Research Information System
Thesis Type: Doctorate
Institution Of The Thesis: Gazi University, Sağlık Bilimleri Enstitüsü, Turkey
Approval Date: 2023
Thesis Language: Turkish
Student: Selen Gözde KAYA
Supervisor: Gökçen Eren
Abstract:
The sirtuin (SIRT) enzymes are a class of nicotinamide adenine dinucleotide (NAD+) dependent histone deacetylases that catalyze the deacetylation reaction at the ε-amino groups of lysine residues in histone and non-histone protein substrates. The discovery of sirtuins began in yeast, and seven mammalian homologs (SIRT1-7) have been identified so far. SIRT2, the cytosolic isoform among these isoforms, has been reported to play an essential role in cellular biological processes such as inflammation, metabolism, oxidative stress, and apoptosis mediated by an increasing number of substrates. Therefore, its inhibition is considered a potential therapeutic strategy for treating pathologies, including cancer, cardiovascular, metabolic, and neurodegenerative diseases. With this aim, a lead optimization study was performed on two hit compounds, which were the output of the pharmacophore-based virtual screening campaign, yielding twenty new derivatives with N aryloxyaryl-2-(arylthio)acetamide scaffold. Among these compounds, the so-called first series, the potency of selective SIRT2 inhibition was enhanced by S1.12 (SIRT2 IC50=9,97 µM) compared to the hit compounds. Following the evaluation of the SAR of the first series, the substituents and the linkers that contributed to the SIRT2 inhibition were identified, and four new compounds were designed as the second series, resulting in S2.2 (SIRT2 IC50=5,74 µM), which displayed more potent and selective SIRT2 inhibitor profile. Finally, based on the SAR data and the crucial interactions in the SIRT2 active site, four derivatives were designed with 1,1’-(9-oxo-9H-fluoren-2,7-diyl)bis(3-(aryl)urea) scaffold. Among these compounds comprising the third series, S3.3 (SIRT2 IC50=2,04 µM) was identified as the most potent and selective SIRT2 inhibitor of the entire compounds designed in the study. Moreover, the compounds displaying potent and selective SIRT2 inhibition were evaluated for their antiproliferative effects on the human MCF-7 breast cancer cell line. According to the results, the selected compounds were subjected to Western blot analysis to determine the relationship between their SIRT2 inhibition potentials and antiproliferative effects.
Key Words : Computer-aided drug design, SIRT2, inhibitor, MCF-7, α-tubulin