{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:34:55Z","timestamp":1790710495114,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["He 1376\/54\u20101"],"award-info":[{"award-number":["He 1376\/54\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,2,12]]},"abstract":"<jats:p>\n                    ABCG2\u2010mediated multidrug resistance (MDR) is a major challenge among chemotherapeutic treatments of colon, pancreatic, and breast cancer, as well as leukemia. Clinical oncology seeks new adjuvant therapeutics to overcome MDR by developing potent but nontoxic ABCG2 inhibitors. Aided by computational docking analyses, based on known substrate and inhibitor structural motifs, a new isoquinolinone framework and several (poly)methoxylated derivatives were designed and synthesized. The novel carborane\u2010containing\n                    <jats:italic>N<\/jats:italic>\n                    \u2010carboranyl isoquinolinones were evaluated for cytotoxicity, ABCG2 inhibition, and reversal of MDR in combination with mitoxantrone (MXN) in an ABCG2\u2010expressing Madin\u2013Darby canine kidney II cell model. While the parental compound\n                    <jats:bold>IC\u20101<\/jats:bold>\n                    showed strong ABCG2 inhibition, its 4\u2010methoxyphenyl, 3,4\u2010dimethoxyphenyl, and 3,4,5\u2010trimethoxyphenyl derivatives (\n                    <jats:bold>IC\u20104<\/jats:bold>\n                    ,\n                    <jats:bold>IC\u20105,<\/jats:bold>\n                    and\n                    <jats:bold>IC\u20106<\/jats:bold>\n                    ) exhibited improved ABCG2 affinity. Nonsubstituted isoquinolinones\n                    <jats:bold>IC\u20101<\/jats:bold>\n                    to\n                    <jats:bold>IC\u20106<\/jats:bold>\n                    displayed higher solubility, lower toxicity, and similar ABCG2 inhibition and reversal of MXN resistance than 6,7\u2010dimethoxy\u2010isoquinolinone derivatives\n                    <jats:bold>IC\u20107<\/jats:bold>\n                    to\n                    <jats:bold>IC\u201011<\/jats:bold>\n                    . Especially, the 4\u2010methoxyphenyl\u2010 and 3,4\u2010dimethoxyphenyl\u2010substituted isoquinolinones (\n                    <jats:bold>IC\u201010<\/jats:bold>\n                    ,\n                    <jats:bold>IC\u201011<\/jats:bold>\n                    ) caused the strongest left shift of the MXN IC\n                    <jats:sub>50<\/jats:sub>\n                    value by 8.1\u2010 and 7.2\u2010fold, indicating effective resensitization to the chemotherapeutic agent. Therefore, carborane\u2010containing isoquinolinones featuring additional methoxy groups represent a promising approach for the development of ABCG2 inhibitors to overcome resistance to anticancer drugs.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500708","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T19:20:24Z","timestamp":1770924024000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Polymethoxylated\n                    <i>N<\/i>\n                    \u2010Carboranyl Isoquinolinones: A New Scaffold for ABCG2 Inhibitors"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9779-2440","authenticated-orcid":false,"given":"Lydia","family":"Kuhnert","sequence":"first","affiliation":[{"name":"Institute of Pharmacology Pharmacy and Toxicology Faculty of Veterinary Medicine Universit\u00e4t Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4174-8539","authenticated-orcid":false,"given":"Philipp","family":"Stockmann","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy Universit\u00e4t Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1335-0897","authenticated-orcid":false,"given":"Peter","family":"L\u00f6nnecke","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy Universit\u00e4t Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara Anna","family":"Wolniewicz","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy Universit\u00e4t Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4267-0603","authenticated-orcid":false,"given":"Evamarie","family":"Hey\u2010Hawkins","sequence":"additional","affiliation":[{"name":"Centre for Biotechnology and Biomedicine (BBZ) Faculty of Chemistry and Mineralogy Institute of Bioanalytical Chemistry Universit\u00e4t Leipzig  Leipzig Germany"},{"name":"Faculty of Chemistry and Chemical Engineering Department of Chemistry Babe\u015f\u2010Bolyai University  Cluj\u2010Napoca Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5954-0659","authenticated-orcid":false,"given":"Walther","family":"Honscha","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Pharmacy and Toxicology Faculty of Veterinary Medicine Universit\u00e4t Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"World Cancer Report. Cancer Research for Cancer Prevention","author":"Wild C.","year":"2020"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.15171\/apb.2017.041"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1706"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0609\u2010546"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6031769"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.648407"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567201043480036"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.71.102301.093055"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010018\u20100005\u20108"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.132225"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.1.265"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.12.010"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2018.09.019"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/jebm.12434"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010021\u201003901\u2010y"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114628"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs\u20102021\u20100116"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01011"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.117542"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.03.067"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.08.020"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00330"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116219"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00441"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15010241"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21428"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0031\u20109422(97)89023\u20101"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2024.116417"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00809"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1039\/D5MD00025D"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2018.04.016"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.2478\/jtim\u20102024\u20100011"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CS00197B"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph16111582"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202300506"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878\u20100261.13527"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.01.012"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00963"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106481"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15041259"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.09.010"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202100588"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2020.131150"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201103051"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo100980p"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b05505"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms231911595"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00208"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22345"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201016155\u20102"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo500355k"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1006\/snmr.2002.0063"},{"key":"e_1_2_9_54_1","volume-title":"Rigaku Oxford Diffraction","author":"Rigaku Corporation UK","year":"2023"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2053273314026370"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2053229614024218"},{"key":"e_1_2_9_57_1","volume-title":"Diamond 4 version 4.6.8\u2014Crystal and Molecular Structure Visualization","author":"Brandenburg K.","year":"2022"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202000106"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500708","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202500708","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500708","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T14:31:57Z","timestamp":1771252317000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202500708"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":57,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,2,12]]}},"alternative-id":["10.1002\/cmdc.202500708"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202500708","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]},"assertion":[{"value":"2025-08-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500708"}}