{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T22:05:21Z","timestamp":1777068321465,"version":"3.51.4"},"reference-count":186,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T00:00:00Z","timestamp":1610668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04423\/2020, UIDP\/04423\/2020, PTDC\/SAU-PUB\/28736\/2017 (reference POCI-01\u20130145-FEDER-028736)"],"award-info":[{"award-number":["UIDB\/04423\/2020, UIDP\/04423\/2020, PTDC\/SAU-PUB\/28736\/2017 (reference POCI-01\u20130145-FEDER-028736)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["NORTE-01-0145-FEDER-000040"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000040"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006742","name":"Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio","doi-asserted-by":"publisher","award":["CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019"],"award-info":[{"award-number":["CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019"]}],"id":[{"id":"10.13039\/501100006742","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This work reviews the contributions of the corresponding author (M.M.M.P.) and her research group to Medicinal Chemistry concerning the isolation from plant and marine sources of xanthone derivatives as well as their synthesis, biological\/pharmacological activities, formulation and analytical applications. Although her group activity has been spread over several chemical families with relevance in Medicinal Chemistry, the main focus of the investigation and research has been in the xanthone family. Xanthone derivatives have a variety of activities with great potential for therapeutic applications due to their versatile framework. The group has contributed with several libraries of xanthones derivatives, with a variety of activities such as antitumor, anticoagulant, antiplatelet, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective, antioxidant, and multidrug resistance reversal effects. Besides therapeutic applications, our group has also developed xanthone derivatives with analytical applications as chiral selectors for liquid chromatography and for maritime application as antifouling agents for marine paints. Chemically, it has been challenging to afford green chemistry methods and achieve enantiomeric purity of chiral derivatives. In this review, the structures of the most significant compounds will be presented.<\/jats:p>","DOI":"10.3390\/molecules26020431","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T12:44:05Z","timestamp":1610714645000},"page":"431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":83,"title":["From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4676-1409","authenticated-orcid":false,"given":"Madalena M. M.","family":"Pinto","sequence":"first","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"given":"Andreia","family":"Palmeira","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0940-9163","authenticated-orcid":false,"given":"Carla","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4077-6060","authenticated-orcid":false,"given":"Diana I. S. P.","family":"Resende","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0715-1779","authenticated-orcid":false,"given":"Honorina","family":"Cidade","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3320-730X","authenticated-orcid":false,"given":"Maria Elizabeth","family":"Tiritan","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"},{"name":"CESPU, Instituto de Investiga\u00e7\u00e3o e Forma\u00e7\u00e3o Avan\u00e7ada em Ci\u00eancias e Tecnologias da Sa\u00fade, Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-8532","authenticated-orcid":false,"given":"Marta","family":"Correia-da-Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9314-8669","authenticated-orcid":false,"given":"Sara","family":"Cravo","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Pharmaceutical Chemistry (LQOF), Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal"},{"name":"Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,15]]},"reference":[{"key":"ref_1","first-page":"414","article-title":"X-ray crystallographic studies of xanthones","volume":"20","author":"Biswas","year":"1982","journal-title":"Indian J. Pure Appl. Phys."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1107\/S0108270190000543","article-title":"Structure of xanthone","volume":"46","author":"Onuma","year":"1990","journal-title":"Acta Crystallogr. Sect. C"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.2174\/092986705774370727","article-title":"Xanthones-A Structural Perspective","volume":"12","author":"Gales","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_4","unstructured":"Hepworth, H. (1924). Chemical Synthesis: Studies in the Investigation of Natural Organic Products, Blackie and Son."},{"key":"ref_5","unstructured":"Henry, L., and Cavenfou, J.-B. (1821). J. Pharm. Chim., 7, 178."},{"key":"ref_6","unstructured":"Kamal, A., Husain, S.A., Noorani, R., Murtaza, N., Qureshi, I.H., and Qureshi, A.A. (1970). Studies in the biochemistry of microorganisms. XI. Isolation of tajixanthone, shamixanthone, ajamxanthone, shahenxanthone, najamxanthone, radixanthone and mannitol from mycelium of Aspergillus stellatus, Curzi. Pak. J. Sci. Indus. Res., 251\u2013255. in press."},{"key":"ref_7","first-page":"81","article-title":"On the action of aromatic oxy-acids on phenols","volume":"5","author":"Michael","year":"1883","journal-title":"Am. Chem. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/BF01538596","article-title":"\u00dcber das Gentisin","volume":"12","author":"Kostanecki","year":"1891","journal-title":"Mon. Chem. Verwandte Teile And. Wiss."},{"key":"ref_9","unstructured":"(2020, December 02). Organic Syntheses. Available online: http:\/\/online.fliphtml5.com\/jocd\/yqzh\/#p=1."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1002\/cber.19060390298","article-title":"Ueber phenylirungen bei gegenwart von kupfer als katalysator","volume":"39","author":"Goldberg","year":"1906","journal-title":"Ber. Dtsch. Chem. Ges."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/jlac.18550930105","article-title":"Ueber das Mangostin","volume":"93","author":"Schmid","year":"1855","journal-title":"Justus Liebigs Ann. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rai, M., and Chikindas, M.L. (2011). Natural Antimicrobials in Food Safety and Quality, CAB International.","DOI":"10.1079\/9781845937690.0000"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"621459","DOI":"10.1155\/2013\/621459","article-title":"Naturally Occurring Xanthones: Chemistry and Biology","volume":"2013","author":"Negi","year":"2013","journal-title":"J. Appl. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.2174\/092986705774370745","article-title":"Editorial [Hot Topic: Xanthone (Dibenzo-\u03b3-Pyrone): An Interesting Framework In Medicinal Chemistry (Guest Editor: Madalena M.M. Pinto)]","volume":"12","author":"Madalena","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.2174\/092986705774370682","article-title":"Naturally-Occurring Xanthones: Recent Developments","volume":"12","author":"Vieira","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.2174\/092986705774370736","article-title":"Synthesis of Xanthones: An Overview","volume":"12","author":"Sousa","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.2174\/092986705774370718","article-title":"Structure Elucidation of Xanthone Derivatives: Studies of Nuclear Magnetic Resonance Spectroscopy","volume":"12","author":"Silva","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.2174\/092986705774370691","article-title":"Xanthone Derivatives: New Insights in Biological Activities","volume":"12","author":"Pinto","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.2174\/092986705774370709","article-title":"Xanthones as Antimalarial Agents: Discovery, Mode of Action, and Optimization","volume":"12","author":"Riscoe","year":"2005","journal-title":"Curr. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1021\/jm00120a002","article-title":"Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists","volume":"31","author":"Evans","year":"1988","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1021\/np800644y","article-title":"Antitumor Psoropermum Xanthones and Sarcomelicope Acridones: Privileged Structures Implied in DNA Alkylation","volume":"72","author":"Nguyen","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/anie.200352154","article-title":"A Short, Atom-Economical Entry to Tetrahydroxanthenones","volume":"43","author":"Lesch","year":"2004","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.2174\/092986709788682056","article-title":"Naturally Occurring Xanthones; Latest Investigations: Isolation, Structure Elucidation and Chemosystematic Significance","volume":"16","author":"Hesham","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_24","unstructured":"Khan, M.T.H. (2007). Xanthones in Hypericum: Synthesis and BiologicalActivities. Bioactive Heterocycles III, Springer."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wezeman, T., and Masters, K.-S. (2016). Chapter 12 Xanthones are Privileged Scaffolds in Medicinal Chemistry\u2014But are they Over-privileged?. Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation, The Royal Society of Chemistry.","DOI":"10.1039\/9781782622246-00312"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0031-9422(00)00303-4","article-title":"Tetraoxygenated naturally occurring xanthones","volume":"55","author":"Peres","year":"2000","journal-title":"Phytochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Loureiro, D.R.P., Soares, J.X., Costa, J.C., Magalh\u00e3es, \u00c1.F., Azevedo, C.M.G., Pinto, M.M.M., and Afonso, C.M.M. (2019). Structures, activities and drug-likeness of anti-infective xanthone derivatives isolated from the marine environment: A review. Molecules, 24.","DOI":"10.3390\/molecules24020243"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kumla, D., Dethoup, T., Gales, L., Pereira, J.A., Freitas-Silva, J., Costa, P.M., Silva, A.M.S., Pinto, M.M.M., and Kijjoa, A. (2019). Erubescensoic Acid, a new polyketide and a xanthonopyrone SPF-3059-26 From the culture of the marine sponge-associated fungus penicillium erubescens KUFA 0220 and Antibacterial activity evaluation of some of its constituents. Molecules, 24.","DOI":"10.3390\/molecules24010208"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Resende, D., Pereira-Terra, P., In\u00e1cio, \u00c2., Costa, P., Pinto, E., Sousa, E., and Pinto, M. (2018). Lichen Xanthones as Models for New Antifungal Agents. Molecules, 23.","DOI":"10.3390\/molecules23102617"},{"key":"ref_30","unstructured":"Pinto, M.M.M., Castanheiro, R.A.P., and Kijjoa, A. (2006). Xanthones from Marine-Derived Microorganisms: Isolation, Structure Elucidation and Biological Activities. Encyclopedia of Analytical Chemistry, John Wiley & Sons, Ltd."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3717","DOI":"10.1021\/cr100446h","article-title":"Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis","volume":"112","author":"Masters","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1039\/b301926h","article-title":"Marine-derived fungi: A chemically and biologically diverse group of microorganisms","volume":"21","author":"Bugni","year":"2004","journal-title":"Nat. Prod. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1021\/cr60214a003","article-title":"Naturally Occurring Xanthones","volume":"61","author":"Roberts","year":"1961","journal-title":"Chem. Rev."},{"key":"ref_34","unstructured":"Narosa, G.B. (2009). Natural Prenylated xanthones: Chemistry and biological activities. Natural Products: Chemistry, Biochemistry and Pharmacology, Publishing House PVT."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1016\/S0031-9422(00)81755-0","article-title":"Xanthonolignoids from Kielmeyera coriacea","volume":"26","author":"Mesquita","year":"1987","journal-title":"Phytochemistry"},{"key":"ref_36","first-page":"128","article-title":"Anticomplementary activity and constituents of Cratoxylum maingayi DYER","volume":"7","author":"Pinto","year":"1997","journal-title":"Pharm. Pharmacol. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/S0031-9422(98)00381-1","article-title":"Xanthones from Cratoxylum maingayi","volume":"49","author":"Kijjoa","year":"1998","journal-title":"Phytochemistry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1055\/s-2006-960790","article-title":"Immunomodulatory activity of xanthones from Calophyllum teysmannii var. inuphylloide","volume":"65","author":"Gonzalez","year":"1999","journal-title":"Planta Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/S0031-9422(00)00289-2","article-title":"Xanthones from Calophyllum teysmannii var. inophylloide","volume":"55","author":"Kijjoa","year":"2000","journal-title":"Phytochemistry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1055\/s-2008-1074544","article-title":"Cytotoxicity of prenylated xanthones and other constituents from the wood of Garcinia merguensis","volume":"74","author":"Kijjoa","year":"2008","journal-title":"Planta Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Freitas, V.L.S., and Ribeiro da Silva, M.D.M.C. (2018). Influence of Hydroxyl Functional Group on the Structure and Stability of Xanthone: A Computational Approach. Molecules, 23.","DOI":"10.3390\/molecules23112962"},{"key":"ref_42","first-page":"125","article-title":"Anticomplementary activity of hydroxy- and methoxyxanthones","volume":"7","author":"Pinto","year":"1997","journal-title":"Pharm. Pharmacol. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1002\/(SICI)1097-458X(199804)36:4<305::AID-OMR193>3.0.CO;2-N","article-title":"1H and 13C NMR Spectroscopy of mono-, di-, tri- and tetrasubstituted xanthones","volume":"36","author":"Fernandes","year":"1998","journal-title":"Magn. Reson. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1107\/S010827010101349X","article-title":"Naturally occurring 1,2,8-trimethoxy-xanthone and biphenyl ether intermediates leading to 1,2-dimethoxy-xanthone","volume":"57","author":"Gales","year":"2001","journal-title":"Acta Crystallogr. Sect. C Cryst. Struct. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"o2213","DOI":"10.1107\/S1600536805018994","article-title":"3,4-Dihydroxy-9H-xanthen-9-one trihydrate","volume":"61","author":"Gales","year":"2005","journal-title":"Acta Crystallogr. Sect. E Struct. Rep. Online"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Resende, D.I.S.P., Dur\u00e3es, F., Maia, M., Sousa, E., and Pinto, M.M.M. (2020). Recent advances in the synthesis of xanthones and azaxanthones. Org. Chem. Front.","DOI":"10.1039\/D0QO00659A"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/chromsci\/41.7.371","article-title":"A validated HPLC method for the assay of xanthone and 3-methoxyxanthone in PLGA nanocapsules","volume":"41","author":"Teixeira","year":"2003","journal-title":"J. Chromatogr. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3725","DOI":"10.1016\/S0968-0896(02)00379-6","article-title":"Xanthones as inhibitors of growth of human cancer cell lines and Their effects on the proliferation of human lymphocytes In Vitro","volume":"10","author":"Pedro","year":"2002","journal-title":"Bioorg. Med. Chem."},{"key":"ref_49","unstructured":"Cidade, H., Rocha, V., Palmeira, A., Marques, C., Tiritan, M.E., Ferreira, H., Lobo, J.S., Almeida, I.F., Sousa, M.E., and Pinto, M. (2017). In silico and in vitro antioxidant and cytotoxicity evaluation of oxygenated xanthone derivatives. Arab. J. Chem."},{"key":"ref_50","first-page":"1756","article-title":"Hepatoprotective Activity of Xanthones and Xanthonolignoids Against tert-Butylhydroperoxide-Induced Toxicity in Isolated Rat Hepatocytes\u2014Comparison with Silybin","volume":"12","author":"Fernandes","year":"1995","journal-title":"Pharm. Res. Off. J. Am. Assoc. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1111\/j.1747-0285.2010.01072.x","article-title":"Antifungal Activity of Xanthones: Evaluation of their Effect on Ergosterol Biosynthesis by High-performance Liquid Chromatography","volume":"77","author":"Pinto","year":"2011","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1089\/mdr.2014.0162","article-title":"Synergistic effects between thioxanthones and oxacillin against methicillin-resistant staphylococcus aureus","volume":"21","author":"Bessa","year":"2015","journal-title":"Microb. Drug Resist."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Resende, D.I.S.P., Pereira-Terra, P., Moreira, J., Freitas-Silva, J., Lemos, A., Gales, L., Pinto, E., De Sousa, M.E., Da Costa, P.M., and Pinto, M.M.M. (2020). Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity. Molecules, 25.","DOI":"10.3390\/molecules25102405"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ejmech.2018.03.036","article-title":"Lipid reducing activity and toxicity profiles of a library of polyphenol derivatives","volume":"151","author":"Urbatzka","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Almeida, J.R., Palmeira, A., Campos, A., Cunha, I., Freitas, M., Felpeto, A.B., Turkina, M.V., Vasconcelos, V., Pinto, M., and Correia-Da-silva, M. (2020). Structure-antifouling activity relationship and molecular targets of bio-inspired(Thio)xanthones. Biomolecules, 10.","DOI":"10.3390\/biom10081126"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1002\/1522-2675(20010321)84:3<552::AID-HLCA552>3.0.CO;2-X","article-title":"Natural and Synthetic Xanthones as Monoamine Oxidase Inhibitors: Biological Assay and 3D-QSAR","volume":"84","author":"Gnerre","year":"2001","journal-title":"Helv. Chim. Acta"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1007\/s00204-014-1193-y","article-title":"Induction and activation of P-glycoprotein by dihydroxylated xanthones protect against the cytotoxicity of the P-glycoprotein substrate paraquat","volume":"88","author":"Silva","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Martins, E., Silva, V., Lemos, A., Palmeira, A., Puthongking, P., Sousa, E., Rocha-Pereira, C., Ghanem, C.I., Carmo, H., and Remi\u00e3o, F. (2019). Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies. Molecules, 24.","DOI":"10.3390\/molecules24040707"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1016\/S0968-0896(02)00169-4","article-title":"Synthesis and in vivo modulatory activity of protein kinase C of xanthone derivatives","volume":"10","author":"Saraiva","year":"2002","journal-title":"Bioorg. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/S0968-0896(02)00641-7","article-title":"Inhibition of protein kinase C by synthetic xanthone derivatives","volume":"11","author":"Saraiva","year":"2003","journal-title":"Bioorg. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"115873","DOI":"10.1016\/j.bmc.2020.115873","article-title":"Xanthones for melanogenesis inhibition: Molecular docking and QSAR studies to understand their anti-tyrosinase activity","volume":"29","author":"Rosa","year":"2021","journal-title":"Bioorg. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2862","DOI":"10.1002\/1522-2675(200209)85:9<2862::AID-HLCA2862>3.0.CO;2-R","article-title":"Isomeric Kielcorins and Dihydroxyxanthones: Synthesis, Structure Elucidation, and Inhibitory Activities of Growth of Human Cancer Cell Lines and on the Proliferation of Human Lymphocytes In Vitro","volume":"85","author":"Sousa","year":"2002","journal-title":"Helv. Chim. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.canlet.2019.01.014","article-title":"New inhibitor of the TAp73 interaction with MDM2 and mutant p53 with promising antitumor activity against neuroblastoma","volume":"446","author":"Gomes","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Silva, V., Cerqueira, F., Nazareth, N., Medeiros, R., Sarmento, A., Sousa, E., and Pinto, M. (2019). 