{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:02:56Z","timestamp":1772118176098,"version":"3.50.1"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T00:00:00Z","timestamp":1699228800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off\u2010target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc\u2010binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild\u2010type and NTR\u2010transfected THP1 cells. Cellular assays showed that both 2\u2010nitroimidazole\u2010based prodrugs\n                    <jats:bold>5<\/jats:bold>\n                    and\n                    <jats:bold>6<\/jats:bold>\n                    were best activated by the NTR and exhibited potent activity against NTR\u2010THP1 cells. Compound\n                    <jats:bold>6<\/jats:bold>\n                    showed the highest cellular activity (GI\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200977\u2009nM) and exhibited moderate selectivity. Moreover, activation of prodrug\n                    <jats:bold>6<\/jats:bold>\n                    by NTR was confirmed by liquid chromatography\u2010mass spectrometry analysis, which showed the release of the parent inhibitor after incubation with\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    NTR. Thus, compound\n                    <jats:bold>6<\/jats:bold>\n                    can be considered a novel prodrug selective for class I HDACs, which could be used as a good starting point for increasing selectivity and for further optimization.\n                  <\/jats:p>","DOI":"10.1002\/ardp.202300536","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T21:13:16Z","timestamp":1699305196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells"],"prefix":"10.1002","volume":"357","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6559-2527","authenticated-orcid":false,"given":"Mohamed","family":"Abdelsalam","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry Martin\u2010Luther University of Halle\u2010Wittenberg  Halle\/Saale Germany"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Alexandria University  Alexandria Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariia","family":"Zmyslia","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry University of Freiburg  Freiburg i. Br. Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Schmidtkunz","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences University of Freiburg  Freiburg i. Br. Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Vecchio","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Martin\u2010Luther University of Halle\u2010Wittenberg  Halle\/Saale Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0611-7365","authenticated-orcid":false,"given":"Sebastian","family":"Hilscher","sequence":"additional","affiliation":[{"name":"Department of Enzymology, Institute of Biochemistry Martin\u2010Luther\u2010University of Halle\u2010Wittenberg  Halle\/Saale Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1048-4059","authenticated-orcid":false,"given":"Hany S.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Martin\u2010Luther University of Halle\u2010Wittenberg  Halle\/Saale Germany"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy Egyptian Russian University  Cairo Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0919-7076","authenticated-orcid":false,"given":"Mike","family":"Schutkowski","sequence":"additional","affiliation":[{"name":"Department of Enzymology, Institute of Biochemistry Martin\u2010Luther\u2010University of Halle\u2010Wittenberg  Halle\/Saale Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6361-7716","authenticated-orcid":false,"given":"Manfred","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences University of Freiburg  Freiburg i. Br. Germany"},{"name":"CIBSS \u2013 Centre for Integrative Biological Signalling Studies University of Freiburg  Freiburg i. Br. Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4216-8189","authenticated-orcid":false,"given":"Claudia","family":"Jessen\u2010Trefzer","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry University of Freiburg  Freiburg i. Br. Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-9261","authenticated-orcid":false,"given":"Wolfgang","family":"Sippl","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Martin\u2010Luther University of Halle\u2010Wittenberg  Halle\/Saale Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,11,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb500846u"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2011.22"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2015.00108"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a018713"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0382-4"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9030780"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2007.01.001"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0b013e3283127095"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2022.948217"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.576391"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2017.1417274"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-013-0226-1"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000934"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml300081u"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0388-4"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2185"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201500486"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010369"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm701079h"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph3092751"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920107783018417"},{"key":"e_1_2_7_23_1","first-page":"1057","volume":"18","author":"Gao X.","year":"2019","journal-title":"Exp. 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