{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T06:02:35Z","timestamp":1792303355756,"version":"4.4.0"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["17-75-20120"],"award-info":[{"award-number":["17-75-20120"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["121031300044-5"],"award-info":[{"award-number":["121031300044-5"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Russian State-funded budget project of ICBFM SB RAS","award":["17-75-20120"],"award-info":[{"award-number":["17-75-20120"]}]},{"name":"Russian State-funded budget project of ICBFM SB RAS","award":["121031300044-5"],"award-info":[{"award-number":["121031300044-5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of \u03b1O-SM and \u03b2O-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18\u03b2H-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with \u03b1- and \u03b2-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7\u20134.1 \u00b5M) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, \u03b1O-SM and \u03b2O-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), \u03b1O-SM and \u03b2O-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.<\/jats:p>","DOI":"10.3390\/ijms23116214","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T12:48:31Z","timestamp":1654087711000},"page":"6214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo"],"prefix":"10.3390","volume":"23","author":[{"given":"Oksana V.","family":"Salomatina","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 8, 630090 Novosibirsk, Russia"},{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5729-9910","authenticated-orcid":false,"given":"Aleksandra V.","family":"Sen\u2019kova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arseny D.","family":"Moralev","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 8, 630090 Novosibirsk, Russia"},{"name":"Faculty of Natural Sciences, Novosibirsk State University, Pirogova Str., 1, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-858X","authenticated-orcid":false,"given":"Innokenty A.","family":"Savin","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina I.","family":"Komarova","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nariman F.","family":"Salakhutdinov","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4044-1049","authenticated-orcid":false,"given":"Marina A.","family":"Zenkova","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7569-9555","authenticated-orcid":false,"given":"Andrey V.","family":"Markov","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Lavrent\u2019ev Avenue, 8, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"key":"ref_1","unstructured":"Silverman, R.B., and Holladay, M.W. (2014). The Organic Chemistry of Drug Design and Drug Action, Elsevier Science."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1021\/acscentsci.5b00131","article-title":"Modeling epoxidation of drug-like molecules with a deep machine learning network","volume":"1","author":"Hughes","year":"2015","journal-title":"ACS Cent. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"112327","DOI":"10.1016\/j.ejmech.2020.112327","article-title":"Epoxide containing molecules: A good or a bad drug design approach","volume":"201","author":"Gomes","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Uetrecht, J. (2010). Role of Reactive Metabolites in Drug-Induced Hepatotoxicity BT\u2014Adverse Drug Reactions, Springer.","DOI":"10.1007\/978-3-642-00663-0"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1002\/cbdv.200900055","article-title":"Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?","volume":"6","author":"Kalgutkar","year":"2009","journal-title":"Chem. Biodivers."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1515\/BC.2008.134","article-title":"Molecular mechanisms of aromatase inhibition by new A, D-ring modified steroids","volume":"389","author":"Cepa","year":"2008","journal-title":"Biol Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.biocel.2015.10.024","article-title":"Exemestane metabolites suppress growth of estrogen receptor-positive breast cancer cells by inducing apoptosis and autophagy: A comparative study with Exemestane","volume":"69","author":"Amaral","year":"2015","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.bioorg.2018.11.054","article-title":"The synthesis and anticancer activities of chiral epoxy-substituted chromone analogs","volume":"84","author":"Jo","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.bbrc.2018.10.022","article-title":"Alisol B-23-acetate, a tetracyclic triterpenoid isolated from Alisma orientale, induces apoptosis in human lung cancer cells via the mitochondrial pathway","volume":"505","author":"Wang","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.3748\/wjg.15.2870","article-title":"Alisol B acetate induces apoptosis of SGC7901 cells via mitochondrial and phosphatidylinositol 3-kinases\/Akt signaling pathways","volume":"15","author":"Xu","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111652","DOI":"10.1016\/j.ejmech.2019.111652","article-title":"Highly potent non-steroidal FXR agonists protostane-type triterpenoids: Structure-activity relationship and mechanism","volume":"182","author":"Luan","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.taap.2015.01.020","article-title":"Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis","volume":"283","author":"Meng","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1055\/s-2006-947178","article-title":"A New Triterpene and Anti-Hepatitis B Virus Active Compounds from Alisma orientalis","volume":"72","author":"Jiang","year":"2006","journal-title":"Planta Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104345","DOI":"10.1016\/j.fitote.2019.104345","article-title":"Five 11\u03b1, 12\u03b1-epoxy pentacyclic triterpenoid saponins with antithrombus activities from Glechoma longituba","volume":"138","author":"Ouyang","year":"2019","journal-title":"Fitoterapia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/cbic.201000618","article-title":"Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives","volume":"12","author":"Logashenko","year":"2011","journal-title":"ChemBioChem"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1134\/S0026893318020073","article-title":"Novel Glycyrrhetinic Acid Derivative Soloxolone Methyl Inhibits the Inflammatory Response and Tumor Growth in vivo","volume":"52","author":"Markov","year":"2018","journal-title":"Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Markov, A.V., Odarenko, K.V., Sen\u2019kova, A.V., Salomatina, O.V., Salakhutdinov, N.F., and Zenkova, M.A. (2020). Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo. Molecules, 25.","DOI":"10.3390\/molecules25245925"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Markov, A.V., Sen\u2019kova, A.V., Babich, V.O., Odarenko, K.V., Talyshev, V.A., Salomatina, O.V., Salakhutdinov, N.F., Zenkova, M.A., and Logashenko, E.B. (2020). Dual effect of soloxolone methyl on LPS-induced inflammation in vitro and in vivo. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217876"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13968","DOI":"10.1038\/s41598-017-14029-0","article-title":"Soloxolone methyl inhibits influenza virus replication and reduces virus-induced lung inflammation","volume":"7","author":"Markov","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sen\u2019kova, A.V., Savin, I.A., Brenner, E.V., Zenkova, M.A., and Markov, A.V. (2021). Core genes involved in the regulation of acute lung injury and their association with COVID-19 and tumor progression: A bioinformatics and experimental study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0260450"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/j.bmcl.2005.03.031","article-title":"Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: Implications for a molecular mechanism of action","volume":"15","author":"Couch","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1021\/acs.jmedchem.5b01292","article-title":"Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites","volume":"59","author":"Wong","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1111\/bph.12999","article-title":"Novel Nrf2 activators from microbial transformation products inhibit blood\u2013retinal barrier permeability in rabbits","volume":"172","author":"Nakagami","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1111\/jnc.14029","article-title":"RS9, a novel Nrf2 activator, attenuates light-induced death of cells of photoreceptor cells and M\u00fcller glia cells","volume":"141","author":"Inoue","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1021\/acs.chemrestox.9b00289","article-title":"In Vitro Biotransformation of the Nrf2 Activator Bardoxolone: Formation of an Epoxide Metabolite That Undergoes Two Novel Glutathione-Mediated Metabolic Pathways: Epoxide Reduction and Oxidative Elimination of Nitrile Moiety","volume":"32","author":"Kamel","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Markov, O.V., Filatov, A.V., Kupryushkin, M.S., Chernikov, I.V., Patutina, O.A., Strunov, A.A., Chernolovskaya, E.L., Vlassov, V.V., Pyshnyi, D.V., and Zenkova, M.A. (2020). Transport Oligonucleotides\u2014A Novel System for Intracellular Delivery of Antisense Therapeutics. Molecules, 25.","DOI":"10.3390\/molecules25163663"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Borella, R., Forti, L., Gibellini, L., De Gaetano, A., De Biasi, S., Nasi, M., Cossarizza, A., and Pinti, M. (2019). Synthesis and anticancer activity of CDDO and CDDO-me, two derivatives of natural triterpenoids. Molecules, 24.","DOI":"10.3390\/molecules24224097"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.2174\/0929867324666170112115313","article-title":"Modulation of Tumour-Related Signaling Pathways by Natural Pentacyclic Triterpenoids and their Semisynthetic Derivatives","volume":"24","author":"Markov","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"104845","DOI":"10.1016\/j.fitote.2021.104845","article-title":"Natural pentacyclic triterpenoid acids potentially useful as biocompatible nanocarriers","volume":"151","year":"2021","journal-title":"Fitoterapia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"21211","DOI":"10.18632\/oncotarget.25014","article-title":"Chemopreventive activity of celastrol in drug\u2013resistant human colon carcinoma cell cultures","volume":"9","author":"Moreira","year":"2018","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/s41401-018-0038-2","article-title":"Asiatic acid enhances intratumor delivery and the antitumor effect of pegylated liposomal doxorubicin by reducing tumor-stroma collagen","volume":"40","author":"Fang","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/jebm.12434","article-title":"ATP-binding cassette (ABC) transporters in cancer: A review of recent updates","volume":"14","author":"Wang","year":"2021","journal-title":"J. Evid. Based. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1007\/s00109-021-02105-y","article-title":"ABCB1 in dermatology: Roles in skin diseases and their treatment","volume":"99","author":"Weng","year":"2021","journal-title":"J. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.20892\/j.issn.2095-3941.2019.0284","article-title":"ABC transporters and the hallmarks of cancer: Roles in cancer aggressiveness beyond multidrug resistance","volume":"17","author":"Muriithi","year":"2020","journal-title":"Cancer Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.ejca.2007.01.017","article-title":"Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential","volume":"43","author":"Monzani","year":"2007","journal-title":"Eur. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bcp.2015.12.007","article-title":"Drug\u2013protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein","volume":"101","author":"Chufan","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.2174\/1871520620666200516144403","article-title":"Benzophenone Sulfonamide Derivatives as Interacting Partners and Inhibitors of Human P-glycoprotein","volume":"20","author":"Farman","year":"2020","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1021\/acs.jcim.0c00892","article-title":"(+\/\u2212)-Borneol Reverses Mitoxantrone Resistance against P-Glycoprotein","volume":"61","author":"Yang","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1021\/acs.jmedchem.0c01826","article-title":"Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor","volume":"64","author":"Smolinski","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114207","DOI":"10.1016\/j.ejmech.2022.114207","article-title":"Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles","volume":"232","author":"Huang","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113403","DOI":"10.1016\/j.ejmech.2021.113403","article-title":"Discovery of new pyrimidopyrrolizine\/indolizine-based derivatives as P-glycoprotein inhibitors: Design, synthesis, cytotoxicity, and MDR reversal activities","volume":"218","author":"Shawky","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_42","first-page":"31","article-title":"Chapter 2\u2014Efflux transporters in anti-cancer drug resistance: Molecular and functional identification and characterization of multidrug resistance proteins (MRPs\/ABCCs)","volume":"Volume 7","author":"Sosnik","year":"2020","journal-title":"Cancer Sensitizing Agents for Chemotherapy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9931","DOI":"10.1021\/acs.jmedchem.8b00834","article-title":"Discovery of Novel Flavonoid Dimers To Reverse Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediated Drug Resistance in Cancers Using a High Throughput Platform with \u201cClick Chemistry\u201d","volume":"61","author":"Wong","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.addr.2016.06.003","article-title":"Biochemical studies on the structure\u2013function relationship of major drug transporters in the ATP-binding cassette family and solute carrier family","volume":"116","author":"Hong","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1208\/s12248-014-9668-6","article-title":"Role of the Breast Cancer Resistance Protein (BCRP\/ABCG2) in Drug Transport\u2014An Update","volume":"17","author":"Mao","year":"2015","journal-title":"AAPS J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1021\/bi902085q","article-title":"Mutational Analysis of Threonine 402 Adjacent to the GXXXG Dimerization Motif in Transmembrane Segment 1 of ABCG2","volume":"49","author":"Polgar","year":"2010","journal-title":"Biochemistry"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wu, C.-P., Hsiao, S.-H., Huang, Y.-H., Hung, L.-C., Yu, Y.-J., Chang, Y.-T., Hung, T.-H., and Wu, Y.-S. (2020). Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs. Cancers, 12.","DOI":"10.3390\/cancers12010195"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.3389\/fphar.2018.01545","article-title":"Y6, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance","volume":"9","author":"Zhao","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1021\/acs.molpharmaceut.7b00334","article-title":"Alpha-Mangostin Reverses Multidrug Resistance by Attenuating the Function of the Multidrug Resistance-Linked ABCG2 Transporter","volume":"14","author":"Wu","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"109645","DOI":"10.1016\/j.cbi.2021.109645","article-title":"Triterpenoids with modified A-ring as modulators of P-gp-dependent drug-resistance in cancer cells","volume":"348","author":"Rybalkina","year":"2021","journal-title":"Chem. Biol. Interact."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"112397","DOI":"10.1016\/j.biopha.2021.112397","article-title":"Anticancer activity of oleanolic acid and its derivatives: Recent advances in evidence, target profiling and mechanisms of action","volume":"145","author":"Tang","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_52","first-page":"323","article-title":"Chapter Four\u2014Dacarbazine","volume":"Volume 41","author":"Brittain","year":"2016","journal-title":"Brittain Excipients and Related Methodology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Fujimura, T., Kambayashi, Y., Ohuchi, K., Muto, Y., and Aiba, S. (2020). Treatment of Advanced Melanoma: Past, Present and Future. Life, 10.","DOI":"10.3390\/life10090208"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Markov, A.V., Sen\u2019kova, A.V., Salomatina, O.V., Logashenko, E.B., Korchagina, D.V., Salakhutdinov, N.F., and Zenkova, M.A. (2020). Trioxolone methyl, a novel cyano enone-bearing 18\u03b2H-glycyrrhetinic acid derivative, ameliorates dextran sulphate sodium-induced colitis in mice. Molecules, 25.","DOI":"10.3390\/molecules25102406"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101550","DOI":"10.1016\/j.redox.2020.101550","article-title":"Nitric oxide in cellular adaptation and disease","volume":"34","author":"Gantner","year":"2020","journal-title":"Redox Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/imr.13061","article-title":"Real-time imaging of inflammation and its resolution: It\u2019s apparent because it\u2019s transparent","volume":"306","author":"Robertson","year":"2022","journal-title":"Immunol. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"Software news and update AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Guzm\u00e1n, C., Bagga, M., Kaur, A., Westermarck, J., and Abankwa, D. (2014). ColonyArea: An ImageJ plugin to automatically quantify colony formation in clonogenic assays. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092444"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Markov, A.V., Sen\u2019kova, A.V., Popadyuk, I.I., Salomatina, O.V., Logashenko, E.B., Komarova, N.I., Ilyina, A.A., Salakhutdinov, N.F., and Zenkova, M.A. (2020). Novel 3\u2032-substituted-1\u2032,2\u2032,4\u2032-oxadiazole derivatives of 18\u03b2H-glycyrrhetinic acid and their o-acylated amidoximes: Synthesis and evaluation of antitumor and anti-inflammatory potential in vitro and in vivo. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103511"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:23:29Z","timestamp":1760138609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23116214"],"URL":"https:\/\/doi.org\/10.3390\/ijms23116214","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,1]]}}}