1,2-Dihydroxyxanthone: Effect on A375-C5 Melanoma Cell Growth Associated with Interference with THP-1 Human Macrophage Activity. Pharmaceuticals, 12.","DOI":"10.3390\/ph12020085"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.2174\/0929867323666160425113058","article-title":"Drug-like Properties and ADME of Xanthone Derivatives: The Antechamber of Clinical Trials","volume":"23","author":"Gomes","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1007\/s00044-012-0203-y","article-title":"Bioactive xanthones with effect on P-glycoprotein and prediction of intestinal absorption","volume":"22","author":"Sousa","year":"2013","journal-title":"Med. Chem. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Resende, D.I.S.P., Almeida, M.C., Maciel, B., Carmo, H., Sousa Lobo, J., Dal Pozzo, C., Cravo, S.M., Rosa, G.P., Kane-Pag\u00e8s, A., and Do Carmo Barreto, M. (2020). Efficacy, Stability, and Safety Evaluation of New Polyphenolic Xanthones Towards Identification of Bioactive Compounds to Fight Skin Photoaging. Molecules, 25.","DOI":"10.3390\/molecules25122782"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/chir.23142","article-title":"New chiral stationary phases for liquid chromatography based on small molecules: Development, enantioresolution evaluation and chiral recognition mechanisms","volume":"32","author":"Phyo","year":"2020","journal-title":"Chirality"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/chir.22706","article-title":"New chiral stationary phases based on xanthone derivatives for liquid chromatography","volume":"29","author":"Fernandes","year":"2017","journal-title":"Chirality"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1080\/10837450.2019.1638398","article-title":"Development and characterization of PLGA nanoparticles containing 1,3-dihydroxy-2-methylxanthone with improved antitumor activity on a human breast cancer cell line","volume":"24","author":"Teixeira","year":"2019","journal-title":"Pharm. Dev. Technol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ejpb.2004.09.002","article-title":"Development and characterization of PLGA nanospheres and nanocapsules containing xanthone and 3-methoxyxanthone","volume":"59","author":"Teixeira","year":"2005","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Malta, R., Loureiro, J.B., Costa, P., Sousa, E., Pinto, M., Saraiva, L., and Amaral, M.H. (2020). Development of lipid nanoparticles containing the xanthone LEM2 for topical treatment of melanoma. J. Drug Deliv. Sci. Technol.","DOI":"10.1016\/j.jddst.2020.102226"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/cmdc.201900735","article-title":"Yicathins B and C and Analogues: Total Synthesis, Lipophilicity and Biological Activities","volume":"15","author":"Loureiro","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1007\/s00044-020-02544-1","article-title":"Oxygenated xanthones as P-glycoprotein modulators at the intestinal barrier: In vitro and docking studies","volume":"29","author":"Silva","year":"2020","journal-title":"Med. Chem. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/513481a","article-title":"Chemistry: Chemical con artists foil drug discovery","volume":"513","author":"Baell","year":"2014","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1021\/acschembio.7b00903","article-title":"Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017\u2014Utility and Limitations","volume":"13","author":"Baell","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.2174\/138527209788921747","article-title":"Synthesis of prenylated xanthones: An overview","volume":"13","author":"Pinto","year":"2009","journal-title":"Curr. Org. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.ejmech.2013.09.012","article-title":"Pyranoxanthones: Synthesis, growth inhibitory activity on human tumor cell lines and determination of their lipophilicity in two membrane models","volume":"69","author":"Azevedo","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3848","DOI":"10.1016\/j.tet.2009.03.019","article-title":"Improved methodologies for synthesis of prenylated xanthones by microwave irradiation and combination of heterogeneous catalysis (K10 clay) with microwave irradiation","volume":"65","author":"Castanheiro","year":"2009","journal-title":"Tetrahedron"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1016\/j.bmc.2013.03.079","article-title":"Multidimensional optimization of promising antitumor xanthone derivatives","volume":"21","author":"Azevedo","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Fran\u00e7a, F., Silva, P.M.A., Soares, J.X., Henriques, A.C., Loureiro, D.R.P., Azevedo, C.M.G., Afonso, C.M.M., and Bousbaa, H. (2020). A Pyranoxanthone as a Potent Antimitotic and Sensitizer of Cancer Cells to Low Doses of Paclitaxel. Molecules, 25.","DOI":"10.3390\/molecules25245845"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/j.phytochem.2007.01.019","article-title":"Chemistry and pharmacology of oxyprenylated secondary plant metabolites","volume":"68","author":"Epifano","year":"2007","journal-title":"Phytochemistry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0006-2952(01)00810-3","article-title":"Inhibition of cyclooxygenase and prostaglandin E2 synthesis by \u03b3-mangostin, a xanthone derivative in mangosteen, in C6 rat glioma cells11Abbreviations: AA, arachidonic acid; BSA, bovine serum albumin; COX, cyclooxygenase; COX-1, constitutive COX.; COX-2, inducible COX; cPLA2, cytosolic PLA2; EMEM, Eagle\u2019s minimum essential medium; ERK, extracellular signal regulated kinase; HEPES, 2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethanesulfonic acid; MAPK, mitogen-activated protein kinase;PGE2, prostaglandin E2; sPLA2, secretory phospholipase A2; TBST, Tris-buffered saline containing 0.05% Tween 20","volume":"63","author":"Nakatani","year":"2002","journal-title":"Biochem. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6080","DOI":"10.1016\/j.bmc.2007.06.037","article-title":"Dihydroxyxanthones prenylated derivatives: Synthesis, structure elucidation, and growth inhibitory activity on human tumor cell lines with improvement of selectivity for MCF-7","volume":"15","author":"Castanheiro","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3390\/ph2020033","article-title":"Antitumor activity of some prenylated xanthones","volume":"2","author":"Castanheiro","year":"2009","journal-title":"Pharmaceuticals"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1747-0285.2010.00978.x","article-title":"Insights into the in vitro antitumor mechanism of action of a new pyranoxanthone","volume":"76","author":"Palmeira","year":"2010","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1007\/s00044-011-9562-z","article-title":"Prenylated xanthones: Antiproliferative effects and enhancement of the growth inhibitory action of 4-hydroxytamoxifen in estrogen receptor-positive breast cancer cell line","volume":"21","author":"Paiva","year":"2012","journal-title":"Med. Chem. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1021\/np400049j","article-title":"\u03b1-Mangostin and Gambogic Acid as Potential Inhibitors of the p53\u2013MDM2 Interaction Revealed by a Yeast Approach","volume":"76","author":"Gomes","year":"2013","journal-title":"J. Nat. Prod."},{"key":"ref_89","first-page":"789","article-title":"Medicinal Chemistry Strategies to Disrupt the p53\u2013MDM2\/MDMX Interaction","volume":"36","author":"Lemos","year":"2016","journal-title":"Med. Chem. Res."},{"key":"ref_90","unstructured":"Inga, A., Pinto, M.M.d.M., Saraiva, L.H.A., Sousa, M.E.d.S.P.d., Pereira, C.I.F., Paiva, A.M.G., and Le\u00e3o, M.V.C.F. (2013). Inhibitors of p53-mdm2 Interaction. (WO\/2013\/105037)."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1016\/j.ejmech.2017.10.074","article-title":"DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions","volume":"143","author":"Liu","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.ijpharm.2013.07.017","article-title":"Development of noncytotoxic PLGA nanoparticles to improve the effect of a new inhibitor of p53-MDM2 interaction","volume":"454","author":"Paiva","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_93","first-page":"224","article-title":"Development and validation of an HPLC method for the quantification of a cytotoxic dihydropyranoxanthone in biodegradable nanoparticles","volume":"5","author":"Paiva","year":"2013","journal-title":"Int. J. Drug Deliv."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.gdata.2015.02.001","article-title":"Transcription profiling of the Neurospora crassa response to a group of synthetic (thio)xanthones and a natural acetophenone","volume":"4","author":"Silva","year":"2015","journal-title":"Genom. Data"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Le Pogam, P., and Boustie, J. (2016). Xanthones of Lichen Source: A 2016 Update. Molecules, 21.","DOI":"10.3390\/molecules21030294"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1039\/b110543b","article-title":"Lichens as a potential source of pesticides","volume":"12","author":"Dayan","year":"2001","journal-title":"Pestic. Outlook"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3830","DOI":"10.1016\/j.ejmech.2009.04.011","article-title":"Bromoalkoxyxanthones as promising antitumor agents: Synthesis, crystal structure and effect on human tumor cell lines","volume":"44","author":"Sousa","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/mrc.3903","article-title":"Three new xanthone derivatives from an algicolous isolate of Aspergillus wentii","volume":"51","author":"Sun","year":"2013","journal-title":"Magn. Reson. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.4155\/fmc-2017-0086","article-title":"Dual\/multitargeted xanthone derivatives for Alzheimer\u2019s disease: Where do we stand?","volume":"9","author":"Cruz","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1155\/2017\/8587260","article-title":"Xanthone and Flavone Derivatives as Dual Agents with Acetylcholinesterase Inhibition and Antioxidant Activity as Potential Anti-Alzheimer Agents","volume":"2017","author":"Cruz","year":"2017","journal-title":"J. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Lemos, A., Gomes, A.S., Loureiro, J.B., Brand\u00e3o, P., Palmeira, A., Pinto, M.M.M., Saraiva, L., and Sousa, M.E. (2019). Synthesis, Biological Evaluation, and In Silico Studies of Novel Aminated Xanthones as Potential p53-Activating Agents. Molecules, 24.","DOI":"10.3390\/molecules24101975"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1016\/j.bmc.2004.03.060","article-title":"Definition of an electronic profile of compounds with inhibitory activity against hematin aggregation in malaria parasite","volume":"12","author":"Portela","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0014-5793(03)00692-6","article-title":"Receptor\u2013drug association studies in the inhibition of the hematin aggregation process of malaria","volume":"547","author":"Portela","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1023\/B:JCAM.0000005754.24588.a0","article-title":"Computational studies of new potential antimalarial compounds\u2014Stereoelectronic complementarity with the receptor","volume":"17","author":"Portela","year":"2003","journal-title":"J. Comput.-Aided Mol. Des."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1002\/cbdv.200790130","article-title":"Synthesis and Antimalarial Properties of New Chloro-9H-xanthones with an Aminoalkyl Side Chain","volume":"4","author":"Portela","year":"2007","journal-title":"Chem. Biodivers."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Neves, A.R., Correia-da-Silva, M., Sousa, E., and Pinto, M. (2016). Strategies to overcome heparins\u2019 low oral bioavailability. Pharmaceuticals, 9.","DOI":"10.3390\/ph9030037"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.4155\/fmc.13.117","article-title":"The promise of sulfated synthetic small molecules as modulators of glycosaminoglycan function","volume":"5","author":"Desai","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"5373","DOI":"10.1021\/jm2006589","article-title":"Polysulfated Xanthones: Multipathway Development of a New Generation of Dual Anticoagulant\/Antiplatelet Agents","volume":"54","author":"Sousa","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s12944-017-0449-y","article-title":"Mangiferin: A natural miracle bioactive compound against lifestyle related disorders","volume":"16","author":"Imran","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"36","DOI":"10.4103\/0976-9668.127282","article-title":"Elucidating the specificity of non-heparin-based conformational activators of antithrombin for factor Xa inhibition","volume":"5","author":"Rashid","year":"2014","journal-title":"J. Nat. Sci. Biol. Med."},{"key":"ref_111","unstructured":"Pinto, M., Sousa, M.E., Da Silva, M.C., Marques, F., and Carvalho, F. (2011). Patente Portuguesa N\u00ba 104739: Xantonas Sulfatadas e An\u00e1logos Xant\u00f3nicos Glicosilados Sulfatados com Actividade Anticoagulante e Processos Para a Sua Prepara\u00e7\u00e3o. (Portuguese Patent n\u00ba 104739, Boletim da Propriedade Industrial n\u00ba 47\/2011)."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.4155\/fmc-2015-0020","article-title":"Structure-activity relationship studies for multitarget antithrombotic drugs","volume":"8","author":"Neves","year":"2016","journal-title":"Future Med. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s11239-012-0712-z","article-title":"Limitations of conventional anticoagulant therapy and the promises of non-heparin based conformational activators of antithrombin","volume":"34","author":"Rashid","year":"2012","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Kaltenbach, D.D., Jaishankar, D., Hao, M., Beer, J.C., Volin, M.V., Desai, U.R., and Tiwari, V. (2018). Sulfotransferase and Heparanase: Remodeling Engines in Promoting Virus Infection and Disease Development. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01315"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3412","DOI":"10.2174\/0929867325666181120101147","article-title":"Sulfated Non-Saccharide Glycosaminoglycan Mimetics as Novel Drug Discovery Platform for Various Pathologies","volume":"27","author":"Daniel","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/cbdd.12109","article-title":"Sulfated small molecules targeting EBV in Burkitt lymphoma: From in silico screening to the evidence of in vitro effect on viral episomal DNA","volume":"81","author":"Lima","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1080\/08927014.2017.1391951","article-title":"An antifouling model from the sea: A review of 25 years of zosteric acid studies","volume":"33","author":"Sousa","year":"2017","journal-title":"Biofouling"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Almeida, J.R., Correia-Da-Silva, M., Sousa, E., Antunes, J., Pinto, M., Vasconcelos, V., and Cunha, I. (2017). Antifouling potential of Nature-inspired sulfated compounds. Sci. Rep., 7.","DOI":"10.1038\/srep42424"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Alves, A., Correia-da-Silva, M., Nunes, C., Campos, J., Sousa, E., Silva, P.M.A., Bousbaa, H., Rodrigues, F., Ferreira, D., and Costa, P.C. (2019). Discovery of a new xanthone against glioma: Synthesis and Development of (Pro)liposome Formulations. Molecules, 24.","DOI":"10.3390\/molecules24030409"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Neves, A.R., Correia-da-Silva, M., Silva, P.M.A., Ribeiro, D., Sousa, E., Bousbaa, H., and Pinto, M. (2018). Synthesis of new glycosylated flavonoids with inhibitory activity on cell growth. Molecules, 23.","DOI":"10.3390\/molecules23051093"},{"key":"ref_121","unstructured":"Kirk-Othmer, M. (2016). Chiral pharmaceuticals. Encyclopedia of Chemical Technology, John Wiley & Sons, Inc."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s11101-014-9385-x","article-title":"Drugs based on natural compounds: Recent achievements and future perspectives","volume":"13","author":"Lanzotti","year":"2014","journal-title":"Phytochem. Rev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.2174\/138527212804546921","article-title":"Routes to Xanthones: An Update on the Synthetic Approaches","volume":"16","year":"2012","journal-title":"Curr. Org. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s12210-012-0220-2","article-title":"Chirality and its implications for the pharmaceutical industry","volume":"24","author":"Blaser","year":"2013","journal-title":"Rend. Lincei"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Fernandes, C., Carraro, M.L., Ribeiro, J., Araujo, J., Tiritan, M.E., and Pinto, M.M.M. (2019). Synthetic chiral derivatives of xanthones: Biological activities and enantioselectivity studies. Molecules, 24.","DOI":"10.3390\/molecules24040791"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Ara\u00fajo, J., Fernandes, C., Pinto, M., and Elizabeth Tiritan, M. (2019). Chiral derivatives of xanthones with antimicrobial activity. Molecules, 24.","DOI":"10.3390\/molecules24020314"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/0929867033368574","article-title":"Natural and synthetic xanthonolognoids: Chemistry and biological activities","volume":"10","author":"Pinto","year":"2003","journal-title":"Curr. Med. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3987\/COM-98-8371","article-title":"Synthesis and structural elucidation of xanthonolignoids: Trans-(\u00b1)- kielcorin B and trans-(\u00b1)-isokielcorin B","volume":"51","author":"Fernandes","year":"1999","journal-title":"Heterocycles"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1081\/JLC-120017150","article-title":"Quantitative Analysis of Kielcorins in Biomimetic Synthesis by Liquid Chromatography\/UV Detection","volume":"26","author":"Afonso","year":"2003","journal-title":"J. Liq. Chromatogr. Relat. Technol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/147563601000118400","article-title":"Inhibition of \u03b1, \u03b2I, \u03b4, \u03b7 and \u03b6 protein kinase C isoforms by xanthonolignoids","volume":"18","author":"Saraiva","year":"2003","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/chir.20031","article-title":"Enantiomeric resolution of kielcorin derivatives by HPLC on polysaccharide stationary phases using multimodal elution","volume":"16","author":"Sousa","year":"2004","journal-title":"Chirality"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.jchromb.2018.10.002","article-title":"Multi-milligram resolution and determination of absolute configuration of pentedrone and methylone enantiomers","volume":"1100\u20131101","author":"Silva","year":"2018","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Pinto, M.M.M., Fernandes, C., and Tiritan, M.E. (2020). Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View. Molecules, 25.","DOI":"10.3390\/molecules25081931"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.chroma.2005.12.071","article-title":"Multimilligram enantioresolution of low-solubility xanthonolignoids on polysaccharide chiral stationary phases using a solid-phase injection system","volume":"1120","author":"Sousa","year":"2006","journal-title":"J. Chromatogr. A"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.bmc.2013.12.042","article-title":"New chiral derivatives of xanthones: Synthesis and investigation of enantioselectivity as inhibitors of growth of human tumor cell lines","volume":"22","author":"Fernandes","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"10285","DOI":"10.1002\/slct.202002588","article-title":"Synthesis of New Chiral Derivatives of Xanthones with Enantioselective Effect on Tumor Cell Growth and DNA Crosslinking","volume":"5","author":"Carraro","year":"2020","journal-title":"ChemistrySelect"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejmech.2012.06.049","article-title":"Synthesis of new chiral xanthone derivatives acting as nerve conduction blockers in the rat sciatic nerve","volume":"55","author":"Fernandes","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Ribeiro, J., Veloso, C., Fernandes, C., Tiritan, M.E., and Pinto, M.M.M. (2019). Carboxyxanthones: Bioactive agents and molecular scaffold for synthesis of analogues and derivatives. Molecules, 24.","DOI":"10.3390\/molecules24010180"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1021\/ol201005s","article-title":"Efficient and Controllably Selective Preparation of Esters Using Uronium-Based Coupling Agents","volume":"13","author":"Twibanire","year":"2011","journal-title":"Org. Lett."