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    Öğe
    Novel etodolac derivatives as eukaryotic elongation factor 2 kinase (eEF2K) inhibitors for targeted cancer therapy
    (Royal Soc Chemistry, 2022) Onder, Ferah Comert; Siyah, Pinar; Durdagi, Serdar; Ay, Mehmet; Ozpolat, Bulent
    Eukaryotic elongation factor 2 kinase (eEF2K) has been shown to be an important molecular driver of tumorigenesis and validated as a potential novel molecular target in various solid cancers including triple negative breast cancer (TNBC). Therefore, there has been significant interest in identifying novel inhibitors of eEF2K for the development of targeted therapeutics and clinical translation. Herein, we investigated the effects of indole ring containing derivatives of etodolac, a nonsteroidal anti-inflammatory (NSAID) drug, as potential eEF2K inhibitors and we designed and synthesized seven novel compounds with a pyrano[3,4-b] indole core structure. We evaluated the eEF2K inhibitory activity of seven of these novel compounds using in silico molecular modeling and in vitro studies in TNBC cell lines. We identified two novel compounds (EC1 and EC7) with significant in vitro activity in inhibiting eEF2K in TNBC cells. In conclusion, our studies indicate that pyrano[3,4-b] indole scaffold containing compounds demonstrate marked eEF2K inhibitory activity and they may be used as eEF2K inhibitors for the development of eEF2K-targeted therapeutics.
  • [ X ]
    Öğe
    Synthesis, in silico and bio-evaluation studies of new isothiocyanate derivatives with respect to COX inhibition and H2S release profiles
    (Royal Soc Chemistry, 2024) Yilmaz, Yakup Berkay; Gungor, Tugba; Donmez, Serhat; Atalay, Hazal Nazlican; Siyah, Pinar; Durdagi, Serdar; Ay, Mehmet
    The development of H2S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H2S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H2S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H2S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.