Designing Fluorescent Probes For Sensing Hydrogen Sulfide,and Developing Mitochondria-targeted Proxidative Anti-cancer Theranostic Prodrugs

Hydrogen sulfide?H₂S?,as the simplest sulfhydryl compound,plays a crucial role in maintaining intracellular redox homeostasis and normal life activities.Developing an effective detection method for H₂S in living organisms is of great significance for the deep understanding of its physiological and pathological roles.Compared with other bio-detection technologies,Fluorescent probes have become one of the indispensable detection methods in the life science field due to their high sensitivity,good selectivity,strong visibility and small cell damage.The development of anticancer theranostic prodrugs has attracted much attention in the context of personalized and precision cancer therapy because of their conversion to toxic species only at the cancer-specific conditions and their dual ability to offer both diagnosis and therapy.Mitochondria are not only the energy power plant of cells and the main site of production of reactive oxygen species?ROS?,but also the apoptotic signaling hub.Cancer cells maintain their malignant phenotypes by mitochondrial dysfunction,and their mitochondrial function is more dependent on control of redox homeostasis than that of normal cells,providing opportunity to develop mitochondria-targeted pro-oxidative anticancer therapeutic prodrugs.Accordingly,we focused on developing fluorescent probes for H₂S detection and mitochondria-targeted pro-oxidative anticancer therapeutic prodrugs in the master's thesis.The main contents are summarized as follows:?1?We developed a novel near-infrared fluorescent probes DPCM-H₂S composed of a dicyanoisophorone platform as the fluorescence reporter and NBD as the response site of H₂S.The probe shows high selectivity,detection limits as low as0.44?M,large Stokes shift?205 nm?,and low cytotoxicity.Most importantly,the probe was successfully used to detect the production of exogenous and endogenous H₂S in HeLa cells.?2?Using naphthylmethylpyridylethylene as the fluorescent backbone and2,4-dinitrophenyl ether as the responsive group,we developed a"Turn-On"two-photon fluorescent probe HNMP-H₂S with the following features:a)mitochondria-targeting ability,facilitating research on the distribution of H₂S in mitochondria;b)high sensitivity and selectivity for H₂S detection;c)easy preparation.?3?Considering the mitochondrial matrix being markedly alkaline?pH?8?we used the glutathione?GSH?-mediated conversion of 2,4-dinitrobenzenesulfonate to phenols to design pro-catechol-type diphenylhexatriene?Mito-PDHH?as a mitochondria-targeted prooxidative anticancer theranostic prodrug.This molecule is expected to harbor the following advantages:a)allowing mitochondrial localization by virtue of its alkylated triphenylphosphonium targeting group due to the highly negative mitochondrial membrane potential,b)capable of exploiting mitochondrial GSH in cancer cells to in situ release a catechol moiety,c)permitting a turn-on fluorescent response for its localization and therapeutic efficacy after activation by GSH,d)deprotonation of the activated catechol being facilitated on the alkaline mitochondrial matrix to generate its phenolate anion,which is a more potent electron donor than the parent catechol and is easily converted into ortho-quinone via two-electron oxidation along with ROS generation,resulting in preferential redox imbalance,energetic crisis,and death of cancer cells over normal cells.Due to the time limits,the synthesis of Mito-PDHH is in progress.