TY - JOUR AU - Bózsity-Faragó, Noémi AU - Nagy, Viktória AU - Szabó, Johanna AU - Pálházi, Balázs AU - Kele, Zoltán AU - Resch, Vivien Erzsébet AU - Paragi, Gábor AU - Zupkó, István AU - Minorics, Renáta AU - Mernyák, Erzsébet TI - Synthesis of Estrone Heterodimers and Evaluation of Their In Vitro Antiproliferative Activity JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 8 PG - 15 SN - 1661-6596 DO - 10.3390/ijms25084274 UR - https://m2.mtmt.hu/api/publication/34789041 ID - 34789041 AB - Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide–alkyne cycloaddition reactions. The two trans-16-azido-3-(O-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3-O-propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer (12) exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges. LA - English DB - MTMT ER - TY - JOUR AU - Varró, Sándor AU - Hack, Szabolcs AU - Paragi, Gábor AU - Földi, Péter AU - Barna, Imre Ferenc AU - Czirják, Attila TI - Diatomic molecule in a strong infrared laser field: level-shifts and bond-length change due to laser-dressed Morse potential JF - NEW JOURNAL OF PHYSICS J2 - NEW J PHYS VL - 25 PY - 2023 IS - 7 PG - 9 SN - 1367-2630 DO - 10.1088/1367-2630/acde9e UR - https://m2.mtmt.hu/api/publication/34071100 ID - 34071100 N1 - Export Date: 08 March 2024 AB - We present a general mathematical procedure to handle interactions described by a Morse potential in the presence of a strong harmonic excitation. We account for permanent and field-induced terms and their gradients in the dipole moment function, and we derive analytic formulae for the bond-length change and for the shifted energy eigenvalues of the vibrations, by using the Kramers-Henneberger frame. We apply these results to the important cases of H-2 and LiH, driven by a near- or mid-infrared laser in the 10(13) W cm(-2) intensity range. LA - English DB - MTMT ER - TY - JOUR AU - Ali, Hazhmat AU - Traj, Péter AU - Szebeni, Gábor AU - Gémes, Nikolett AU - Resch, Vivien Erzsébet AU - Paragi, Gábor AU - Mernyák, Erzsébet AU - Minorics, Renáta AU - Zupkó, István TI - Investigation of the Antineoplastic Effects of 2-(4-Chlorophenyl)-13α-Estrone Sulfamate against the HPV16-Positive Human Invasive Cervical Carcinoma Cell Line SiHa JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 7 PG - 17 SN - 1661-6596 DO - 10.3390/ijms24076625 UR - https://m2.mtmt.hu/api/publication/33727646 ID - 33727646 N1 - Funding Agency and Grant Number: Hungarian Research Foundation (NKFI) [K 143690, 142877 FK22, OTKA SNN 139323, 2020-1.1.6-JOEVO-2021-00003, TKP2021-EGA-32, TKP2021-EGA-17]; Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund [TKP2021-EGA]; Nemzet Fiatal Tehetsegeiert OEsztoendij [NTP-NFTOE-21-B-0113]; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-22-5-SZTE-535]; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00582/22/8]; KDP-2021 Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund [C1764415 KDP/2021] Funding text: This research was funded by Hungarian Research Foundation (NKFI), grant numbers K 143690, 142877 FK22, OTKA SNN 139323, and 2020-1.1.6-JOEVO-2021-00003. Projects no. TKP2021-EGA-32 and TKP2021-EGA-17 have been implemented with support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-EGA funding scheme. The support provided by Nemzet Fiatal Tehetsegeiert OEsztoendij (NTP-NFTOE-21-B-0113) is also acknowledged. This work was supported by the UNKP-22-5-SZTE-535 New National Excellence Program of the Ministry for Innovation and Technology and by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences BO/00582/22/8. Supported by the KDP-2021 Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund for NG (C1764415 KDP/2021). AB - Cervical carcinoma is one of the most frequent malignant gynecological cancers in women of reproductive age. Because of the poor tolerability of currently available chemotherapeutic