Person: ERDEM, SAFİYE
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ERDEM
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SAFİYE
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Publication Metadata only Design and Synthesis of Pyrrolotriazepine Derivatives: An Experimental and Computational Study(AMER CHEMICAL SOC, 2013) ERDEM, SAFİYE; Menges, Nurettin; Sari, Ozlem; Abdullayev, Yusif; Erdem, Safiye Sag; Balci, MetinThe pyrrole derivatives having carbonyl groups at the C-2 position were converted to N-propargyl pyrroles. The reaction of those compounds with hydrazine monohydrate resulted in the formation of 5H-pyrrolo[2,1-d][1,2,5]-triazepine derivatives. The synthesis of these compounds was accomplished in three steps starting from pyrrole. On the other hand, attempted cyclization of a pyrrole ester substituted with a propargyl group at the nitrogen atom gave, unexpectedly, the six-membered cyclization product, 2-amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one as the major product. The expected cyclization product with a seven-membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo[2,1-d][1,2,5]-triazepin-1-one was formed as the minor product and was converted quantitatively to the major product. The formation mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations.Publication Metadata only A DFT Study on the Mechanism of the Annulation Reaction of Trichloronitroethylene with Aniline in the Synthesis of Quinoxalinone-N-oxides(AMER CHEMICAL SOC, 2009) ERDEM, SAFİYE; Ozpinar, Gul A.; Erdem, Safiye S.; Meyer, Christian; Kaufmann, Dieter E.The new annulation reaction of trichloronitroethylene with aniline results in the formation of a quinoxalinone-N-oxide derivative. The mechanism of this one-pot annulation reaction between trichloronitroethylene (TCNiE) and anilines has been extensively investigated with B3LYP/6-31+G** methodology. Five different paths (1-5) were proposed and modeled by using this method. These paths were compared in terms of the activation energies of their rate-determining steps and in regard to the experimental findings. Paths 3 and 5, proceeding via four-membered heterocyclic rings, were found to be the most plausible paths with activation energies of 32 and 29 kcal/mol for the rate-determining steps, respectively. The effects of substituent, solvent, temperature, and computational method on these steps were also investigated. The results showed that path 5 is the most plausible mechanism for the annulation reaction of trichloronitroethylene with aniline.Publication Open Access Stable hemiaminals from axially chiral pyridine compounds(2023-01-01) ERDEM, SAFİYE; Tuncel S. T., Demir I., ERDEM S., Dogan I.© 2023 Wiley Periodicals LLC.In this study, we have synthesized a series of 3-(pyridin-2-yl)-2-(pyridin-2-ylimino)thiazolidin-4-ol derivatives regioselectively from 2-iminothiazolidin-4-ones using LiAlH4 at room temperature. Due to the presence of the restricted rotation around the N3-Caryl single bond, the formation of M/P isomers was observed. The OH group of the hemiaminal was found to orient itself on the same side with pyridyl nitrogen during this restricted rotation to form an intramolecular hydrogen bond, which was demonstrated by the computational DFT study. This orientation presumably inhibited the occurrence of dehydration and stabilized the molecule.Publication Open Access In vitro and in silico investigation of inhibitory activities of 3-arylcoumarins and 3-phenylazo-4-hydroxycoumarin on MAO isoenzymes(2022-11-01) DANIŞ, ÖZKAN; DEMİR, SERAP; ERDEM, SAFİYE; OGAN, AYŞE; Yuce-Dursun B., DANIŞ Ö., Ozalp L., Sahin E., DEMİR S., ERDEM S., OGAN A.A series of 3-aryl coumarin derivatives and 3-phenylazo-4-hydroxycoumarin were evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity by fluorometric enzymological assays. Among 21 coumarin derivatives, compound 21 (3-phenylazo-4-hydroxycoumarin) displayed a good inhibitory activity (0.12 +/- 0.02 mu M) and very high selectivity for MAO-B (SI > 833.33). The inhibition was determined as mixed-type and not time-dependent. Docking studies, molecular dynamics and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations were performed to elucidate in vitro results. Our results reveal that the insertion of an azo linker between coumarin and phenyl rings in 3-arylcoumarins enhances MAO-B selectivity enormously since such a linker leads to the perfect alignment of the coumarin ring in the aromatic cage and the phenyl ring in the entrance cavity of MAO-B active site. Hydrogen bond interactions with Cys172 in the active site entrance of MAO-B also contributes to the remarkably higher inhibitory