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 - Senobar Tahaei, Seyyed Ashkan AU - Kulmány, Ágnes Erika AU - Minorics, Renáta AU - Kiss, Anita AU - Szabó, Zoltán AU - Germán, Péter AU - Szebeni, Gábor AU - Gémes, Nikolett AU - Mernyák, Erzsébet AU - Zupkó, István TI - Antiproliferative and Antimetastatic Properties of 16-Azidomethyl Substituted 3-O-Benzyl Estrone Analogs JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 18 PG - 16 SN - 1661-6596 DO - 10.3390/ijms241813749 UR - https://m2.mtmt.hu/api/publication/34131836 ID - 34131836 N1 - Funding Agency and Grant Number: The authors thank Dora Bokor, PharmD, for proofreading the manuscript. Funding text: The authors thank Dora Bokor, PharmD, for proofreading the manuscript. AB - Four diastereomers of 16-azidomethyl substituted 3-O-benzyl estradiol (1–4) and their two estrone analogs (16AABE and 16BABE) were tested for their antiproliferative properties against human gynecological cancer cell lines. The estrones were selected for additional experiments based on their outstanding cell growth-inhibiting activities. Both compounds increased hypodiploid populations of breast cancer cells, and 16AABE elicited cell cycle disturbance as evidenced by flow cytometry. The two analogs substantially increased the rate of tubulin polymerization in vitro. 16AABE and 16BABE inhibited breast cancer cells’ migration and invasive ability, as evidenced by wound healing and Boyden chamber assays. Since both estrone analogs exerted remarkable estrogenic activities, as documented by a luciferase reporter gene assay, they can be considered as promising drug candidates for hormone-independent malignancies. LA - English DB - MTMT ER - TY - JOUR AU - Zottel, A. AU - Jójárt, Rebeka AU - Ágoston, H. AU - Hafner, E. AU - Lipušček, N. AU - Mernyák, Erzsébet AU - Rižner, T.L. TI - Cytotoxic effect of 13α-estrane derivatives on breast, endometrial and ovarian cancer cell lines JF - JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY J2 - J STEROID BIOCHEM MOL BIOL VL - 232 PY - 2023 PG - 7 SN - 0960-0760 DO - 10.1016/j.jsbmb.2023.106350 UR - https://m2.mtmt.hu/api/publication/34101587 ID - 34101587 N1 - Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, 1000, Slovenia Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Export Date: 17 August 2023 CODEN: JSBBE Correspondence Address: Mernyák, E.; University of Szeged, Dóm tér 8, Hungary; email: bobe@chem.u-szeged.hu Correspondence Address: Rižner, T.L.; Institute of Biochemistry and Molecular Genetics, Vrazov trg 2, Slovenia; email: Tea.Lanisnik-Rizner@mf.uni-lj.si Funding details: Magyar Tudományos Akadémia, MTA Funding details: Javna Agencija za Raziskovalno Dejavnost RS, ARRS Funding details: National Research, Development and Innovation Office, OTKA SNN 124329, SNN 139323 Funding text 1: This work was supported by projects N1–0066 and N1–0234 from the Slovenian Research Agency to T.L.R. and by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and the National Research, Development and Innovation Office-NKFIH project OTKA SNN 124329 and SNN 139323 to E.M. AB - Hormone-dependent cancers such as breast, uterine, and ovarian cancers account for more than 35% of all cancers in women. Worldwide, these cancers occur in more than 2.7 million women/year and account for 22% of cancer-related deaths/year. The generally accepted mechanism for the pathophysiology of estrogen-dependent cancers is estrogen receptor-mediated cell proliferation associated with an increased number of mutations. Therefore, drugs that can interfere with either local estrogen formation or estrogen action via estrogen receptors are needed. Estrane derivatives that have low or minimal estrogenic activity can affect both pathways. In this study, we investigated the effect of 36 different estrane derivatives on the proliferation of eight breast, endometrial, and ovarian cancer cell lines and the corresponding three control cell lines. Estrane derivatives 3 and 4_2Cl showed a stronger effect on the endometrial cancer cell lines KLE and Ishikawa, respectively, compared with the control cell line HIEEC, with IC50 values of 32.6 microM and 17.9 microM, respectively. Estrane derivative 4_2Cl was most active in