agents, efforts have been focused on developing innovative molecules, including steroids, that exert antineoplastic effects with a better safety profile. In addition to their endocrine properties, certain estrogens exhibit additional biological activities, such as antiangiogenic and anticancer effects. Based on previous studies, the antineoplastic properties of 13α-estrone sulfamate derivatives (13AES1-3) were investigated, and the mechanism of action for the most promising compound 13AES3 was explored. Based on their effects on the viability of different human adherent gynecological cancer cells, the SiHa cervical cell line was used for mechanistic experiments. The most active analog 13AES3 was shown to exert considerable proapoptotic effects, as evidenced by a colorimetric caspase-3 assay and fluorescent double staining. It also elicited antimigratory and anti-invasive effects in a concentration-dependent manner, as evidenced by wound healing and Boyden chamber assays, respectively. Regarding their mechanism of action, 13AES derivatives were shown to inhibit tubulin polymerization, and computer simulations provided a possible explanation for the importance of the presence of the chlorophenyl ring on the estrane skeleton. 13AES3 is considered to be the first 13α-estrone derivative with a significant antineoplastic potency against SiHa cancer cells. Therefore, it might serve as a valuable lead molecule for the design of anticancer agents targeting cervical carcinomas. LA - English DB - MTMT ER - TY - JOUR AU - Tököli, Attila AU - Bodnár, Brigitta AU - Bogár, Ferenc AU - Paragi, Gábor AU - Hetényi, Anasztázia AU - Bartus, Éva AU - Wéber, Edit AU - Hegedüs, Zsófia AU - Szabó, Zoltán AU - Kecskeméti, Gábor AU - Szakonyi, Gerda AU - Martinek, Tamás TI - Structural Adaptation of the Single-Stranded DNA-Binding Protein C-Terminal to DNA Metabolizing Partners Guides Inhibitor Design JF - PHARMACEUTICS J2 - PHARMACEUTICS VL - 15 PY - 2023 IS - 4 PG - 17 SN - 1999-4923 DO - 10.3390/pharmaceutics15041032 UR - https://m2.mtmt.hu/api/publication/33712712 ID - 33712712 N1 - Department of Medical Chemistry, University of Szeged, Szeged, H6720, Hungary ELKH-SZTE Biomimetic Systems Research Group, Eötvös Loránd Research Network (ELKH), Szeged, H6720, Hungary Institute of Physics, University of Pécs, Pécs, H7624, Hungary Department of Theoretical Physics, University of Szeged, Szeged, H6720, Hungary Institute of Pharmaceutical Analysis, University of Szeged, Szeged, H6720, Hungary Export Date: 8 September 2023 Correspondence Address: Martinek, T.A.; Department of Medical Chemistry, Hungary; email: martinek.tamas@med.u-szeged.hu AB - Single-stranded DNA-binding protein (SSB) is a bacterial interaction hub and an appealing target for antimicrobial therapy. Understanding the structural adaptation of the disordered SSB C-terminus (SSB-Ct) to DNA metabolizing enzymes (e.g., ExoI and RecO) is essential for designing high-affinity SSB mimetic inhibitors. Molecular dynamics simulations revealed the transient interactions of SSB-Ct with two hot spots on ExoI and RecO. The residual flexibility of the peptide–protein complexes allows adaptive molecular recognition. Scanning with non-canonical amino acids revealed that modifications at both termini of SSB-Ct could increase the affinity, supporting the two-hot-spot binding model. Combining unnatural amino acid substitutions on both segments of the peptide resulted in enthalpy-enhanced affinity, accompanied by enthalpy–entropy compensation, as determined by isothermal calorimetry. NMR data and molecular modeling confirmed the reduced flexibility of the improved affinity complexes. Our results highlight that the SSB-Ct mimetics bind to the DNA metabolizing targets through the hot spots, interacting with both of segments of the ligands. LA - English DB - MTMT ER - TY - JOUR AU - Kovács, Édua AU - Ali, Hazhmat