İndol türevi yeni sirtuın inhibitörlerinin hepatosellülar karsinoma üzerinde biyoaktivite analizi

Hepatocellular carcinoma is ruthless cancer, a subtype of primary liver cancer and affects many people with various ethnic backgrounds and age intervals. Indole derivative molecules are potent chemicals used in several drugs and target many essential proteins malfunctioning multiple diseases. One of the targets of indole derivatives is histone deacetylases (HDACs), which reverses histone acetylation modifications that open DNA to lead transcription machinery to promote transcription. This study screened 28 novel indole derivatives for their cytotoxicity capacity against three different cancer types. Four of them were selected based on the inhibitory concentration 50 (IC50) values and structure-activity relations. Then, their targets were investigated with the DEEPScreen database and with molecular docking studies. In silico studies predicted that the molecules might interact with Sirt1, which is class III HDAC. For in vitro validation, the nuclear fraction of HCC cells was used in Sirtuin enzymatic activity assays. After the validation, one of the most critical targets of Sirt1, p53, which is also a vital tumor suppressor and mutagenized in HCC, was investigated. As a possible mechanism of action of the compounds, they could increase the acetyl-p53 level by blocking Sirt1 and lead p53-derived G1-mediated apoptosis in HCC cells.