activity and selectivity for MAO-B.Publication Open Access How fullerene derivatives (FDs) act on therapeutically important targets associated with diabetic diseases(2022-01-01) ERDEM, SAFİYE; Fjodorova N., Novic M., Venko K., Drgan V., Rasulev B., SAÇAN M., ERDEM S., Tugcu G., Toropova A. P., Toropov A. A.Fullerene derivatives (FDs) belong to a relatively new family of nano-sized organic compounds. They are widely applied in materials science, pharmaceutical industry, and (bio) medicine. This research focused on the study of FDs in terms of their potential inhibitory effect on therapeutic targets associated with diabetic disease, as well as analysis of protein-ligand binding in order to identify the key binding characteristics of FDs. Therapeutic drug compounds when entering the biological system usually inevitably encounter and interact with a vast variety of biomolecules that are responsible for many different functions in organisms. Protein biomolecules are the most important functional components and used in this study as target structures. The structures of proteins [(PDB ID: 1BMQ, 1FM6, 1GPB, 1H5U, 1US0)] belonging to the class of anti-diabetes targets were obtained from the Protein Data Bank (PDB). Protein binding activity data (binding scores) were calculated for the dataset of 169 FDs related to these five proteins. Subsequently, the resulting data were analyzed using various machine learning and cheminformatics methods, including artificial neural network algorithms for variable selection and property prediction. The Quantitative Structure-Activity Relationship (QSAR) models for prediction of binding scores activity were built up according to five Organization for Economic Co-operation and Development (OECD) principles. All the data obtained can provide important information for further potential use of FDs with different functional groups as promising medical antidiabetic agents. Binding scores activity can be used for ranking of FDs in terms of their inhibitory activity (pharmacological properties) and potential toxicity. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).Publication Metadata only A computational study on heterodimerization of charged porphyrins(JOHN WILEY & SONS LTD, 2001) ERDEM, SAFİYE; Erdem, SSThe structures of the charged porphyrins and their dimers have been investigated with computational methods. Dimers have been formed based on electrostatic attraction of the opposite charges on two different porphyrin monomers, tetra ammonium porphyrin (TAP) and tetra carboxy porphyrin (TCP). Semi-empirical quantum mechanical calculations have been employed to explore the most stable ground-state structures of TCP, TAP and their hetero-dimers. Dimeric structures analyzed are all in face-to-face fashion indicating the strong electrostatic attraction between the two porphyrin rings. Calculations have also predicted that the protons transfer from -NH3+; groups to -COO- groups when the interplanar separation is shorter than 3.7 Angstrom. Copyright (C) 2001 John Wiley & Sons, Ltd.Publication Open Access Cheminformatics and Machine Learning Approaches to Assess Aquatic Toxicity Profiles of Fullerene Derivatives(2023-09-01) ERDEM, SAFİYE; Fjodorova N., Novič M., Venko K., Rasulev B., Türker Saçan M., Tugcu G., Sağ Erdem S., Toropova A. P., Toropov A. A.Fullerene derivatives (FDs) are widely used in nanomaterials production, the pharmaceutical industry and biomedicine. In the present study, we focused on the potential toxic effects of FDs on the aquatic environment. First, we analyzed the binding affinity of 169 FDs to 10 human proteins (1D6U, 1E3K, 1GOS, 1GS4, 1H82, 1OG5, 1UOM, 2F9Q, 2J0D, 3ERT) obtained from the Protein Data Bank (PDB) and showing high similarity to proteins from aquatic species. Then, the binding activity of 169 FDs to the enzyme acetylcholinesterase (AChE)—as a known target of toxins in fathead minnows and Daphnia magna, causing the inhibition of AChE—was analyzed. Finally, the structural aquatic toxicity alerts obtained from ToxAlert were used to confirm the possible mechanism of action. Machine learning and cheminformatics tools were used to analyze the data. Counter-propagation artificial neural network (CPANN) models were used to determine key binding properties of FDs to proteins associated with aquatic toxicity. Predicting the binding affinity of unknown FDs using quantitative structure–activity relationship (QSAR) models eliminates the need for complex and time-consuming calculations. The results of the study show which structural features of FDs have the greatest impact on aquatic organisms and help prioritize FDs and make manufacturing decisions.Publication