Browsing by Author "Ece, Abdulilah"

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New Targets and Biomarkers for Doxorubicin-Induced Cardiotoxicity in Humans: Implications Drawn From Toxicogenomic Data and Molecular Modelling
(Taylor & Francis inc, 2024) Karakus, Fuat; Ece, Abdulilah; Kuzu, Burak
The doxorubicin-induced cardiotoxicity continues to be a life-threatening adverse effect in the clinic. Doxorubicin-induced acute cardiotoxicity is reversible, whereas chronic cardiotoxicity is irreversible, leading to dilated cardiomyopathy and heart failure. The aim of this study was to identify the molecular mechanisms associated with doxorubicin metabolites in doxorubicin-induced chronic cardiotoxicity. For this purpose, literature searches and in silico toxicogenomic analyses were conducted using various tools, including the Comparative Toxicogenomic Database, GeneMANIA, Metascape, MIENTURNET, ChEA3, and AutoDock. Additionally, molecular dynamics simulations were performed for 500 ns using Schr & ouml;dinger software to assess the stability and dynamics of the representative docked complexes. We observed that doxorubicin biotransformed into five metabolites in the human heart and identified 11 common genes related to doxorubicin, its metabolites, dilated cardiomyopathy, and heart failure. Our findings revealed that doxorubicin and its metabolites primarily exhibited binding affinity to the beta-1 adrenergic receptor and fatty acid synthase. Furthermore, we identified several key transcription factors, especially the Homeobox protein Nkx-2.6, and hsa-miR-183-3p associated with this cardiotoxicity. Finally, we observed that, in addition to doxorubicinol, 7-deoxidoxorubicinone, another metabolite of doxorubicin, may also contribute to this cardiotoxicity. These findings contribute to our understanding of the processes underlying doxorubicin-induced chronic cardiotoxicity.
Quinazolinone-Based Benzenesulfonamides With Low Toxicity and High Affinity as Monoamine Oxidase-A Inhibitors: Synthesis, Biological Evaluation and Induced-Fit Docking Studies
(Academic Press inc Elsevier Science, 2022) Yamali, Cem; Gul, Halise Inci; Sakarya, Mehtap Tugrak; Saglik, Begum Nurpelin; Ece, Abdulilah; Demirel, Goksun; Oner, Ahmet Cihat
The research in selective monoamine oxidases (MAO-A and MAO-B) inhibitors has been increased due to their therapeutic value for neurodegenerative diseases. In this study, 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino) benzenesulfonamides were synthesized and their MAOs inhibition potentials were investigated applying in vitro fluorometric technique. The most potent compounds 7 and 8 against MAO-A had IC50 values of 0.058 +/- 0.002 and 0.094 +/- 0.003 mu M, respectively, while the reference moclobemide had an IC50 value of 6.061 mu M. Compounds 7 (> 1724 times) and 8 (> 1063 times) more selective and reversible inhibitors of MAO-A rather than MAO-B. Toxicity studies of 7 (IC50 = 210.23 mu M) and 8 (IC50 = 259.27 mu M) showed that compounds can be considered as non-toxic towards SH-SY5Y cell line at their effective concentrations against MAO-A. In silico docking simulations successfully explained the observed activities and also highlighted structural water molecules to play a key role in the ligand-enzyme interactions. Calculated molecular descriptors are also obeying Lipinski's rule of five and brain/blood partition coefficients, a critical parameter in neurodegenerative diseases. These reversible inhibitors can have considerable advantages compared to irreversible inhibitors which may possess serious pharmacological side effects.