Person: ERDEM, SAFİYE
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ERDEM
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SAFİYE
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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 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.Publication Metadata only Çeşitli Kumarin Bileşiklerinin Nitrit Oksit Sentaz İzoenzimleri ile Olan İlişkisinin In Siliko Olarak İncelenmesi(2022-10-05) MELETLİ, FURKAN; DANIŞ, ÖZKAN; ERDEM, SAFİYE; Meletli F., Ergüven B., Danış Ö., Erdem S.Nitrik oksit (NO), gaz halinde bulunan bir sinyal molekülüdür. Nitrik oksit sentazlar (NOS) ise, arjininden nitrik oksit sentezleyen enzimlerdir. Nitrik oksit sentazın (NOS) insanda 3 izoformu bulunmaktadır. Bunlardan nöronal nitrik oksit sentaz (nNOS) ve endotelyal nitrik oksit sentaz (eNOS) NO üretimi üzerinde etkili iken, indüklenebilir nitrik oksit sentaz (iNOS) ise patojenlere karşı bağışıklık işlemlerinde etkili olurlar.Bu üç enzimde birbirine çok yakın bir yapıya sahiptir. Bu yüzden seçimli inhibitörlerin belirlenebilmesi için farklı ligandlar kullanılarak enzimlerin aktif bölgelerindeki farkları incelemek gerekmektedir. Nöronal nitrik oksit sentazın seçimli inhibisyonu, sinir sistemi üzerinde etkili olan Parkinson ve Alzheimer gibi hastalıklara karşı umut verici tedavi yaklaşımı olarak ortaya çıkmaktadır.Kumarinler, 1,2-benzopiron (C9H6O2) olarak karakterize edilen ve yaygın olarak bitkilerde bulunan doğal ürünlerdir. Ayrıca, bitkiler dışında sentetik olarak üretilmekte olup, bazı bakteri ve mantar türlerinde bulunurlar. Kumarinler, geniş bir yelpazede farklı farmakolojik özellikler göstermektedir. Literatürde kumarin türevlerinin; anti-koagülanlar, anti-HIV ajanları, anti-oksidanlar, anti-tümörler ve serbest radikal temizleyicileri olarak farmakolojik olarak yararlı olduğu ve endüstriyel alanlarda geniş uygulamalara sahip olduğu bilinmektedir. Bu çalışmamızda çeşitli kumarin bileşiklerin nitrik oksit sentaz izoenzimleri üzerindeki etkilerinin moleküler doking yoluyla in siliko olarak incelenmiştir. Ayrıca bu çalışmada kullanılan kumarin bileşiklerinin Emilim, Dağılım, Metabolizma ve Atılım (ADME) özellikleri ve Lipinski 5 kuralına uygunluğu da araştırılmıştır. Bu duruma uygun olan kumarin bileşikleri protein veri bankasından indirilen enzimlerle moleküler doking çalışmaları gerçekleştirilmiş ve bu enzimlere bağlanma durumları incelenmiştir. Moleküler doking sonucunda nNOS enzimine bağlanma afinitesi güçlü olan kumarin türevleri ileride Parkinson ve Alzheimer gibi sinir sistemini etkileyen hastalıklara karşı yeni ilaçların geliştirilmesinde katkıda bulunabileceği düşünülmektedir.Publication Open Access Newly synthesized piperazine derivatives as tyrosinase inhibitors: in vitro and in silico studies(2022-07-01) ERDEM, SAFİYE; DOKUZPARMAK Ç., ÖZ TUNCAY F., Ozdemir S. B., Kurnaz B., Demir I., ÇOLAK A., ERDEM S., YILDIRIM N.In this study, a series of new organic compounds with piperazine as a fundamental skeleton was synthesized and evaluated for their tyrosinase inhibitory potentials by in vitro and in silico studies. The in vitro studies have shown that compounds 10a and 10b bearing 1,2,4, triazole nucleus could be considered potent tyrosinase inhibitors with IC50 values of 31.2 +/- 0.7 and 30.7 +/- 0.2 mu M, respectively. 10b (K-i = 9.54 mu M, mixed type inhibition) with the lowest IC50 value among derivatives was selected to determine kinetic constants and inhibition types. Furthermore, molecular docking analysis was performed for all compounds and it was observed that 4b, 5a, 4c, and 10b showed promising inhibitory effect on tyrosinase activity. Based on docking results, ADME predictions and in vitro studies, 10b might be considered suitable oral drug candidates for further studies.Publication Metadata only Advanced atomistic simulations on amine acetylation reaction in aqueous medium(2020-09-07) FINDIK, VOLKAN; ERDEM, SAFİYE; Fındık V., Erdem S., F. Ruiz-Lopez M.Publication Open Access Identification of some novel amide conjugates as potent and gastric sparing anti-inflammatory agents: In vitro, in vivo, in silico studies and drug safety evaluation(2023-08-05) KULABAŞ, NECLA; DANIŞ, ÖZKAN; OGAN, AYŞE; ERDEM, SAFİYE; KÜÇÜKGÜZEL, İLKAY; KULABAŞ N., Set İ., Aktay G., GÜRSOY Ş., DANIŞ Ö., OGAN A., Sağ Erdem S., Erzincan P., Helvacıoğlu S., Hamitoğlu M., et al.Today, usage of NSAIDs (nonsteroidal anti-inflammatory drugs) is very common. However, it has been proven by many studies that NSAIDs with free carboxylic acid group damage the GI (gastrointestinal) system. Our aim was to mask the acidic groups of NSAIDs to prevent or reduce their side effects while preserving their pharmacological effects. In this study, new amide derivatives of known NSAIDs, compounds 11–20, were synthesized to investigate their analgesic and anti-inflammatory effects using in vivo models. While compound 11 showed the most remarkable anti-inflammatory activity by 60.9% inhibition value at 200 mg/kg dose, compounds 11, 12, 15 and 18 had almost the same analgesic activity to that of acetylsalicylic acid (100 mg/kg) and flurbiprofen (100 mg/kg). In addition, all test compounds used at high dose (200 mg/kg, p.o) did not show any acute toxicity. COX-1 and COX-2 inhibition properties of all compounds were measured by biochemical methods and the interaction of the most active compounds with COX enzymes is elucidated by computer-assisted virtual screening methods. It was determined by in vitro enzyme inhibition studies that compound 11 and 13, synthesized from selective COX-1 inhibitors dexketoprofen and flurbiprofen, are selective COX-2 inhibitors. Moreover, compounds 11–13 were found to be non-mutagenic according to the mutagenicity assay using Salmonella TA98 and TA100 strains with and without metabolic activation. Finally, the prediction of ADMET profile and drug-likeness properties of compounds 11–20 were examined and the obtained results were evaluated.