Metadata only İnsan monoamin oksidaz a ve b inhibitörleri olarak benzokumarin türevlerinin sentezi ve biyolojik olarak değerlendirilmesi(2015-05-07) DANIŞ, ÖZKAN; DEMİR, SERAP; OGAN, AYŞE; ERDEM, SAFİYE; Danış Ö., Yüce Dursun B., Demir S., Alparslan M., Ogan A., Erdem S.Publication Metadata only New horizon in phospha-michael reaction: Ultrafast double addition of P-H bond-bearing nucleophiles to alectron-deficient triple bonds and its use for functional monomer synthesis and polymer modification(2023-01-01) ÇAKMAKÇI, EMRAH; FINDIK, VOLKAN; ERDEM, SAFİYE; Sagdic G., Daglar O., ÇAKMAKÇI E., FINDIK V., ERDEM S., Tunca Ü., Günay U. S., Durmaz H.In this work, a novel, straightforward, robust, fast, and organocatalyst-mediated phospha-Michael reaction (OCPMR) was developed for the addition of phosphorus nucleophiles to electron-deficient alkynes. Several P-H bond-bearing compounds with either fully aliphatic or aromatic units were utilized for this newly developed reaction, and it was found that phosphorous species containing only aromatic groups reacted with activated alkynes within 5 min at room temperature. The reaction led to a fast double-addition of the phosphorous compounds to the triple bond of the alkynes. An in-depth analysis of the reaction mechanism and selectivity of this OCPMR was performed using computational methods. Using the developed method, double-phosphorylated allyl-functional monomers were synthesized and subsequently used for the synthesis of linear and crosslinked polymers via thiol-ene photopolymerization. The thermoset materials exhibited LOI values as high as 26.4%. We also showed that polyesters having electron-deficient triple bonds could be easily functionalized with the P-H bond-bearing compounds. The synthetic method proposed herein promises easy and fast P-C bond formation under mild reaction conditions, and it is a straightforward method for the synthesis of phosphorus-containing monomers, linear or crosslinked polymers, and for polymer post-functionalization. We believe this feature will be of great interest not only to material chemists and polymer scientists but also to organic chemists, pharmaceutical researchers, etc.Publication Metadata only Mechanistic Investigation of Lysine-Targeted Covalent Inhibition of PI3K delta via ONIOM QM:QM Computations(2022-08-01) ERDEM, SAFİYE; FINDIK, VOLKAN; FINDIK V., Gercik B. T. V. , Sinek O., ERDEM S., Ruiz-Lopez M. F.Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets, especially in oncology, and several inhibitors are currently under investigation in clinical trials for the treatment of lymphocytic leukemia, follicular lymphoma, breast, thyroid, colorectal, and lung cancer. Targeted covalent inhibitors hold significant promise for drug discovery research especially for kinases. Targeting the lysine residues attracts attention as a new strategy in designing targeted covalent inhibitors, since the lysine residue provides several advantages over the traditional cysteine residue. Recently, new highly selective covalent inhibitors of PI3K delta with activated ester warheads, targeting the conserved Lys779 residue, were reported. Based on the observed kinetics, a covalent inhibition mechanism was proposed, but the atomistic details of the reaction are still not understood. Therefore, in the present work, we have conducted quantum chemical ONIOM M06-2X/6-31+G(d,p):PM6 calculations on the active site cluster structure of PI3K delta to elucidate the microscopic details of the mechanism of the aminolysis reaction between Lys779 and the ester inhibitors. Our calculations clearly discriminate the noncovalent methyl ester inhibitor and the covalent inhibitors with activated phenolic esters. For the representative p-NO2, p-F, p-H, and p-OCH3 phenolic esters, the Gibbs free energy profiles of alternative mechanistic paths through either Asp782 or Asp911 demonstrate the modulatory role of active site aspartate residues. The most plausible path alters depending on the electron-withdrawing/donating nature of the psubstituted phenolate leaving group. Inhibitors with sufficiently strong electron-withdrawing group prefer direct dissociation of the leaving group from the tetrahedral zwitterion intermediate, while the ones with electron-donating group favor the formation of a neutral tetrahedral intermediate prior to the dissociation. The relative Gibbs free energy barriers of p-NO2 < p- F < p-H < p-OCH3 substituted phenyl esters display the same qualitative trend as the experimentally measured k(inact)/K-1 values. Our results provide in depth insight into the mechanism, which can pave the way for optimizing the inhibitor efficiency.