Person: AKDEMİR, ATİLLA
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- PublicationOpen AccessCarbonic 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, ATİLLAThe 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.
- PublicationOpen AccessNovel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group acting as human carbonic anhydrase IX inhibitors.(2018-12-01) DEMIR, K; Akdemir, ATİLLA; ANGELI, A; GÜZEL-AKDEMIR, Ö; SUPURAN, CT; AKDEMİR, ATİLLAA small collection of 26 structurally novel thiazolidinone-containing compounds, without the well-known sulphonamide zinc-binding group, were synthesised and tested in enzyme inhibition assays against the tumour-associated hCA IX enzyme. Inhibition constants in the lower micromolar region (KI < 25 lM) have been measured for 17 of the 26 compounds. Even though the KI values are relatively weak, the fact that they do not contain a sulphonamide moiety suggests that these compounds do not interact with the active site zinc ion. Therefore, docking studies and molecular dynamics simulations have been performed to suggest binding poses for these structurally novel inhibitors.
- PublicationMetadata onlyMandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations(2022-04-01T00:00:00Z) Trawally, Muhammed; DEMİR YAZICI, Kübra; DİNGİŞ BİRGÜL, SERAP İPEK; Kaya, Kerem; AKDEMİR, ATİLLA; GÜZEL AKDEMİR, Özlen; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLA© 2022A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.
- PublicationMetadata onlyInhibition of tumor-associated human carbonic anhydrase isozymes IX and XII by a new class of substituted-phenylacetamido aromatic sulfonamides.(2013-09-01) Akdemir, ATİLLA; GÜZEL-AKDEMIR, Ö; SCOZZAFAVA, A; CAPASSO, C; SUPURAN, CT; AKDEMİR, ATİLLA
- PublicationMetadata onlyEvaluation of new 2-hydroxy-N-(4-oxo-2-substituted phenyl-1,3- thiazolidin-3-yl)-2-phenylacetamide derivatives as potential antimycobacterial agents(2020-04-01T00:00:00Z) Guzel-Akdemir, Ozlen; DEMİR YAZICI, Kübra; Trawally, Muhammed; AKDEMİR, ATİLLA; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLAA small collection of 2-hydroxy-N-(5-methyl/nonsubstituted 4-oxo-2-substituted phenyl-1,3-thiazolidin-3-yl)-2-phenylacetamides (3-16) was synthesized from the cyclocondensation of 2-hydroxy-2-phenyl-N--[(substitutedphenyl)methylene]acetohydrazides (2) and mercaptoethanoic acid or 2-mercaptopropanoic acid, characterized with spectral and elemental analysis. In order to explore their antimycobacterial potential, newly synthesized fourteen compounds were screened for their inhibitory activity against Mycobacterium tuberculosis strain H37Rv at 6.25 mu g/mL with in-vitro primary tests. Compound 7 was found to provide the highest inhibition (98%) M. tuberculosis strain H37Rv, while most of the new derivatives showed different inhibition ratios. For the search of the putative targets which are considered as related to the antimycobacterial activity of these molecules, docking studies were performed. With molecular dynamic simulations, further possible interactions between ligands and the active site of the selected enzymes were investigated. Eventually, molecular modelling studies indicated that at least part of the mechanism of action of these compounds may be mediated by inhibition of MtInhA.
- PublicationMetadata onlyDesign, synthesis and investigation of dual benefits of 2-methyl indole derivatives in hormone-dependent breast cancer: Aromatase inhibitory and antioxidant activity(2016-09-07) Ozcan Sezer, S; İnci, E; Öztürk Ceylan, O; AKDEMİR, ATİLLA; Suzen, S; Gurer Orhan, H; AKDEMİR, ATİLLA
- PublicationMetadata onlyHit Identification Against DNA Topoisomerases Using Virtual Screenings(2019-03-14T00:00:00Z) Akdemir, Atilla; AKDEMİR, ATİLLAHit Identification Against DNA Topoisomerases Using Virtual ScreeningsAtilla AkdemirComputer-aided drug discovery laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkeyaakdemir@bezmialem.edu.tr DNA is in a supercoiled and compact state in non-dividing cells. However, DNA must be unwound to enable replication and transcription by DNA polymerases and RNA polymerases, respectively. The winding and unwinding of DNA is being performed by DNA topoisomerases and as such these enzymes are crucial in cell division and cell growth. Therefore, DNA topoisomerase inhibitors are clinically used in cancer chemotherapy, as antiviral agents and as antibiotics. Human DNA topoisomerase II isoforms α and β are targets for several chemotherapeutic agents such as etoposide. Here we aim to identify structurally new inhibitors of these enzymes by virtual screening procedures. To this end, a small virtual library has been constructed and this library has subsequently been docked into the active sites of isoforms α and β. Compounds that were expected to inhibit the enzymes were synthesized and subsequently tested in enzyme inhibition assays.
- PublicationMetadata onlyIn Silico Design And Synthesis Of Novel 2-Acylhydrazono-5-Arylmethylene-4-Thiazolidinones As Enoyl-Acyl Carrier Protein Reductase Inhibitors(2021-08-06T00:00:00Z) DİNGİŞ BİRGÜL, SERAP İPEK; KÜÇÜKGÜZEL, İLKAY; AKDEMİR, ATİLLA; DİNGİŞ BİRGÜL, SERAP İPEK; AKDEMİR, ATİLLA
- PublicationMetadata onlyIn vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone.(2021-03-08T00:00:00Z) Aliyev, A T; Ozcan-Sezer, S; Akdemir, Atilla; Gurer-Orhan, H; AKDEMİR, ATİLLA
- PublicationOpen AccessDiscovery of novel isatin-based sulfonamides with potent and selective inhibition of the tumor-associated carbonic anhydrase isoforms IX and XII.(2015-06-21) GÜZEL-AKDEMIR, Ö; Akdemir, ATİLLA; KARALı, N; SUPURAN, CT; AKDEMİR, ATİLLAA series of 2/3/4-[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)amino]benzenesulfonamides, obtained from substituted isatins and 2-, 3- or 4-aminobenzenesulfonamide, showed low nanomolar inhibitory activity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII – recently validated antitumor drug targets, being much less effective as inhibitors of the off-target cytosolic isoforms CA I and II.