AU - Minorics, Renáta AU - Traj, Péter AU - Resch, Vivien Erzsébet AU - Paragi, Gábor AU - Bruszel, Bella AU - Zupkó, István AU - Mernyák, Erzsébet TI - Synthesis and Antiproliferative Activity of Steroidal Diaryl Ethers JF - MOLECULES J2 - MOLECULES VL - 28 PY - 2023 IS - 3 PG - 17 SN - 1420-3049 DO - 10.3390/molecules28031196 UR - https://m2.mtmt.hu/api/publication/33594496 ID - 33594496 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Office-NKFIH [OTKA SNN 139323, TKP2021-EGA-17] Funding text: This work was supported by National Research, Development and Innovation Office-NKFIH through projects OTKA SNN 139323 and TKP2021-EGA-17. AB - Novel 13α-estrone derivatives have been synthesized via direct arylation of the phenolic hydroxy function. Chan–Lam couplings of arylboronic acids with 13α-estrone as a nucleophilic partner were carried out under copper catalysis. The antiproliferative activities of the newly synthesized diaryl ethers against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231, HeLa, SiHa) were investigated by means of MTT assays. The quinoline derivative displayed substantial antiproliferative activity against MCF-7 and HeLa cell lines with low micromolar IC50 values. Disturbance of tubulin polymerization has been confirmed by microplate-based photometric assay. Computational calculations reveal significant interactions of the quinoline derivative with the taxoid binding site of tubulin. LA - English DB - MTMT ER - TY - JOUR AU - Miklovics, Nikolett AU - Duzs, Ágnes AU - Balogh, Fanni AU - Paragi, Gábor AU - Rákhely, Gábor AU - Tóth, András TI - Quinone binding site in a type VI sulfide:quinone oxidoreductase JF - APPLIED MICROBIOLOGY AND BIOTECHNOLOGY J2 - APPL MICROBIOL BIOT VL - 106 PY - 2022 IS - 22 SP - 7505 EP - 7517 PG - 13 SN - 0175-7598 DO - 10.1007/s00253-022-12202-8 UR - https://m2.mtmt.hu/api/publication/33181371 ID - 33181371 N1 - Funding Agency and Grant Number: ELKH Biological Research Center; European Social Fund [EFOP-3.6.2-16-201700010, GINOP-2.3.2-15-2016-00036]; New National Excellence Program of the Ministry for Innovation and Technology [UNKP-19-3]; State of Hungary Funding text: Open access funding provided by ELKH Biological Research Center. This work headed by GR was supported by the State of Hungary, co-financed by the European Social Fund (EFOP-3.6.2-16-201700010). GP received funding from GINOP-2.3.2-15-2016-00036. NM was supported by the UNKP-19-3 New National Excellence Program of the Ministry for Innovation and Technology. AB - Monotopic membrane-bound flavoproteins, sulfide:quinone oxidoreductases (SQRs), have a variety of physiological functions, including sulfide detoxification. SQR enzymes are classified into six groups. SQRs use the flavin adenine dinucleotide (FAD) cofactor to transfer electrons from sulfide to quinone. A type VI SQR of the photosynthetic purple sulfur bacterium, Thiocapsa roseopersicina (TrSqrF), has been previously characterized, and the mechanism of sulfide oxidation has been proposed. This paper reports the characterization of quinone binding site (QBS) of TrSqrF composed of conserved aromatic and apolar amino acids. Val331, Ile333, and Phe366 were identified near the benzoquinone ring of enzyme-bound decylubiquinone (dUQ) using the TrSqrF homology model. In silico analysis revealed that Val331 and Ile333 alternately connected with the quinone head group via hydrogen bonds, and Phe366 and Trp369 bound the quinones via hydrophobic interactions. TrSqrF variants containing alanine (V331A, I333A, F366A) and aromatic amino acid (V331F, I333F, F366Y), as well as a C-terminal alpha-helix deletion (CTD) mutant were generated. These amino acids are critical for quinone binding and, thus, catalysis. Spectroscopic analyses proved that all mutants contained FAD. I333F replacement resulted in the lack of the charge transfer complex. In summary, the