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    Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses
    (Amer Chemical Soc, 2024) Donmez, Serhat; Lapinskaite, Ringaile; Atalay, Hazal Nazlican; Tokay, Esra; Kockar, Feray; Rycek, Lukas; Ozbil, Mehmet
    The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, SelB-1 selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, SelB-1 showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound's strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, SelB-1 did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that SelB-1 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.
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    Synthesis of Selagibenzophenone A and Its Derivatives for Evaluation of Their Antiproliferative, ROR gamma Inverse Agonistic, and Antimicrobial Effect
    (John Wiley and Sons Inc, 2023) Lapinskaite, Ringaile; Atalay, Hazal Nazlıcan; Malatinec, Stefan; Dönmez, Serhat; Çınar, Zeynep Özlem; Schwarz, Patrik F. F.; Perhal, Alexander F. F.; Tümer Boyuneğmez, Tuğba
    We report a modular synthetic approach towards novel derivatives of the naturally occurring arylated benzophenone selagibenzophenone A. The initial strategy for the construction of the carbon framework of the derivatives relied on the Suzuki reaction of 2,4,6-tribromobenzonitrile, and the addition of the aryl lithium species to nitrile to generate imine. However, the formed imines showed remarkable stability toward hydrolysis. Therefore, Suzuki cross-coupling was carried out with 2,4,6-tribromobenzaldehyde and the subsequent addition of organometallic species to the aldehyde. Oxidation of the resulting alcohol ensured the access to desired ketones. The importance of the developed modular strategy is underlined by the discovery of several derivatives with selective cytotoxic effects and potential anti-inflammatory activity superior to the effect of the natural product.
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    The Biomimetic Synthesis of Polyarylated Fluorenes, Relevant to Selaginellaceae Polyphenols, Leading to the Spontaneous Formation of Stable Radicals
    (John Wiley and Sons Inc, 2023) Nallappan, Sundaravelu; Lapinskaite, Ringaile; Hajicek, Josef; Kunak, Dominik; Cambal, Peter; B. Tümer, Tuğba
    This work reports a biomimetic synthesis of polyarylated fluorene derivatives. The molecules are formed via intramolecular electrophilic aromatic substitution, resembling a cyclization leading towards the natural selaginpulvilins from selaginellins. The scope of the reaction was investigated, and the products were obtained in 60–95 % yields. Some of the compounds decompose to a stable radical. We investigated the nature and the origin of the radical using experimental methods, including EPR or electrochemical measurements, as well as theoretical methods, such as DFT calculations. Based on our observations, we hypothesize, that phenoxy radicals are formed in the first instance, which however undergo internal rearrangement to thermodynamically more stable carbon-centered radicals. The preliminary data also show the cytotoxic properties of some of the molecules.