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 - Kiss, Anita AU - Jójárt, Rebeka AU - Mernyák, Erzsébet AU - Bartha, Sándor AU - Minorics, Renáta AU - Zupkó, István AU - Schneider, Gyula TI - Novel preparation of substituted oxazolines condensed to d-ring of estrane skeleton and characterization of their antiproliferative properties JF - STEROIDS J2 - STEROIDS VL - 176 PY - 2021 PG - 6 SN - 0039-128X DO - 10.1016/j.steroids.2021.108911 UR - https://m2.mtmt.hu/api/publication/32241841 ID - 32241841 LA - English DB - MTMT ER - TY - JOUR AU - Laczkó-Rigó, Réka AU - Bakos, Éva AU - Jójárt, Rebeka AU - Tömböly, Csaba AU - Mernyák, Erzsébet AU - Laczka, Csilla TI - Selective antiproliferative effect of C-2 halogenated 13α-estrones on cells expressing Organic anion-transporting polypeptide 2B1 (OATP2B1) JF - TOXICOLOGY AND APPLIED PHARMACOLOGY J2 - TOXICOL APPL PHARM VL - 429 PY - 2021 PG - 9 SN - 0041-008X DO - 10.1016/j.taap.2021.115704 UR - https://m2.mtmt.hu/api/publication/32178981 ID - 32178981 AB - Organic anion-transporting polypeptide 2B1 (OATP2B1) is a multispecific transporter mediating the cellular uptake of steroids and numerous drugs. OATP2B1 is abundantly expressed in the intestine and is also present in various tumors. Increased steroid hormone uptake by OATP2B1 has been suggested to promote progression of hormone dependent tumors. 13 alpha-estrones are effective inhibitors of endogenous estrogen formation and are potential candidates to inhibit proliferation of hormone dependent cancers. Recently, we have identified a variety of 13 alpha/beta-estrone-based inhibitors of OATP2B1. However, the nature of this interaction, whether these inhibitors are potential transported substrates of OATP2B1 and hence may be enriched in OATP2B1overexpressing cells, has not yet been investigated. In the current study we explored the antiproliferative effect of the most effective OATP2B1 inhibitor 13 alpha/beta-estrones in control and OATP2B1-overexpressing A431 carcinoma cells. We found an increased antiproliferative effect of 3-O-benzyl 13 alpha/beta-estrones in both mock transfected and OATP2B1-overexpressing cells. However, C-2 halogenated 13 alpha-estrones had a selective OATP2B1-mediated cell growth inhibitory effect. In order to demonstrate that increased sensitization can be attributed to OATP2B1-mediated cellular uptake, tritium labeled 2-bromo-13 alpha-estrone was synthesized for direct transport measurements. These experiments revealed increased accumulation of [H-3]2-bromo-13 alpha-estrone due to OATP2B1 function. Our results indicate that C-2 halogenated 13 alpha-estrones are good candidates in the design of anti-cancer drugs targeting OATP2B1. 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 - Jójárt, Rebeka AU - Laczkó-Rigó, Réka AU - Klement, Máté AU - Kőhl, Gabriella AU - Kecskeméti, Gábor AU - Laczka, Csilla AU - Mernyák, Erzsébet TI - Design, synthesis and biological evaluation of novel estrone phosphonates as high affinity organic anion-transporting polypeptide 2B1 (OATP2B1) inhibitors JF - BIOORGANIC CHEMISTRY J2 - BIOORG CHEM VL - 112 PY - 2021 PG - 12 SN - 0045-2068 DO - 10.1016/j.bioorg.2021.104914 UR - https://m2.mtmt.hu/api/publication/32009571 ID - 32009571 N1 - Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Drug Resistance Research Group instead of Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok körútja 2Budapest H-1117, Hungary Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Export Date: 26 August 2021 LA - English DB - MTMT ER - TY - JOUR AU - Jójárt, Rebeka AU - Senobar Tahaei, Seyyed Ashkan AU - Trungel-Nagy, Péter AU - Kele, Zoltán AU - Minorics, Renáta AU - Paragi, Gábor AU - Zupkó, István AU - Mernyák, Erzsébet TI - Synthesis and evaluation of anticancer activities of 2- or 4-substituted 3-(N-benzyltriazolylmethyl)-13α-oestrone derivatives JF - JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY J2 - J ENZYM INHIB MED CH VL - 36 PY - 2021 IS - 1 SP - 58 EP - 67 PG - 10 SN - 1475-6366 DO - 10.1080/14756366.2020.1838500 UR - https://m2.mtmt.hu/api/publication/31645359 ID - 31645359 LA - English DB - MTMT ER - TY - CHAP AU - Jójárt, Rebeka AU - Kóczán , Lili AU - Lilla, Fajka AU - Bartha, Sándor AU - Minorics, Renáta AU - Zupkó, István AU - Mernyák, Erzsébet ED - Alapi, Tünde ED - Berkecz, Róbert ED - Ilisz, István TI - Microwave-assisted phospha-Michael addition reactions on 13α estrane core T2 - Proceedings of the 26th International Symposium on Analytical and Environmental Problems PB - University of Szeged CY - Szeged SN - 9789633067710 PY - 2020 SP - 177 EP - 178 PG - 2 UR - https://m2.mtmt.hu/api/publication/32583626 ID - 32583626 AB - Novel 16-modified 13 α-estrone derivatives were synthesized via phospha-Michael addition reactions. Transformations of steroidal α,β-unsaturated ketons were carried out under different conditions in a microwave (MW) reactor. The antiproliferative activities of the newly synthesized compounds against a range of human adherent cancer cell lines (SCC-131, SCC-154, Hela, SiHa, C33A, A2780, MCF-7, MDA-MB-231, T47D) were investigated by means of MTT assays. Certain potent derivatives were identified. LA - English DB - MTMT ER - TY - JOUR AU - Jójárt, Rebeka AU - Ali, Hazhmat AU - Horváth, Gergely AU - Kele, Zoltán AU - Zupkó, István AU - Mernyák, Erzsébet TI - Pd-Catalyzed Suzuki–Miyaura couplings and evaluation of 13α-estrone derivatives as potential anticancer agents JF - STEROIDS J2 - STEROIDS VL - 164 PY - 2020 PG - 10 SN - 0039-128X DO - 10.1016/j.steroids.2020.108731 UR - https://m2.mtmt.hu/api/publication/31606817 ID - 31606817 N1 - Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., Szeged, H-6720, Hungary Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Export Date: 10 January 2021 CODEN: STEDA Correspondence Address: Zupkó, I.; Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., Hungary Chemicals/CAS: cisplatin, 15663-27-1, 26035-31-4, 96081-74-2 Manufacturers: Ebewe, Austria Funding details: Emberi Eroforrások Minisztériuma, EMMI Funding details: Magyar Tudományos Akadémia, MTA, ÚNKP-19-4-SZTE-71 Funding details: 20391-3/2018/FEKUSTRAT, OTKA SNN 124329 Funding text 1: The work of Erzsébet Mernyák in this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The work of Erzsébet Mernyák in this project was supported by the ÚNKP-19-4-SZTE-71, New National Excellence Program of The Ministry of Human CapacitieS”. This work was supported by National Research, Development and Innovation Office-NKFIH through project OTKA SNN 124329. Support from Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT is acknowledged. LA - English DB - MTMT ER - TY - JOUR AU - Laczkó-Rigó, Réka AU - Jójárt, Rebeka AU - Mernyák, Erzsébet AU - Bakos, Éva AU - Tuerkova, Alzbeta AU - Zdrazil, Barbara AU - Laczka, Csilla TI - Structural dissection of 13-epiestrones based on the interaction with human Organic anion-transporting polypeptide, OATP2B1. JF - JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY J2 - J STEROID BIOCHEM MOL BIOL VL - 200 PY - 2020 PG - 10 SN - 0960-0760 DO - 10.1016/j.jsbmb.2020.105652 UR - https://m2.mtmt.hu/api/publication/31240434 ID - 31240434 N1 - Membrane Protein Research Group, Institute of Enzymology, RCNS, Magyar tudósok krt. 2, Budapest, H-1117, Hungary Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Althanstraße 14, Vienna, A-1090, Austria Export Date: 15 May 2020 CODEN: JSBBE Correspondence Address: Özvegy-Laczka, C.; Membrane Protein Research Group, Institute of Enzymology, RCNS, Magyar tudósok krt. 2, Hungary; email: laczka.csilla@ttk.mta.hu Chemicals/CAS: hydroxysteroid dehydrogenase, 9001-56-3 Funding details: Austrian Science Fund, FWF, P 29712 Funding details: Austrian Science Fund, FWF Funding details: Hungarian Scientific Research Fund, OTKA, SNN 124329, FK 128751 Funding text 1: This work has been supported by research grants from the National Research, Development and Innovation Office (OTKA FK 128751 and SNN 124329 ). E. M. and Cs. Ö-L. are recipients of the János Bolyai fellowship of the Hungarian Academy of Sciences. This work also received funding from the Austrian Science Fund (FWF) (Grant P 29712 ). Membrane Protein Research Group, Institute of Enzymology, RCNS, Magyar tudósok krt. 2, Budapest, H-1117, Hungary Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Althanstraße 14, Vienna, A-1090, Austria Cited By :3 Export Date: 26 August 2021 CODEN: JSBBE Correspondence Address: Özvegy-Laczka, C.; Membrane Protein Research Group, Magyar tudósok krt. 2, Hungary; email: laczka.csilla@ttk.mta.hu AB - Human OATP2B1 encoded by the SLCO2B1 gene is a multispecific transporter mediating the cellular uptake of large, organic molecules, including hormones, prostaglandins and bile acids. OATP2B1 is ubiquitously expressed in the human body, with highest expression levels in pharmacologically relevant barriers, like enterocytes, hepatocytes and endothelial cells of the blood-brain-barrier. In addition to its endogenous substrates, OATP2B1 also recognizes clinically applied drugs, such as statins, antivirals, antihistamines and chemotherapeutic agents and influences their pharmacokinetics. On the other hand, OATP2B1 is also overexpressed in various tumors. Considering that elevated hormone uptake by OATP2B1 results in increased cell proliferation of hormone dependent tumors (e.g. breast or prostate), inhibition of OATP2B1 can be a good strategy to inhibit the growth of these tumors. 13-epiestrones represent a potential novel strategy in the treatment of hormone dependent cancers by the suppression of local estrogen production due to the inhibition of the key enzyme of estrone metabolism, 17ß-hydroxysteroid-dehydrogenase type 1 (HSD17ß1). Recently, we have demonstrated that various phosphonated 13-epiestrones are dual inhibitors also suppressing OATP2B1 function. In order to gain better insights into the molecular determinants of OATP2B1 13-epiestrone interaction we investigated the effect of C-2 and C-4 halogen or phenylalkynyl modified epiestrones on OATP2B1 transport function. Potent inhibitors (with EC50 values in the low micromolar range) as well as non-inhibitors of OATP2B1 function were identified. Based on the structure-activity relationship (SAR) of the various 13-epiestrone derivatives we could define structural elements important for OATP2B1 inhibition. Our results may help to understand the drug/inhibitor interaction profile of OATP2B1, and also may be a useful strategy to block steroid hormone entry into tumors. LA - English DB - MTMT ER -