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  1. Article ; Online: Design of Multifaceted Antioxidants

    Ariadni Tzara / George Lambrinidis / Angeliki Kourounakis

    Molecules, Vol 26, Iss 4928, p

    Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

    2021  Volume 4928

    Abstract: Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is ...

    Abstract Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1 – 17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.
    Keywords antioxidant ; anti-inflammatory ; multitarget ; NSAID ; LOX ; in vitro ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Ochraceopyronide, a Rare α-Pyrone-C-lyxofuranoside from a Soil-Derived Fungus Aspergillus ochraceopetaliformis

    Mostafa A. Asmaey / Dennis Abatis / Ahmed S. Abdel-Razek / George Lambrinidis / Ioanna Chinou / Nikolas Fokialakis / Nikolaos Tsafantakis / Mohamed Shaaban / Nektarios Aligiannis

    Molecules, Vol 26, Iss 3976, p

    2021  Volume 3976

    Abstract: The fungal strain was isolated from a soil sample collected in Giza province, Egypt, and was identified as Aspergillus ochraceopetaliformis based on phenotypic and genotypic data. The ethyl acetate extract of the fungal strain exhibited promising ... ...

    Abstract The fungal strain was isolated from a soil sample collected in Giza province, Egypt, and was identified as Aspergillus ochraceopetaliformis based on phenotypic and genotypic data. The ethyl acetate extract of the fungal strain exhibited promising activity levels against several pathogenic test organisms and through a series of 1 H NMR guided chromatographic separations, a new α-pyrone-C-lyxofuranoside ( 1 ) along with four known compounds ( 2 – 5 ) were isolated. The planar structure of the new metabolite was elucidated by detailed analysis of its 1D/2D NMR and HRMS/IR/UV spectroscopic data, while the relative configuration of the sugar moiety was determined by a combined study of NOESY and coupling constants data, with the aid of theoretical calculations. The structures of the known compounds—isolated for the first time from A . ochraceopetaliformis —were established by comparison of their spectroscopic data with those in the literature. All isolated fungal metabolites were evaluated for their antibacterial and antifungal activities against six Gram-positive and Gram-negative bacteria as well as against three human pathogenic fungi.
    Keywords Aspergillus ochraceopetaliformis ; α-pyrones ; C-lyxofuranosides ; sugar conformations ; triterpenoids ; polyketides ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Biological Evaluation and In Silico Study of Benzoic Acid Derivatives from Bjerkandera adusta Targeting Proteostasis Network Modules

    Katerina Georgousaki / Nikolaos Tsafantakis / Sentiljana Gumeni / George Lambrinidis / Victor González-Menéndez / Jose R. Tormo / Olga Genilloud / Ioannis P. Trougakos / Nikolas Fokialakis

    Molecules, Vol 25, Iss 3, p

    2020  Volume 666

    Abstract: A main cellular functional module that becomes dysfunctional during aging is the proteostasis network. In the present study, we show that benzoic acid derivatives isolated from Bjerkandera adusta promote the activity of the two main protein degradation ... ...

    Abstract A main cellular functional module that becomes dysfunctional during aging is the proteostasis network. In the present study, we show that benzoic acid derivatives isolated from Bjerkandera adusta promote the activity of the two main protein degradation systems, namely the ubiquitin-proteasome (UPP) and especially the autophagy-lysosome pathway (ALP) in human foreskin fibroblasts. Our findings were further supported by in silico studies, where all compounds were found to be putative binders of both cathepsins B and L. Among them, compound 3 (3-chloro-4-methoxybenzoic acid) showed the most potent interaction with both enzymes, which justifies the strong activation of cathepsins B and L (467.3 ± 3.9%) on cell-based assays. Considering that the activity of both the UPP and ALP pathways decreases with aging, our results suggest that the hydroxybenzoic acid scaffold could be considered as a promising candidate for the development of novel modulators of the proteostasis network, and likely of anti-aging agents.
    Keywords fungi ; bjerkandera adusta ; benzoic acid derivatives ; cathepsins activity ; molecular docking ; proteasome activity ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Discovery of SARS-CoV‑2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay

    Chunlong Ma / Michael Dominic Sacco / Zilei Xia / George Lambrinidis / Julia Alma Townsend / Yanmei Hu / Xiangzhi Meng / Tommy Szeto / Mandy Ba / Xiujun Zhang / Maura Gongora / Fushun Zhang / Michael Thomas Marty / Yan Xiang / Antonios Kolocouris / Yu Chen / Jun Wang

    ACS Central Science, Vol 7, Iss 7, Pp 1245-

    2021  Volume 1260

    Keywords Chemistry ; QD1-999
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher American Chemical Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Novel Carbonyl Analogs of Tamoxifen

    Konstantinos M. Kasiotis / George Lambrinidis / Nikolas Fokialakis / Evangelia N. Tzanetou / Emmanuel Mikros / Serkos A. Haroutounian

    Frontiers in Chemistry, Vol

    Design, Synthesis, and Biological Evaluation

    2017  Volume 5

    Abstract: Aim of this work was to provide tamoxifen analogs with enhanced estrogen receptor (ER) binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated ... ...

    Abstract Aim of this work was to provide tamoxifen analogs with enhanced estrogen receptor (ER) binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known ER inhibitor ICI182,780. Theoretical calculations and molecular modeling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.
    Keywords tamoxifen ; synthesis ; derivatives ; docking ; MCF-7 ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2017-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Identification of the substrate recognition and transport pathway in a eukaryotic member of the nucleobase-ascorbate transporter (NAT) family.

    Vasiliki Kosti / George Lambrinidis / Vassilios Myrianthopoulos / George Diallinas / Emmanuel Mikros

    PLoS ONE, Vol 7, Iss 7, p e

    2012  Volume 41939

    Abstract: Using the crystal structure of the uracil transporter UraA of Escherichia coli, we constructed a 3D model of the Aspergillus nidulans uric acid-xanthine/H(+) symporter UapA, which is a prototype member of the Nucleobase-Ascorbate Transporter (NAT) family. ...

    Abstract Using the crystal structure of the uracil transporter UraA of Escherichia coli, we constructed a 3D model of the Aspergillus nidulans uric acid-xanthine/H(+) symporter UapA, which is a prototype member of the Nucleobase-Ascorbate Transporter (NAT) family. The model consists of 14 transmembrane segments (TMSs) divided into a core and a gate domain, the later being distinctly different from that of UraA. By implementing Molecular Mechanics (MM) simulations and quantitative structure-activity relationship (SAR) approaches, we propose a model for the xanthine-UapA complex where the substrate binding site is formed by the polar side chains of residues E356 (TMS8) and Q408 (TMS10) and the backbones of A407 (TMS10) and F155 (TMS3). In addition, our model shows several polar interactions between TMS1-TMS10, TMS1-TMS3, TMS8-TMS10, which seem critical for UapA transport activity. Using extensive docking calculations we identify a cytoplasm-facing substrate trajectory (D360, A363, G411, T416, R417, V463 and A469) connecting the proposed substrate binding site with the cytoplasm, as well as, a possible outward-facing gate leading towards the substrate major binding site. Most importantly, re-evaluation of the plethora of available and analysis of a number of herein constructed UapA mutations strongly supports the UapA structural model. Furthermore, modeling and docking approaches with mammalian NAT homologues provided a molecular rationale on how specificity in this family of carriers might be determined, and further support the importance of selectivity gates acting independently from the major central substrate binding site.
    Keywords Medicine ; R ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Biological evaluation of isoflavonoids from Genista halacsyi using estrogen-target cells

    Nikolas Fokialakis / Xanthippi Alexi / Nektarios Aligiannis / Athina Boulaka / Aggeliki K Meligova / George Lambrinidis / Eleftherios Kalpoutzakis / Harris Pratsinis / Antigoni Cheilari / Dimitra J Mitsiou / Sofia Mitakou / Michael N Alexis

    PLoS ONE, Vol 14, Iss 1, p e

    Activities of glucosides compared to aglycones.

    2019  Volume 0210247

    Abstract: The purpose of this study was to evaluate the response of estrogen target cells to a series of isoflavone glucosides and aglycones from Genista halacsyi Heldr. The methanolic extract of aerial parts of this plant was processed using fast centrifugal ... ...

    Abstract The purpose of this study was to evaluate the response of estrogen target cells to a series of isoflavone glucosides and aglycones from Genista halacsyi Heldr. The methanolic extract of aerial parts of this plant was processed using fast centrifugal partition chromatography, resulting in isolation of four archetypal isoflavones (genistein, daidzein, isoprunetin, 8-C-β-D-glucopyranosyl-genistein) and ten derivatives thereof. 7-O-β-D-glucopyranosyl-genistein and 7,4΄-di-O-β-D-glucopyranosyl-genistein were among the most abundant constituents of the isolate. All fourteen, except genistein, displayed low binding affinity for estrogen receptors (ER). Models of binding to ERα could account for the low binding affinity of monoglucosides. Genistein and its glucosides displayed full efficacy in inducing alkaline phosphatase (AlkP) in Ishikawa cells, proliferation of MCF-7 cells and ER-dependent gene expression in reporter cells at low concentrations (around 0.3 μM). ICI182,780 fully antagonized these effects. The AlkP-inducing efficacy of the fourteen isoflavonoids was more strongly correlated with their transcriptional efficacy through ERα. O-monoglucosides displayed higher area under the dose-response curve (AUC) of AlkP response relative to the AUC of ERα-transcriptional response compared to the respective aglycones. In addition, 7-O-β-D-glucopyranosyl-genistein and 7,4΄-di-O-β-D-glucopyranosyl-genistein displayed estradiol-like efficacy in promoting differentiation of MC3T3-E1 cells to osteoblasts, while genistein was not convincingly effective in this respect. Moreover, 7,4΄-di-O-β-D-glucopyranosyl-genistein suppressed lipopolysaccharide-induced tumor necrosis factor mRNA expression in RAW 264.7 cells, while 7-O-β-D-glucopyranosyl-genistein was not convincingly effective and genistein was ineffective. However, genistein and its O-glucosides were ineffective in inhibiting differentiation of RAW 264.7 cells to osteoclasts and in protecting glutamate-challenged HT22 hippocampal neurons from oxidative stress-induced ...
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Structure of eukaryotic purine/H+ symporter UapA suggests a role for homodimerization in transport activity

    Yilmaz Alguel / Sotiris Amillis / James Leung / George Lambrinidis / Stefano Capaldi / Nicola J. Scull / Gregory Craven / So Iwata / Alan Armstrong / Emmanuel Mikros / George Diallinas / Alexander D. Cameron / Bernadette Byrne

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 9

    Abstract: UapA is a uric acid/xanthine H+symporter from a filamentous fungus. Here, the authors solve the crystal structure of the transporter in complex with xanthine revealing it to be a dimer, and this homodimerisation is proposed to be important for function. ...

    Abstract UapA is a uric acid/xanthine H+symporter from a filamentous fungus. Here, the authors solve the crystal structure of the transporter in complex with xanthine revealing it to be a dimer, and this homodimerisation is proposed to be important for function.
    Keywords Science ; Q
    Language English
    Publishing date 2016-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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