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AKDEMİR, ATİLLA

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ATİLLA
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AKDEMİR
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2020 - 20229
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Author: AKDEMİR, ATİLLA × Has files: true × Start date: 2020 × End date: 2022 ×

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Now showing 1 - 9 of 9
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    PublicationOpen Access
    Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII
    (2022-07-01T00:00:00Z) GÜMÜŞ PALABIYIK, ARZU; Bozdag, Murat; AKDEMİR, ATİLLA; Angeli, Andrea; Selleri, Silvia; Carta, Fabrizio; Supuran, Claudiu T.; AKDEMİR, ATİLLA
    A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.
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    PublicationOpen Access
    The neutralization effect of montelukaston SARS-CoV-2 is shown by multiscale in silicosimulations and combined in vitro studies
    (2021-10-19T00:00:00Z) Durdagi, Serdar; Avsar, Timucin; Orhan, Muge Didem; Serhatli, Muge; Balcioglu, Bertan Koray; Ozturk, Hasan Umit; Kayabolen, Alisan; Cetin, Yuksel; Aydinlik, Seyma; Bagci-Onder, Tugba; Tekin, Saban; Demirci, Hasan; Guzel, Mustafa; Akdemir, ATİLLA; Calis, Seyma; Oktay, Lalehan; Tolu, Ilayda; Butun, Yasar Enes; Erdemoglu, Ece; Olkan, Alpsu; Tokay, Nurettin; Işık, Şeyma; Ozcan, Aysenur; Acar, Elif; Buyukkilic, Sehriban; Yumak, Yesim; AKDEMİR, ATİLLA
    Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).
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    PublicationOpen Access
    Synthesis and biological evaluation of new chloro/acetoxy substituted isoindole analogues as new tyrosine kinase inhibitors.
    (2020-01-01T00:00:00Z) Köse, A; Kaya, M; Kishalı, NH; Akdemir, ATİLLA; Şahin, E; Kara, Y; Şanlı-Mohamed, G; AKDEMİR, ATİLLA
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    PublicationOpen Access
    Novel Indole-Based Hydrazones as Potent Inhibitors of the α-class Carbonic Anhydrase from Pathogenic Bacterium <i>Vibrio cholerae</i>.
    (2020-04-29T00:00:00Z) Demir-Yazıcı, K; Güzel-Akdemir, Ö; Angeli, A; Supuran, Ct; Akdemir, Atilla; AKDEMİR, ATİLLA
    Due to the increasing resistance of currently used antimicrobial drugs, there is an urgent problem for the treatment of cholera disease, selective inhibition of the α-class carbonic anhydrases (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VcCA) presents an alternative therapeutic target. In this study, a series of hydrazone derivatives, carrying the 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold, have been evaluated as inhibitors of the VcCA with molecular modeling studies. The results suggest that these compounds may bind to the active site of VcCA. To verify this, VcCA enzyme inhibition studies were performed and as predicted most of the tested compounds displayed potent inhibitory activities against VcCA with three compounds showing KI values lower than 30 nM. In addition, all these compounds showed selectivity for VcCA and the off-targets hCA I and II.
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    PublicationOpen Access
    Anti-SARS-CoV-2 and cytotoxic activity of two marine alkaloids from green alga Caulerpa cylindracea Sonder in the Dardanelles
    (2022-10-01T00:00:00Z) Erol, Ebru; Alim Toraman, Gulbahar Ozge; Orhan, Muge Didem; Avsar, Timucin; Akdemir, Atilla; Okudan, Emine Sukran; Topcu, Gulacti; EROL, EBRU; AKDEMİR, ATİLLA; ALİM TORAMAN, GÜLBAHAR ÖZGE; TOPÇU, GÜLAÇTI
    Caulerpa cylindracea Sonder is a green alga belonging to the CauIerpaceae family. This is the first chemical investigation of C. cylindracea in the Dardanelles which resulted in the isolation of four compounds, caulerpin (1), monomethyl caulerpinate (2), beta-sitosterol (3), and palmitic acid (4). Their structures were elucidated by spectroscopic analyses including 1D- and 2D NMR and mass. The isolated compounds 1 and 2 were tested against the SARS-CoV-2 viral targets spike protein and main protease (3CL) enzyme, and both compounds significantly inhibit the interaction of spike protein and ACE2, while the main protease activity was not significantly reduced. Docking studies suggested that compounds 1 and 2 may bind to the ACE2 binding pocket on spike, and compound 2 may aka bind to an allosteric site on spike. As such, these compounds may inhibit the spike-ACE2 complex formation competitively and/or allosterically and have the potential to be used against SARS-CoV-2 virus infection. In addition, compounds 1 and 2 showed at [east two-fold higher cytotoxicity against breast cancer cell Lines MCF7 and MDA-MB-231 compared to the CCD fibroblast control cell Line
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    PublicationOpen Access
    Development of Thiazolidinones as Fungal Carbonic Anhydrase Inhibitors.
