Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors

Bruno, Agostino
Guntekin-Ergun, Sezen
Atalay, Rengül
Ozgencil, Fikriye
Gozelle, Mahmut
Kaya, Selen Gozde
Costantino, Gabriele
Sirtuins (SIRTs) are a class of NAD(+)-dependent protein histone deacetylases (HDACs) that catalyse the reversible deacetylation of lysine residues in the histones or non-histone substrates. Mammalian sirtuins consist of seven isoforms (SIRT1-7), which show different subcellular localizations and enzymatic functions. Among the seven human sirtuins, SIRT2 predominantly located in the cytoplasm but is enriched in the nucleus during mitosis. Its activity has been found to be modulate the pathophysiology of various diseases such as cancer, metabolic and neurodegenerative disorders. Therefore, selective SIRT2 inhibitors are of growing interest as potentially candidate therapeutic agents to treat SIRT2-driven pathologies as well as valuable tools to investigate and define the biological roles of SIRT2. Herein, in order to identify potent leads against SIRT2, a multi-step pharmacophore based-virtual screening campaign was performed and 31 predicted compounds were subjected to in vitro biological evaluation. Finally, compound 2 and 3 showing better SIRT2 inhibition potency were selected for further in vitro cytotoxic assays against a panel of three human cancer cell lines. This study will hopefully provide a basis for developing potent and selective SIRT2 inhibitors.


The synthesis and characterization of new metal-free and metallo phthalocyanines substituted with four dithiatetraoxa macrocyclic moieties
Kantekin, Halit; Rakap, Murat; Misir, Mirac Nedim; Goek, Halil Zeki; Acar, Irfan (Informa UK Limited, 2007-01-01)
New metal-free phthalocyanine ( 7) fused symmetrically in peripheral positions with four dithiatetraoxa macrocycles, has been synthesized by cyclotetramerization of the isoindoline-diimine derivative of macrocyclic 6. Metallophthalocyanine ( 8) was synthesized by reaction of phthalonitrile derivative ( 5) with anhydrous nickel( II) chloride. The new compounds were characterized by elemental analysis, H-1 and C-13-NMR, IR UV-Vis and mass spectroscopies.
Intermolecular one-pot cyclization of formyl-pyrroles of amino acid esters with norephedrine: stereoselective routes to new tricyclic pyrrole-pyrazine-oxazole fused structures
Demir, Ayhan Sıtkı; Subasi, N. Tuna; Sahin, Ertan (Elsevier BV, 2006-10-16)
The treatment of esters of amino acids with dimethoxytetrahydrofuran furnished pyrrole derivatives of amino acid esters. The Wilsmeier-Haack formylation followed by the reaction of the formylated pyrroles with norephedrine afforded a selective formation of the tricyclic pyrrole-pyrazine-oxazole fused structures in one step via the formation of an oxazoline structure and intramolecular lactam formation. Pyrrole-pyrazine-oxazole fused structures were achieved in good yields. The cyclization reaction for the f...
Coupling of ferrocenyl chromium carbene complex with cyclobutenediones
Zora, Metin; Bekir Peynircioglu, N. (Elsevier BV, 2002-08-15)
The coupling of ferrocenyl chromium carbene complex with cyclobutenediones leads to ferrocenyl-substituted 5-alkylidenefuranones and 4-cyclopentene-1,3-diones, methyl ferrocenoate and acetylferrocene in varying amounts. The scope and limitations of these processes are investigated. In comparison with the phenyl analog, ferrocenyl chromium carbene complex has been found to be less reactive. This is also supported by PM3 calculations. The coupling of ferrocenyl chromium carbene complex with cyclobutenediones...
A new and efficient chemoenzymatic route to both enantiomers of alpha '-acetoxy-alpha-methyl and gamma-hydroxy-alpha-methyl cyclic enones
Demir, Ayhan Sıtkı; Findik, H; Kose, E (Elsevier BV, 2004-03-08)
A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting alpha'-acetoxy-alpha-methyl and gamma-hydroxy-alpha-methyl cyclic enones starting from alpha-methyl-beta-methoxy cyclic enones is reported. Manganese(Ill) acetate-mediated acetoxylation followed by the enzyme-mediated hydrolysis of alpha'-acetoxy enone provides acetoxy enones 1a and 2a and hydroxy enones 1b and 2b with high enantiomeric excesses in good yields. The reduction of the acetoxy and hydroxy enones furnished both e...
Investigation of thermal characteristics of naphthoxazines and polynaphthoxazines via pyrolysis mass spectrometry
Koyuncu, Zeynep; Hacaloğlu, Jale; Department of Chemistry (2009)
In this study, polymerization mechanisms of aromatic (C6H5 or C6F5) and alkyl (CH3, C2H5, C3H7, C6H13, C12H25 or C18H37) amine based naphthoxazine monomers (15-Na, 15Na-C1, 15Na-C2, 15Na-C3, 15Na-C6, 15Na-C12 and 15Na-C18) and thermal degradation mechanisms of polynaphthoxazines synthesized by curing the naphthoxazine monomers (P-15-Na, P-15NaF, P-15Na-C1, P-15Na-C2, P-15Na-C3, P-15Na-C6, P-15Na-C12 and P-15Na-C18) were studied by direct pyrolysis mass spectrometry. During the curing process, the evolutions...
Citation Formats
G. EREN et al., “Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors,” JOURNAL OF MOLECULAR GRAPHICS & MODELLING, pp. 60–73, 2019, Accessed: 00, 2020. [Online]. Available: