{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:20:31Z","timestamp":1791404431414,"version":"4.3.3"},"reference-count":64,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Education and Science in the Regional Initiative of Excellence program for the years 2019-2022","award":["016\/RID\/2018\/19"],"award-info":[{"award-number":["016\/RID\/2018\/19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Olivacine and ellipticine are model anticancer drugs acting as topoisomerase II inhibitors. Here, we present investigations performed on four olivacine derivatives in light of their antitumor activity. The aim of this study was to identify the best antitumor compound among the four tested olivacine derivatives. The study was performed using CCRF\/CEM and MCF-7 cell lines. Comet assay, polarography, inhibition of topoisomerase II activity, histone acetylation, and molecular docking studies were performed. Each tested compound displayed interaction with DNA and topoisomerase II, but did not cause histone acetylation. Compound 2 (9-methoxy-5,6-dimethyl-1-({[1-hydroxy-2-(hydroxymethyl)butan-2-yl]amino}methyl)-6H-pyrido[4,3-b]carbazole) was found to be the best candidate as an anticancer drug because it had the highest affinity for topoisomerase II and caused the least genotoxic damage in cells.<\/jats:p>","DOI":"10.3390\/ijms22168492","type":"journal-article","created":{"date-parts":[[2021,8,8]],"date-time":"2021-08-08T21:49:41Z","timestamp":1628459381000},"page":"8492","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evaluation of Interactions of Selected Olivacine Derivatives with DNA and Topoisomerase II"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2094-6533","authenticated-orcid":false,"given":"Beata","family":"Tyli\u0144ska","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1400-1819","authenticated-orcid":false,"given":"Agnieszka","family":"Dobosz","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Spycha\u0142a","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7736-1427","authenticated-orcid":false,"given":"\u0141ucja","family":"Cwynar-Zaj\u0105c","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-9667","authenticated-orcid":false,"given":"\u017baneta","family":"Czy\u017cnikowska","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8216-9085","authenticated-orcid":false,"given":"Amadeusz","family":"Ku\u017aniarski","sequence":"additional","affiliation":[{"name":"Department of Prosthetic Dentistry, Wroclaw Medical University, 50-425 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8742-0790","authenticated-orcid":false,"given":"Tomasz","family":"G\u0119barowski","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Wroclaw Medical University, 50-556 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tringali, C. (2001). Bioactive Compounds from Natural Sources, CRC Press.","DOI":"10.1201\/9781482289268"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0003-9861(87)90463-2","article-title":"Multimodal action of antitumor agents on DNA\u2014The ellipticine series","volume":"259","author":"Auclair","year":"1987","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1107\/S0907444905015404","article-title":"The anticancer agent ellipticine unwinds DNA by intercaltive binding in an orientation parallel to base pairs","volume":"D61","author":"Canals","year":"2005","journal-title":"Acta Cryst. Sect. D"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.canlet.2004.09.046","article-title":"The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells","volume":"223","author":"Kuo","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1016\/S0006-2952(01)00806-1","article-title":"The anticancer agent ellipticine on activation by cytochrome P450 forms covalent DNA adducts","volume":"62","author":"Bieler","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.5507\/bp.2006.002","article-title":"Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine","volume":"150","author":"Rupertova","year":"2006","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1021\/ja01517a031","article-title":"Alkaloids of Ochrosia elliptica Labill","volume":"81","author":"Goodwin","year":"1959","journal-title":"J. Am. Chem. Soc."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.pharmthera.2011.07.006","article-title":"Antracyclines and ellipticines as DNA-damaging anticancer drugs: Recent advances","volume":"133","author":"Kizek","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1021\/ja00860a022","article-title":"Synthesis of olivacine","volume":"84","author":"Wenkert","year":"1962","journal-title":"J. Am. Chem. Soc. ACS Publ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/BF00944185","article-title":"Phase II study of a combination of elliptinium and vinblastine in metastatic breast cancer","volume":"10","author":"Kayitalire","year":"1992","journal-title":"Investig. New Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1093\/annonc\/mdg114","article-title":"Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer","volume":"14","author":"Pivot","year":"2003","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1124\/mol.53.2.213","article-title":"S16020-2, a new highly cytotoxic antitumor olivacine derivative: DNA interaction and DNA topoisomerase II inhibition","volume":"53","author":"Markovits","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1124\/dmd.32.1.80","article-title":"The olivacine derivative S16020 (9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-b)-carbazole-1-carboxamide) induces CYP1A and its own metabolism in human hepatocytes in primary culture","volume":"32","author":"Weaver","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","first-page":"1909","article-title":"Hydroxy-9-methyl-2-ellipticinium for osseous metastases from breast cancer: A 5-year experience","volume":"66","author":"Juret","year":"1982","journal-title":"Cancer Treat Rep."},{"key":"ref_15","first-page":"823","article-title":"New pyridocarbazole derivatives. Synthesis and their in vitro anticancer activity","volume":"70","author":"Gasiorowski","year":"2013","journal-title":"Acta Pol. Pharm. Drug Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Piasny, J., Wiatrak, B., Dobosz, A., Tyli\u0144ska, B., and G\u0119barowski, T. (2020). Antitumor activity of new olivacine derivatives. Molecules, 25.","DOI":"10.3390\/molecules25112512"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0165-1110(94)00013-3","article-title":"The comet assay: A comprehensive review","volume":"339","author":"Fairbairn","year":"1995","journal-title":"Mutat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s43440-019-00004-1","article-title":"Effect of new olivacine derivatives on p53 protein level","volume":"72","author":"Wiatrak","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S1383-5718(02)00174-2","article-title":"Detection of topoisomerase inhibitor-induced DNA strand breaks and apoptosis by the alkaline comet assay","volume":"520","author":"Godard","year":"2002","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagenesis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/S0039-9140(01)00649-X","article-title":"Past, present and future of nucleic acids electrochemistry","volume":"56","year":"2002","journal-title":"Talanta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0302-4598(98)80015-9","article-title":"New trends in electrochemical analysis of nucleic acids","volume":"20","year":"1988","journal-title":"Bioelectrochem. Bioenerg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/elan.1140080103","article-title":"From Polarography of DNA to Microanalysis with Nucleic Acid-Modified Electrodes","volume":"8","year":"1996","journal-title":"Electroanalysis"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Milazzo, G. (1983). Topics in Bioelectrochemistry and Bioenergetics, Wiley.","DOI":"10.1007\/978-1-4613-3697-6_2"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/0302-4598(81)80005-0","article-title":"433\u2014Nucleic acid analysis by voltammetry at carbon electrodes","volume":"8","author":"Brabec","year":"1981","journal-title":"Bioelectrochem. Bioenerg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R546","DOI":"10.1016\/j.cub.2004.07.007","article-title":"Histones and histone modifications","volume":"14","author":"Peterson","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/cr.2011.22","article-title":"Regulation of chromatin by histone modifications","volume":"21","author":"Bannister","year":"2011","journal-title":"Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/jcb.20532","article-title":"Prospects: Histone Deacetylase Inhibitors","volume":"96","author":"Dokmanovic","year":"2005","journal-title":"J. Cell. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.molonc.2007.01.001","article-title":"The role of histone deacetylases (HDACs) in human cancer","volume":"1","author":"Ropero","year":"2007","journal-title":"Mol. Oncol."},{"key":"ref_29","first-page":"85","article-title":"A Sensitive Genotoxicity Test for the Detection of DNA Damage. Methods in Molecular Biology","volume":"Volume 291","author":"Keohavong","year":"2005","journal-title":"Molecular Toxicology Protocols"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/mutage\/18.1.45","article-title":"Recommendations for conducting the in vivo alkaline Comet assay","volume":"18","author":"Hartmann","year":"2003","journal-title":"Mutagenesis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0003-9861(64)90003-7","article-title":"Polarographic behavior of cytosine and some of its derivatives","volume":"105","author":"Janik","year":"1964","journal-title":"Arch. Biochem. Biophys"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0079-6603(08)60767-9","article-title":"Polarographic Techniques in Nucleic Acid Research","volume":"9","year":"1969","journal-title":"Prog. Nucleic Acid Res. Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0020-1693(00)81185-8","article-title":"Differential Pulse-polarographic Approach to Zinc(II)-and Cadmium (II)\u2014DNA System","volume":"138","year":"1987","journal-title":"Inorg. Chim. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0020-1693(00)81152-4","article-title":"Polarographic Studies on Copper(II) and Nickel(II) Ion Interaction with DNA","volume":"136","year":"1987","journal-title":"Inorg. Chim. Acta"},{"key":"ref_35","first-page":"437","article-title":"A structure-function analysis of DNA topoisomerase II inhibitors","volume":"3","author":"Insaf","year":"1996","journal-title":"Curr. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1097\/00001813-199710000-00001","article-title":"DNA topoisomerase targeting drugs: Mechanisms of action and perspectives","volume":"8","author":"Malonne","year":"1997","journal-title":"Anti-Cancer Drugs"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/ardp.200700203","article-title":"Synthesis and anticancer activity of new 1-substituted-6H-pyrido 4,3-b carbazole derivatives","volume":"341","author":"Mastalarz","year":"2008","journal-title":"Arch. Der. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.copbio.2007.09.006","article-title":"DNA as a target for anticancer compounds: Methods to determine the mode of binding and the mechanism of action","volume":"18","author":"Palchaudhuri","year":"2007","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_39","first-page":"3189","article-title":"A Novel Use for Comet Assay: Detection of Topoisomerase II Inhibitors","volume":"20","author":"Salti","year":"2000","journal-title":"Anticancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s10565-007-9043-9","article-title":"Comet Assay measurements: A perspective","volume":"25","author":"Kumaravel","year":"2009","journal-title":"Cell Biol. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"86","DOI":"10.2307\/3577587","article-title":"Heterogeneity in radiationinduced DNA damage and repair in tumor and normal cells measured using the \u201cComet\u201d assay","volume":"122","author":"Olive","year":"1990","journal-title":"Radiat. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cree, I. (2011). Cell Sensitivity Assay. Cancer Cell Culture. Methods in Molecular Biology (Methods and Protocols), Humana Press.","DOI":"10.1007\/978-1-61779-080-5"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1126\/science.1204117","article-title":"Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide","volume":"333","author":"Wu","year":"2011","journal-title":"Science"},{"key":"ref_44","first-page":"95","article-title":"Molecular mechanisms of etoposide","volume":"14","author":"Montecucco","year":"2015","journal-title":"EXCLI J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1021\/jm00320a020","article-title":"Preparation and antitumor activity of olivacine and some new analogs","volume":"9","author":"Mosher","year":"1966","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2715","DOI":"10.1071\/CH9672715","article-title":"Synthesis of tumour-inhibitory alkaloids ellipticine 9-methoxyellipticine and related pyrido 4,3-b carbazoles","volume":"20","author":"Dalton","year":"1967","journal-title":"Aust. J. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Chandra, P. (1986). Antitumor Activity, Pharmacology and Clinical Trials of Elliptinium (NSC 264-137). New Experimental Modalities in the Control of Neoplasia, Springer.","DOI":"10.1007\/978-1-4684-5242-6"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/S0959-8049(05)80424-1","article-title":"Phase-ii study of elliptinium acetate salvage treatment of advanced breast-cancer","volume":"29A","author":"Rouesse","year":"1993","journal-title":"Eur. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Avendano, C., and Menendez, J.C. (2015). Chapter 7\u2014Other Anticancer Drugs Targeting DNA and DNA-Associated Enzymes. Medicinal Chemistry of Anticancer Drugs, Elsevier Science. [2nd ed.].","DOI":"10.1016\/B978-0-444-62649-3.00007-7"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/B978-0-444-62615-8.00006-0","article-title":"Chapter 6\u2014Emerging Targets in the Bioactivity of Ellipticines and Derivatives","volume":"Volume 39","year":"2013","journal-title":"Studies in Natural Products Chemistry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s00432-020-03213-x","article-title":"Selected ellipticine derivatives, known to target topoisomerase II, suppress the alternative lengthening of telomere (ALT) pathway in telomerase\u2013negative cells","volume":"146","author":"Zencir","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"363","DOI":"10.2174\/1568011054222364","article-title":"Etoposide, topoisomerase II and cancer","volume":"5","author":"Baldwin","year":"2005","journal-title":"Curr. Med. Chem. Anticancer Agents"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s10495-010-0559-8","article-title":"Mutant p53 exhibits trivial effects on mitochondrial functions which can be reactivated by ellipticine in lymphoma cells","volume":"16","author":"Wang","year":"2011","journal-title":"Apoptosis"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/0014-4827(88)90265-0","article-title":"A simple technique for quantitation of low levels of DNA damage in individual cells","volume":"175","author":"Singh","year":"1988","journal-title":"Exp. Cell Res."},{"key":"ref_55","unstructured":"CycLex Cellular Histone Acetylation Assay Kit (2021, August 02). User\u2019s Manual. Available online: https:\/\/www.mblintl.com\/products\/wp-content\/uploads\/sites\/2\/2021\/06\/CY-1140-_ver.210531.pdf."},{"key":"ref_56","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (2016). Gaussian 09 Citation, Gaussian, Inc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s00894-007-0233-4","article-title":"Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements","volume":"13","author":"Stewart","year":"2007","journal-title":"J. Mol. Model."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2999","DOI":"10.1021\/cr9904009","article-title":"Quantum Mechanical Continuum Solvation Models","volume":"105","author":"Tomasi","year":"2005","journal-title":"Chem. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10861","DOI":"10.1093\/nar\/gkx742","article-title":"Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1093\/bioinformatics\/btaa018","article-title":"LigRMSD: A web server for automatic structure matching and RMSD calculations among identical and similar compounds in protein-ligand docking","volume":"36","author":"Caballero","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Tyli\u0144ska, B., Wiatrak, B., Czy\u017cnikowska, \u017b., Cie\u015bla-Niechwiadowicz, A., G\u0119barowska, E., and Janicka-K\u0142os, A. (2021). Novel pyrimidine derivatives as potential anticancer agents: Synthesis, biological evaluation and molecular docking study. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083825"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/prot.21249","article-title":"Accounting for ligand-bound metal ions in docking small molecules on adenylyl cyclase toxins","volume":"67","author":"Chen","year":"2007","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera? A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8492\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:42:01Z","timestamp":1760164921000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,6]]},"references-count":64,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168492"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168492","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,6]]}}}