uni-leipzig-open-access/json/cmdc.202300094

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Cancer cells exploit efflux transporters, like the breast cancer resistance protein (BCRP, ABCG2), to secrete chemotherapeutic substances. In this study, an <jats:italic>N<\/jats:italic>\u2010phenyl\u20102\u2010carboranylquinazolin\u20104\u2010amine (<jats:bold>8<\/jats:bold>) was designed as inorganic\u2010organic hybrid BCRP inhibitor. In particular, the ABCG2\u2010transporter inhibitor\u2010prominent scaffold <jats:italic>N<\/jats:italic>\u2010phenylquinazolin\u20104\u2010amine was combined with a boron\u2212carbon cluster (carborane) moiety. Introducing a carborane at 2\u2010position of the quinazoline scaffold resulted in an increased inhibitory activity towards human ABCG2 (hABCG2) compared to its recently published regioisomer <jats:italic>N<\/jats:italic>\u2010carboranyl\u20102\u2010phenyl\u2010quinazolin\u20104\u2010amine. The carboranylquinazoline <jats:bold>8<\/jats:bold> further showed the ability to reverse hABCG2\u2010mediated drug resistance in MDCKII\u2010hABCG2 cells by lowering the IC<jats:sub>50<\/jats:sub> value of the BCRP\u2010substrate mitoxantrone, similar to the standard reference and strong inhibitor Ko143, without exhibiting intrinsic toxicity in the lower micromolar ranges. These results make compound <jats:bold>8<\/jats:bold> a promising scaffold for the design of further BCRP inhibitors.<\/jats:p>","DOI":"10.1002\/cmdc.202300094","type":"journal-article","created":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T12:35:52Z","timestamp":1680093352000},"update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["2\u2010Carboranylquinazoline: The Path to an ABCG2 Inhibitor"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"http:\/\/orcid.org\/0000-0002-4174-8539","authenticated-orcid":false,"given":"Philipp","family":"Stockmann","sequence":"first","affiliation":[{"name":"Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy Universit\u00e4t Leipzig  Johannisallee 29 04103 Leipzig Germany"}]},{"ORCID":"http:\/\/orcid.org\/0000-0002-9779-2440","authenticated-orcid":false,"given":"Lydia","family":"Kuhnert","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Pharmacy and Toxicology Faculty of Veterinary Medicine Universit\u00e4t Leipzig  An den Tierkliniken 15 04103 Leipzig Germany"}]},{"given":"Lisa","family":"Z\u00f6rner","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy Universit\u00e4t Leipzig  Johannisallee 29 04103 Leipzig Germany"}]},{"ORCID":"http:\/\/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  An den Tierkliniken 15 04103 Leipzig Germany"}]},{"ORCID":"http:\/\/orcid.org\/0000-0003-4267-0603","authenticated-orcid":false,"given":"Evamarie","family":"Hey\u2010Hawkins","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry Faculty of Chemistry and Mineralogy Universit\u00e4t Leipzig  Johannisallee 29 04103 Leipzig Germany"}]}],"member":"311","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6031769"},{"key":"e_1_2_9_2_1","unstructured":"\u00a0"},{"key":"e_1_2_9_3_2","first-page":"6175","volume":"52","author":"Nakagawa M.","year":"1992","journal-title":"Cancer Res."},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1360704"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(76)90160-7"},{"key":"e_1_2_9_6_1","unstructured":"\u00a0"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.1.265"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201411164"},{"key":"e_1_2_9_9_1","unstructured":"\u00a0"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.12703\/P7-14"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2008.07.004"},{"key":"e_1_2_9_12_2","first-page":"8","volume":"59","author":"Miyake K.","year":"1999","journal-title":"Cancer Res."},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.184901"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-014-9668-6"},{"key":"e_1_2_9_15_1","unstructured":"\u00a0"},{"key":"e_1_2_9_16_2","first-page":"1","volume":"3","author":"Mo W.","year":"2012","journal-title":"Int. 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