Screening Of Thiophene-based Natural Photosensitizers And The Synthesis And Application Of Their Derivatives

Photodynamic therapy is a non-invasive treatment method for the diagnosis and treatment of diseases such as tumors,skin diseases,and bacterial infections.The basic principle is to activate the photosensitizer at a specific wavelength to convert oxygen into highly toxic singlet oxygen（¹O₂）,resulting in the death of bacteria or tumor tissue.Photosensitizers,as the core of photodynamic therapy,have gone through three generations;however,there are still problems such as low fluorescence brightness,high cytotoxicity,and poor tissue penetration,so it is important to design and develop new photosensitizers.In view of the rich chemical structure and good biocompatibility of natural products,screening and isolating natural active molecules from them is one of the most important means to obtain novel photosensitizers.On this basis,photosensitizers with low toxicity,high ¹O₂ yield,and high fluorescence intensity were designed and synthesized,and their applications in photodynamic antibacterial and selective oxidation were studied.The main research contents are as follows:（1）A magnetic nano-fluorescent probe,NMF-RP,with a specific response to ¹O₂,was designed and prepared,and it was applied to the screening of natural photosensitizers in plant extracts.Finally,five plants containing potential photosensitizers were identified,including Eclipta herba,Euphorbia humifusa,Gynostemma,Eriocaulis buergerianum,and Spirodelaf herba.Taking Eclipta prostrata as an example,three new natural photosensitizers,trithiophene methanol（TSF-OH）,trithiophene formaldehyde（TSF-CHO）,and trithiophene formic acid（TSF-COOH）,were obtained by separation and purification.To improve its optical properties and ¹O₂ generation ability,derivatives L-A to L-E were designed and synthesized based on TSF-CHO and Gaussian theory.These derivatives showed excellent biocompatibility and photodynamic antibacterial effects.Compared with TSF-CHO,the maximum absorption wavelength of L-E was red-shifted from 400 nm to 485 nm,and the fluorescence emission wavelength was red-shifted from 525 nm to 650 nm.The minimum bactericidal concentration（MBC）of L-E against P.aeruginosa was reduced from 4.5×10^-5 M of TSF-CHO to 6.6×10^-6 M,indicating the effectiveness of the derivative design.（2）It is of great significance for wound healing to realize the early detection and killing of wound bacteria and reduce the adhesion between wound and dressing.The compounds from Ester-A to Ester-J responding to lipase were synthesized by esterification of the natural photosensitizer TSF-OH with different acids.Among them,Ester-J had the most obvious response to lipase.After contact with lipase,the fluorescence intensity was enhanced by 24.98 folds,and bright blue fluorescence was emitted to achieve effective detection of bacteria.To facilitate the application,Ester-J was co-electrospun with polylactic acid-hydroxyacetic acid copolymer（PLGA）and polydimethylsiloxane（PDMS）to prepare PP-EsJ hydrophobic and anti-adhesive electrostatic spinning film with a contact angle of 140.7°.When the PP-EsJ composite membrane was in contact with bacteria,the attached Ester-J was hydrolyzed to Tph-TSF-OH,releasing bright blue fluorescence,thus providing early warning for bacterial infection.The detection limits for P.aeruginosa（ATCC 27853）and S.aureus（ATCC 33592）were 1.0×10⁵ and 1.0×10⁶ CFU/mL,respectively.When the fluorescence signal of bacterial infection was observed,the photodynamic therapy process of activating Tph-TSF-OH was irradiated with a xenon lamp to kill bacteria and accelerate wound healing.At the same time,with the help of the hydrophobic properties of the PP-EsJ electrospinning membrane,it has excellent anti-fouling and self-cleaning abilities,which can reduce blood exudation,the risk of infection,and the adhesion of dressing to skin.（3）Based on the antibacterial properties of quaternary ammonium salt,a series of cationic quaternary ammonium salt photosensitizers,ThPy-Cx,with different carbon chain lengths were synthesized,which had antibacterial ability under dark and light conditions.The relationship between carbon chain length and antibacterial activity showed that when the carbon chain length was 6,the MBC of ThPy-C6 against S.aureus under dark and light conditions was 1.07 m M and 1.13μM,respectively.Carboxymethyl chitosan（CTC6）with excellent photodynamic antibacterial ability was prepared by grafting OH-ThPy-C6 with carboxymethyl chitosan through an ester bond.The MBC of CTC6 against S.aureus and P.aeruginosa under simulated sunlight was 8.5μg/mL and12.6μg/mL,respectively.The cross-linking of CTC6 with silane coupling agent（KH560）can easily construct an antibacterial coating on the surface of medical devices and wearable devices by spraying or dipping,which can effectively sterilize and prevent bacterial growth.（4）Based on the high efficiency and selectivity of singlet oxygen in catalytic oxidation,three photosensitizers with a D-π-A configuration from QT-A to QT-C were synthesized by using thiophene and p-phenylenediacetonitrile as electron-donating and electron-withdrawing units.Furthermore,the porous polymer molecule QT-D was designed and synthesized by polymerization to enhance the photosensitive effect.QT-D has excellent ¹O₂ generation efficiency,a wide spectral absorption range,and a strong photocurrent intensity.Under visible light irradiation,QT-D can achieve selective oxidation of sulfide to sulfoxide with air as a clean oxidant and has a wide range of substrate applications.Furthermore,QT-D was co-electrospun with polyvinylidene fluoride（PVDF）and polyvinylpyrrolidone（PVP）to prepare the PP-QD electrospun catalytic membrane.Compared with QT-D,the PP-QD electrospun membrane has higher catalytic activity and more convenient recycling.The conversion of p-phenylene sulfide（1.0 mmol）reached 98.3%within 3.5 h,and the catalytic activity did not decrease significantly after 5 cycles.The PP-QD electrospun membrane was applied to the synthesis of clinical drugs albendazole and modafinil,and the conversion rates reached 97.10%and96.06%within 6.0 h,respectively.The synthesis and application of QT-D catalysts not only provide a theoretical reference for the design of polymer photosensitizers,but also provide a practical and available reaction platform for the selective oxidation of sulfides.