quenching.After the reaction between the probe and glutathione,the reactive group containing nitro group was cleaved,and correspondingly fluorescence was restored,thus realizing the fluorescence detection of glutathione.The probe shows good selectivity for the detection of glutathione.Finally,a near infrared fluorescent/photoacoustic dual-model probe?NP-SPT-NO₂?containing cyclobutanone was designed and prepared.Triphenylamine group containing nitro group was introduced into the molecule by coupling reaction,which made the probe have aggregation-enhanced fluorescence?AEE?and the specific response towards nitroreductase.After the reaction between the probe and nitroreductase,the nitro group in its molecule will be reduced to amino group,which would be transformed into the activated nanoprobe NP-SPT-NH₂,and generate strong fluorescence and photoacoustic signals at the same time,thus it can realize fluorescence and photoacoustic detection and imaging for nitroreductase.The probe can successfully detect and image the tumor in the subcutaneous tumor model by detecting nitroreductase,and also realize fluorescence imaging and optoacoustic imaging of the tumor lymph node metastasis in the lymphatic metastasis mouse model.