Triplet Photosensitizers Based On Thio-pentamethine Cyanine Dyes For Cancer Phototherapy

Triplet photosensitizers（PSs）have received extensive attention and research due to their good application prospects in the fields of energy and biology.To design efficient triplet PSs,researchers have proposed several conjugation-site-based modification strategies that successfully endow dye chromophores with the ability to generating triplet states.However,the conjugated modification of dyes often reduces the flexibility of the molecule and increases the tendency to aggregate,thus limiting the application in specific fields.Therefore,it is urgent to develop new modification strategies to obtain PSs with excellent properties.This thesis focuses on the side chain sites of thio-pentamethine cyanine dyes（TCy5）,expecting to selectively tune the triplet properties through a non-conjugated modification strategy.Through the comparison of different structures,the possible molecular structure-activity relationship was studied and high-efficiency triplet PSs suitable for photodynamic therapy in tumor was obtained.The specific research contents are as follows:（1）In order to verify the feasibility of the non-conjugated modification strategy,three examples of heavy-atom-free triplet PSs were designed by introducing different heterocycles methyl into the unique nitrogen site of TCy5,the three compounds exhibit consistent fluorescence quantum yields and near-infrared absorptions,while singlet oxygen（¹O₂）quantum yields are significantly different.Theoretical calculation results show that the variation of different heterocycles can simultaneously reduce the singlet-triplet energy gaps and increase the spin-orbit coupling constant to promote the intersystem crossing（ISC）process.More importantly,the ¹O₂ quantum yield,molar absorption coefficient,triplet excited state lifetime and ISC rate constant of TCy5 increase synchronically with the enhancement of heterocyclic electron-donating ability.The thienyl with the strongest electron-donating ability transforms TCy5-S into a high-performance triplet PS,in which the ¹O₂ quantum yield is as high as 50%,and the triplet excited state lifetime is extended to 472.4μs.TCy5-S with excellent biocompatibility can kill normoxic/hypoxic cells at low light doses and effectively inhibit rapid tumor growth in vivo.（2）In order to fully explore the molecular structure-activity relationship of the side chain sites,four compounds were designed by introducing different substituents at the para position of the benzyl of the side chain of TCy5,realizing the selective control of triplet state generation,and the ¹O₂ quantum yield was increased from 33.8%to 69.9%.Theoretical calculation results show that the introduction of different substituents distorts the molecular configuration of the compound and effectively increases the spin-orbit coupling constant.The twistedπ-conjugated frameworks induce ISC mechanism of cyanine dye structure has not been reported in the literature.It is found that the electron-withdrawing ability and steric hindrance of substituents are positively and negatively correlated with the degree of twist,and the greater the degree of twist,the more favorable ISC process occurs.Among them,the ¹O₂ quantum yield of TCy5-CF3 is 51.7%,with good biocompatibility,showing excellent in vitro photodynamic therapy effect and the potential for further application in living tumor therapy.