    (2020-04-22T00:00:00Z) Güzel-Akdemir, Ö; Carradori, S; Grande, R; Demir-Yazıcı, K; Angeli, A; Supuran, CT; AKDEMİR, ATİLLA
    In our efforts to find new and selective thiazolidinone-based anti-Candida agents, we synthesized and tested 26 thiazolidinones against several Candida spp. and Gram-positive and Gram-negative bacteria. The compounds showed selective antifungal activity with potency similar to fluconazole and clotrimazole, while lacking strong antibacterial activity. Molecular docking and molecular dynamics studies were performed on Candida CYP51a1 and carbonic anhydrase (CA) enzymes to further suggest putative targets that could mediate the antifungal effects of these compounds. Finally, the compounds were tested in enzyme inhibition assays to assess their putative mechanism of action and showed promising KI values in the 0.1–10 µM range against the Candida glabrata β-CA enzyme CgNce103.
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    PublicationOpen Access
    Molecular modelling studies to suggest novel scaffolds against SARS-CoV-2 target enzymes
    (2021-12-01T00:00:00Z) Akdemir, Atilla; AKDEMİR, ATİLLA
    In this study, molecular modelling study of previously synthesized compounds against SARS-CoV-2 target enzyme was performed. A subset of 156 compounds from an in-house database has been subjected to molecular modelling studies against the SARS-CoV-2 ADP-ribose phosphatase (ADRP, NSP3), Papain-like protease (PLpro), and uridine specific endoribonuclease (NSP15) enzymes. We have identified one compound that is expected to inhibit the SARS-CoV-2 ADRP enzyme and one compound that is expected to inhibit the NSP15 enzyme.
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    PublicationOpen Access
    New azolyl-derivatives as multitargeting agents against breast cancer and fungal infections: synthesis, biological evaluation and docking study
    (2021-01-01T00:00:00Z) Maccallini, Cristina; Gallorini, Marialucia; Sisto, Francesca; AKDEMİR, ATİLLA; Ammazzalorso, Alessandra; De Filippis, Barbara; Fantacuzzi, Marialuigia; Giampietro, Letizia; Carradori, Simone; Cataldi, Amelia; Amoroso, Rosa; AKDEMİR, ATİLLA
    Nonsteroidal aromatase inhibitors (NSAIs) are well-established drugs for the therapy of breast cancer. However, they display some serious side effects, and their efficacy can be compromised by the development of chemoresistance. Previously, we have reported different indazole-based carbamates and piperidine-sulphonamides as potent aromatase inhibitors. Starting from the most promising compounds, here we have synthesised new indazole and triazole derivatives and evaluated their biological activity as potential dual agents, targeting both the aromatase and the inducible nitric oxide synthase, being this last dysregulated in breast cancer. Furthermore, selected compounds were evaluated as antiproliferative and cytotoxic agents in the MCF-7 cell line. Moreover, considering the therapeutic diversity of azole-based compounds, all the synthesized compounds were also evaluated as antifungals on different Candida strains. A docking study, as well as molecular dynamics simulation, were carried out to shed light on the binding mode of the most interesting compound into the different target enzymes catalytic sites.
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    PublicationOpen Access
    Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment
    (2020-10-01T00:00:00Z) Angeli, Andrea; Carta, Fabrizio; Nocentini, Alessio; Winum, Jean-Yves; Zalubovskis, Raivis; AKDEMİR, ATİLLA; Onnis, Valentina; Eldehna, Wagdy M.; Capasso, Clemente; De Simone, Giuseppina; Monti, Simona Maria; Carradori, Simone; Donald, William A.; Dedhar, Shoukat; Supuran, Claudiu T.; AKDEMİR, ATİLLA
    The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.