Thesis Type: Postgraduate
Institution Of The Thesis: Gazi University, Sağlık Bilimleri Enstitüsü, FARMASÖTİK KİMYA ANABİLİM DALI, Turkey
Approval Date: 2021
Thesis Language: Turkish
Student: SEMİH YAĞCI
Supervisor: Gökçen Eren
Abstract:
Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein
histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals.
This group of enzymes catalyses the reversible deacetylation of lysine residues in the
histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have
demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various
diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed
a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative
displaying SIRT1/2 inhibitory effect was identified as a hit compound (inh%, SIRT1: 31,45%;
SIRT2: 42,47% @300 μM). In the current study, the hit-to-lead optimization on the hit
compound was explored in order to improve the SIRT inhibition. Fourteen compounds, ten
of which were new, have been synthesized and subjected to in vitro biological evaluation
for their inhibitory activity against SIRT1-3. By the structural modifications performed, a
significant improvement was observed in selective SIRT1 inhibition for GS01, GS02, and
GS11 (inh%, SIRT1: 56,53%, 48,15%, 46,04%; SIRT2: 10,80%, no inhibition, no inhibition
@100 μM, respectively). Moreover, the highest SIRT2 inhibitory activity was observed for
GS14 (inh%, SIRT1: 47,16%; SIRT2: 51,61% @100 μM). Furthermore, GS01, GS02, GS11, and
GS14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell
line to determine the influence of the improvement in SIRT1/2 inhibition along with the
structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of
the compounds was found to be correlated with their SIRT inhibitory profiles. Overall, the
compounds with more potent and selective SIRT inhibition compared to that of the hit
compound were obtained.
Keywords : Sirtuin, Drug design, Enzyme inhibition