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Fernandes, C., Palmeira, A., Ramos, I.I., Carneiro, C., Afonso, C., Tiritan, M.E., Cidade, H., Pinto, P.C.A.G., Saraiva, M.L.M.F.S., and Reis, S. (2017). Chiral derivatives of xanthones: Investigation of the effect of enantioselectivity on inhibition of cyclooxygenases (COX-1 and COX-2) and binding interaction with human serum albumin. Pharmaceuticals, 10.","DOI":"10.3390\/ph10020050"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jchromb.2017.10.018","article-title":"Lipophilicity assessement in drug discovery: Experimental and theoretical methods applied to xanthone derivatives","volume":"1072","author":"Santos","year":"2018","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/chir.22112","article-title":"Enantioresolution of Chiral Derivatives of Xanthones on (S,S)-Whelk-O1 and l-Phenylglycine Stationary Phases and Chiral Recognition Mechanism by Docking Approach for (S,S)-Whelk-O1","volume":"25","author":"Fernandes","year":"2013","journal-title":"Chirality"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/chir.22703","article-title":"Resolution, determination of enantiomeric purity and chiral recognition mechanism of new xanthone derivatives on (S,S)-whelk-O1 stationary phase","volume":"29","author":"Carraro","year":"2017","journal-title":"Chirality"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.chroma.2012.04.011","article-title":"Enantioseparation and chiral recognition mechanism of new chiral derivatives of xanthones on macrocyclic antibiotic stationary phases","volume":"1241","author":"Fernandes","year":"2012","journal-title":"J. Chromatogr. A"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Phyo, Y.Z., Cravo, S., Palmeira, A., Tiritan, M.E., Kijjoa, A., Pinto, M.M.M., and Fernandes, C. (2018). Enantiomeric Resolution and Docking Studies of Chiral Xanthonic Derivatives on Chirobiotic Columns. Molecules, 23.","DOI":"10.3390\/molecules23010142"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.4155\/bio-2019-0074","article-title":"Enantioseparation, recognition mechanisms and binding of xanthones on human serum albumin by liquid chromatography","volume":"11","author":"Phyo","year":"2019","journal-title":"Bioanalysis"},{"key":"ref_147","unstructured":"Pinto, M., Tiritan, M.E., Fernandes, C., and Cass, Q. (2011). Fases Estacion\u00e1rias Quirais baseadas em Derivados Xant\u00f3nicos. (WO\/2011\/010284A2)."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s10337-013-2469-8","article-title":"Small Molecules as Chromatographic Tools for HPLC Enantiomeric Resolution: Pirkle-Type Chiral Stationary Phases Evolution","volume":"76","author":"Fernandes","year":"2013","journal-title":"Chromatographia"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1023\/A:1006267517726","article-title":"Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin","volume":"17","author":"Corbett","year":"1999","journal-title":"Investig. New Drugs"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1007\/s002800050971","article-title":"Phase I\/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule","volume":"44","author":"Stevenson","year":"1999","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4269\/ajtmh.1985.34.112","article-title":"Studies on the Mode of Action of Oxamniquine and Related Schistosomicidal Drugs","volume":"34","author":"Cioli","year":"1985","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1021\/jm00317a025","article-title":"Hycanthone,1 a New Active Metabolite of Lucanthone2","volume":"10","author":"Rosi","year":"1967","journal-title":"J. Med. Chem."},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Naidu, M.D., Agarwal, R., Pena, L.A., Cunha, L., Mezei, M., Shen, M., Wilson, D.M., Liu, Y., Sanchez, Z., and Chaudhary, P. (2011). Lucanthone and Its Derivative Hycanthone Inhibit Apurinic Endonuclease-1 (APE1) by Direct Protein Binding. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023679"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0163-7258(95)00026-7","article-title":"Antischistosomal drugs: Past, present \u2026 and future?","volume":"68","author":"Cioli","year":"1995","journal-title":"Pharmacol. Ther."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1080\/15287397509529326","article-title":"Mutagenic evaluation of antischistosomal drugs and their derivatives in Neurospora crassa","volume":"1","author":"Ong","year":"1975","journal-title":"J. Toxicol. Environ. Health"},{"key":"ref_156","first-page":"3088","article-title":"Phase I Pharmacokinetic Study of the Novel Antitumor Agent SR233377","volume":"6","author":"LoRusso","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s10637-008-9135-2","article-title":"Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies","volume":"26","author":"Goncalves","year":"2008","journal-title":"Investig. New Drugs"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/COC.0b013e318178331b","article-title":"A Phase I Dose-Escalation Study of SR271425, an Intravenously Dosed Thioxanthone Analog, Administered Weekly in Patients With Refractory Solid Tumors","volume":"32","author":"Lockhart","year":"2009","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1097\/01.coc.0000255604.32888.b5","article-title":"QTc Monitoring During a Phase I Study: Experience With SR271425","volume":"30","author":"Soria","year":"2007","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"339","DOI":"10.15171\/apb.2017.041","article-title":"The Different Mechanisms of Cancer Drug Resistance: A Brief Review","volume":"7","author":"Mansoori","year":"2017","journal-title":"Adv. Pharm. Bull."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1126\/science.aar7389","article-title":"Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation","volume":"359","author":"Kim","year":"2018","journal-title":"Science"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"7468","DOI":"10.1038\/sj.onc.1206948","article-title":"P-glycoprotein: From genomics to mechanism","volume":"22","author":"Ambudkar","year":"2003","journal-title":"Oncogene"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"4197","DOI":"10.2174\/138161212802430530","article-title":"Structure and Ligand-based design of P-glycoprotein inhibitors: A historical perspective","volume":"18","author":"Palmeira","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.pharmthera.2006.10.003","article-title":"How can we best use structural information on P-glycoprotein to design inhibitors?","volume":"113","author":"McDevitt","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.1365-2710.2003.00487.x","article-title":"Structure\u2013activity relationship: Analyses of p-glycoprotein substrates and inhibitors","volume":"28","author":"Wang","year":"2003","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.2174\/092986712800167392","article-title":"Three decades of P-gp Inhibitors: Skimming through several generations and scaffolds","volume":"19","author":"Palmeira","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S1359-6446(04)03163-0","article-title":"From magic bullets to designed multiple ligands","volume":"9","author":"Morphy","year":"2004","journal-title":"Drug Discov. Today"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"587","DOI":"10.2174\/138161209787315594","article-title":"Designing Multiple Ligands\u2014Medicinal Chemistry Strategies and Challenges","volume":"15","author":"Richard","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40169-017-0181-2","article-title":"A perspective on multi-target drug discovery and design for complex diseases","volume":"7","author":"Ramsay","year":"2018","journal-title":"Clin. Transl. Med."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.bcp.2011.10.004","article-title":"Dual inhibitors of P-glycoprotein and tumor cell growth: (Re)discovering thioxanthones","volume":"83","author":"Palmeira","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1747-0285.2011.01089.x","article-title":"New Uses for Old Drugs: Pharmacophore-Based Screening for the Discovery of P-Glycoprotein Inhibitors","volume":"78","author":"Palmeira","year":"2011","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1111\/j.1432-1033.1997.00664.x","article-title":"Competitive and Non-Competitive Inhibition of the Multidrug-Resistance-Associated P-glycoprotein ATPase","volume":"244","author":"Garrigos","year":"1997","journal-title":"Eur. J. Biochem."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0925-4439(97)00027-6","article-title":"Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity","volume":"1361","author":"Litman","year":"1997","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cbi.2014.04.009","article-title":"Colchicine effect on P-glycoprotein expression and activity: In silico and in vitro studies","volume":"218","author":"Silva","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Barbosa, J., Lima, R.T., Sousa, D., Gomes, A.S., Palmeira, A., Seca, H., Choosang, K., Pakkong, P., Bousbaa, H., and Pinto, M.M. (2016). Screening a small library of xanthones for antitumor activity and identification of a hit compound which induces apoptosis. Molecules, 21.","DOI":"10.3390\/molecules21010081"},{"key":"ref_176","unstructured":"(2020, November 25). Safety and Efficacy Study of Lucanthone When Used in Combination With Temozolomide(TMZ) and Radiation to Treat Glioblastoma Multiforme(GBM), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01587144."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Lima, R.T., Sousa, D., Paiva, A.M., Palmeira, A., Barbosa, J., Pedro, M., Pinto, M.M., Sousa, E., and Vasconcelos, M.H. (2016). Modulation of autophagy by a thioxanthone decreases the viability of melanoma cells. Molecules, 21.","DOI":"10.3390\/molecules21101343"},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Lima, R.T., Sousa, D., Gomes, A.S., Mendes, N., Matthiesen, R., Pedro, M., Marques, F., Pinto, M.M., Sousa, E., and Helena Vasconcelos, M. (2018). The antitumor activity of a lead thioxanthone is associated with alterations in cholesterol localization. Molecules, 23.","DOI":"10.3390\/molecules23123301"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"31","DOI":"10.18433\/J3BG65","article-title":"Multidrug resistance reversal effects of aminated thioxanthones and interaction with cytochrome P450 3A4","volume":"15","author":"Palmeira","year":"2011","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1021\/cn100078a","article-title":"The \u201cSpecific\u201d P-Glycoprotein Inhibitor Tariquidar Is Also a Substrate and an Inhibitor for Breast Cancer Resistance Protein (BCRP\/ABCG2)","volume":"2","author":"Kannan","year":"2011","journal-title":"ACS Chem. Neurosci."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Lopes, A., Martins, E., Silva, R., Pinto, M.M.M., Remi\u00e3o, F., Sousa, E., and Fernandes, C. (2018). Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies. Molecules, 23.","DOI":"10.3390\/molecules23030626"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2014.11.013","article-title":"Modulation of P-glycoprotein efflux pump: Induction and activation as a therapeutic strategy","volume":"149","author":"Silva","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1124\/mol.62.3.638","article-title":"Nuclear Pregnane X Receptor and Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic Detoxification","volume":"62","author":"Maglich","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1007\/s00204-014-1333-4","article-title":"P-glycoprotein induction in Caco-2 cells by newly synthetized thioxanthones prevents paraquat cytotoxicity","volume":"89","author":"Silva","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Ferreira, A.F., Ponte, F., Silva, R., Rocha-Pereira, C., Sousa, E., Pinto, M., Bastos, M.D.L., and Remi\u00e3o, F. (2017). Quantification of 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5), a newly synthetized P-glycoprotein inducer\/activator, in biological samples: Method development and validation. Biomed. Chromatogr., 31.","DOI":"10.1002\/bmc.3802"},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Silva, V., Gil-Martins, E., Silva, B., Rocha-Pereira, C., Sousa, M.E., Remi\u00e3o, F., and Silva, R. (2020). Xanthones as P-glycoprotein modulators and their impact on drug bioavailability. Expert Opin. Drug Metab. Toxicol.","DOI":"10.1080\/17425255.2021.1861247"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/2\/431\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:11:33Z","timestamp":1760159493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/2\/431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,15]]},"references-count":186,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["molecules26020431"],"URL":"https:\/\/doi.org\/10.3390\/molecules26020431","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,15]]}}}