6-(7-nitro-2-1-3-benzoxadiazol-4-ylthio)hexanol and Liver-Neoplasms

Tryptophan-2,3-dioxygenase (TDO) is an immune checkpoint enzyme expressed in human tumors and involved in immune evasion and tumor tolerance. While glutathione S-transferases (GSTs) are pharmacological targets for several cancer. Here we demonstrated the utility of NBDHEX (GSTs inhibitor) and TDO inhibitor by the combinatorial linker design. Two novel conjugates with different linkers were prepared to reverse tumor immune suppression. The conjugates displayed significant antitumor activity against TDO and GSTs expression of HepG2 cancer cells. Further study indicated that compound 4 could induce higher apoptotic effect than its mother compounds via a mitochondrial-dependent pathway, simultaneously more effective to inhibit TDO and GSTs protein expression. Further study indicated that 4 could decrease the production of kynurenine and deactivate aryl hydrocarbon receptor (AHR), leading to CD3

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Glutathione Transferase; Humans; Kynurenine; Liver Neoplasms; Mitochondria; Molecular Structure; Oxadiazoles; Receptors, Aryl Hydrocarbon; Signal Transduction; Structure-Activity Relationship; T-Lymphocytes; Tryptophan Oxygenase