DESIGN, SYNTHESIS AND BIOLOGICAL ACTIVITY STUDIES ON ARYLOXY BENZAMIDE DERIVATIVES WITH POTENTIAL INHIBITORY EFFECT AGAINST SIRTUIN

---

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