Thiol “click” chromene mediated cascade reaction forming coumarin for in-situ imaging of thiol flux in drug-induced liver injury

Abstract

Drug-induced organ damage has long been considered as a serious public health concern. Drug-induced liver injury (DILI) is one of the common clinical side effects of drugs and the main cause of acute liver failure. Previous evidence showed that there is a potential relationship between thiols and DILI. Many studies have reported that oxidative stress is involved in many drug-induced liver injury mechanisms. APAP, as the most representative drug for clinical DILI, is considered to cause large amounts of intracellular reactive oxygen species. However, thiols as the effective antioxidant maintain the normal redox balance of organisms and play a vital role in the liver injury and other diseases. Therefore, a new NIR fluorescent probe DCI-Ac-HMPC was developed based on thiol-chromene “click” reaction, which triggered the intramolecular cascade reaction to in-situ generate NIR coumarin fluorophore. In addition, we found that thiols levels in the liver of mice with DILI were significantly reduced, revealing a negative correlation between thiols and DILI. Furthermore, the therapeutic effects of three kinds of liver-protecting drugs on hepatotoxicity induced by acetaminophen (APAP) in vivo based on thiols fluctuations. This work provides a new idea for the in-situ synthesis strategy of NIR coumarin dyes, which is helpful for the diagnosis of DILI and the further study of the role of thiols in related diseases.