interactions described above maintain the quinone molecule's head in an optimal position for direct electron transfer from FAD. Surprisingly, the CTD mutant retained a relatively high level of specific activity while remaining membrane-anchored. This is a unique study because it focuses on the QBS and the oxidative stage of a type VI sulfide-dependent quinone reduction. LA - English DB - MTMT ER - TY - JOUR AU - Váradi, Zoltán AU - Paragi, Gábor AU - Kupihár, Zoltán AU - Kele, Zoltán AU - Kovács, Lajos TI - Synthesis of Heterocycles and Nucleosides Forming Higher—Order Structures JF - CHEMISTRY PROCEEDINGS J2 - CHEM PROC VL - 8 PY - 2022 IS - 1 PG - 6 SN - 2673-4583 DO - 10.3390/ecsoc-25-11705 UR - https://m2.mtmt.hu/api/publication/32818711 ID - 32818711 LA - English DB - MTMT ER - TY - JOUR AU - Mernyák, Erzsébet AU - Bartha, Sándor AU - Kóczán , Lili AU - Jójárt, Rebeka AU - Resch, Vivien Erzsébet AU - Paragi, Gábor AU - Vágvölgyi, Máté AU - Hunyadi, Attila AU - Bruszel, Bella AU - Zupkó, István AU - Minorics, Renáta TI - Microwave-assisted Phospha-Michael addition reactions in the 13alpha-oestrone series and in vitro antiproliferative properties JF - JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY J2 - J ENZYM INHIB MED CH VL - 36 PY - 2021 IS - 1 SP - 1931 EP - 1937 PG - 7 SN - 1475-6366 DO - 10.1080/14756366.2021.1963241 UR - https://m2.mtmt.hu/api/publication/32161034 ID - 32161034 LA - English DB - MTMT ER - TY - JOUR AU - Sinreih, Maša AU - Jójárt, Rebeka AU - Kele, Zoltán AU - Büdefeld, Tomaž AU - Paragi, Gábor AU - Mernyák, Erzsébet AU - Rižner, Tea Lanišnik TI - Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives JF - JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY J2 - J ENZYM INHIB MED CH VL - 36 PY - 2021 IS - 1 SP - 1500 EP - 1508 PG - 9 SN - 1475-6366 DO - 10.1080/14756366.2021.1937142 UR - https://m2.mtmt.hu/api/publication/32096593 ID - 32096593 LA - English DB - MTMT ER - TY - JOUR AU - Vermeeren, Pascal AU - Wolters, Lando P. AU - Paragi, Gábor AU - Fonseca, Guerra Celia TI - Cooperative Self-Assembly in Linear Chains Based on Halogen Bonds JF - CHEMPLUSCHEM J2 - CHEMPLUSCHEM VL - 86 PY - 2021 IS - 6 SP - 812 EP - 819 PG - 8 SN - 2192-6506 DO - 10.1002/cplu.202100093 UR - https://m2.mtmt.hu/api/publication/32049042 ID - 32049042 N1 - Funding Agency and Grant Number: Netherlands Organization for Scientific Research NWO (ECHO); Dutch Astrochemistry Network (DAN); Marie Curie Intra European Fellowship within the 7th European Community Framework Programme Funding text: We gratefully acknowledge the financial support from the Netherlands Organization for Scientific Research NWO (ECHO), Dutch Astrochemistry Network (DAN), and the Marie Curie Intra European Fellowship within the 7th European Community Framework Programme. AB - Cooperative properties of halogen bonds were investigated with computational experiments based on dispersion-corrected relativistic density functional theory. The bonding mechanism in linear chains of cyanogen halide (X-CN), halocyanoacetylene (X-CC-CN), and 4-halobenzonitrile (X-C6H4-CN) were examined for X = H, Cl, Br, and I. Our energy decomposition and Kohn-Sham molecular-orbital analyses revealed the bonding mechanism of the studied systems. Cyanogen halide and halocyanoacetylene chains possess an extra stabilizing effect with increasing chain size, whereas the 4-halobenzonitrile chains do not. This cooperativity can be traced back to charge separation within the sigma-electronic system by charge-transfer between the lone-pair orbital of the nitrogen (sigma(HOMO)) on one unit and the acceptor orbital of the C-X (sigma*(LUMO)) on the adjacent unit. As such, the HOMO-LUMO gap in the sigma-system decreases, and the cooperativity increases with chain length revealing the similarity in the bonding mechanisms of hydrogen and halogen bonds. LA - English DB - MTMT ER -