the ovarian cancer cell line COV362 compared to the control cell line HIO80 with an IC50 value of 3.6 microM. In addition, estrane derivative 2_4I showed a strong antiproliferative effect on endometrial and ovarian cancer cell lines, while the effect on the control cell line was slight or absent. The addition of halogen at carbon 2 and/or 4 in estrane derivatives 1 and 2 increased the selectivity for endometrial cancer cells. Overall, these results suggest that single estrane derivatives are efficient cytotoxic agents for endometrial and ovarian cancer cell lines, and thus potential lead compounds for drug development. © 2023 The Authors LA - English DB - MTMT ER - TY - JOUR AU - Hlogyik, Tamás AU - Laczkó-Rigó, Réka AU - Bakos, Éva AU - Poór, Miklós AU - Kele, Zoltán AU - Laczka, Csilla AU - Mernyák, Erzsébet TI - Synthesis and in vitro photodynamic activity of aza-BODIPY-based photosensitizers JF - ORGANIC & BIOMOLECULAR CHEMISTRY J2 - ORG BIOMOL CHEM VL - 21 PY - 2023 IS - 29 SP - 6018 EP - 6027 PG - 10 SN - 1477-0520 DO - 10.1039/d3ob00699a UR - https://m2.mtmt.hu/api/publication/34067941 ID - 34067941 N1 - * Megosztott szerzőség AB - Aza-BODIPY dyes have recently come to attention owing to their excellent chemical and photophysical properties. In particular, their absorption and emission maxima can efficiently be shifted to the red or even to the NIR spectral region. On this basis, aza-BODIPY derivatives are widely investigated as fluorescent probes or phototherapeutic agents. Here we report the synthesis of a set of novel aza-BODIPY derivatives as potential photosensitizers for use in photodynamic therapy. Triazolyl derivatives were obtained via Cu(I)-catalyzed azide-alkyne cycloaddition as the key step. In vitro photodynamic activities of the newly synthesized compounds were evaluated on the A431 human epidermoid carcinoma cell line. Structural differences influenced the light-induced toxicity of the test compounds markedly. Compared to the initial tetraphenyl aza-BODIPY derivative, the compound bearing two hydrophilic triethylene glycol side chains showed substantial, more than 250-fold, photodynamic activity with no dark toxicity. Our newly synthesized aza-BODIPY derivative, acting in the nanomolar range, might serve as a promising candidate for the design of more active and selective photosensitizers. 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 - Peřina, Miroslav AU - Kiss, Anita AU - Mernyák, Erzsébet AU - Mada, Lukáš AU - Schneider, Gyula AU - Jorda, Radek TI - Synthesis of hydrocortisone esters targeting androgen and glucocorticoid receptors in prostate cancer in vitro JF - JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY J2 - J STEROID BIOCHEM MOL BIOL VL - 229 PY - 2023 PG - 12 SN - 0960-0760 DO - 10.1016/j.jsbmb.2023.106269 UR - https://m2.mtmt.hu/api/publication/33663109 ID - 33663109 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 - CHAP AU - Ali, Hazhmat AU - Mernyák, Erzsébet AU - Traj, Péter AU - Gábor, J. Szebeni AU - Minorics, Renáta AU - Zupkó, István ED - Muszynska, Bozena TI - In Vitro Evaluation of Antiproliferative and Antimetastatic Activity of the Newly Synthesized 2-(4-Chlorophenyl)-13α-Estrone Sulfamate T2 - Natural vs. Artificial Networks: The Usefulness of the Concept in Health, Life, and Technical Sciences PB - Zakład Optymalizacji Zawodowej Ośrodek Umea Shinoda-Kuracejo CY - Martin CY - Krakow CY - Szeged SN - 9788395955457 PY - 2022 SP - 81 EP - 82 PG - 2 UR - https://m2.mtmt.hu/api/publication/33338885 ID - 33338885 LA - English DB - MTMT ER - TY - CHAP AU - Tamási, Zita AU - Mernyák, Erzsébet TI - BODIPY-típusú fluorofórok szintézise T2 - Vegyészkonferencia 2022 PB - Magyar Kémikusok Egyesülete (MKE) CY - Budapest SN - 9786156018113 PY - 2022 SP - 107 PG - 1 UR - https://m2.mtmt.hu/api/publication/33272208 ID - 33272208 LA - Hungarian DB - MTMT ER - TY - CHAP AU - Hlogyik, Tamás AU - Mernyák, Erzsébet TI - Biomolekulák konjugálására alkalmas aza-BODIPY-típusú fluorofórok szintézise T2 - Vegyészkonferencia 2022 PB - Magyar Kémikusok Egyesülete (MKE) CY - Budapest SN - 9786156018113 PY - 2022 SP - 84 PG - 1 UR - https://m2.mtmt.hu/api/publication/33272206 ID - 33272206 LA - Hungarian DB - MTMT ER -