{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:24:27Z","timestamp":1790807067124,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004505","name":"Universit\u00e0 di Catania","doi-asserted-by":"publisher","award":["Programma Ricerca di Ateneo Pia.Ce.Ri 2020\u20132022 Linea 3"],"award-info":[{"award-number":["Programma Ricerca di Ateneo Pia.Ce.Ri 2020\u20132022 Linea 3"]}],"id":[{"id":"10.13039\/501100004505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004505","name":"Universit\u00e0 di Catania","doi-asserted-by":"publisher","award":["POLYPHARMA-CT"],"award-info":[{"award-number":["POLYPHARMA-CT"]}],"id":[{"id":"10.13039\/501100004505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004505","name":"Universit\u00e0 di Catania","doi-asserted-by":"publisher","award":["57722172141"],"award-info":[{"award-number":["57722172141"]}],"id":[{"id":"10.13039\/501100004505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004505","name":"Universit\u00e0 di Catania","doi-asserted-by":"publisher","award":["Programma Ricerca di Ateneo Pia.Ce.Ri 2020\u20132022 linea 2"],"award-info":[{"award-number":["Programma Ricerca di Ateneo Pia.Ce.Ri 2020\u20132022 linea 2"]}],"id":[{"id":"10.13039\/501100004505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004505","name":"Universit\u00e0 di Catania","doi-asserted-by":"publisher","award":["57722172126"],"award-info":[{"award-number":["57722172126"]}],"id":[{"id":"10.13039\/501100004505","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":[[2023,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In this work, we extend the concept of 5\u2010fluorouracil\/heme oxygenase 1 (5\u2010FU\/HO\u20101) inhibitor hybrid as an effective strategy for enhancing 5\u2010FU\u2010based anticancer therapies. For this purpose, we designed and synthesized new mutual prodrugs, named SI 1\/20 and SI 1\/22, in which the two active parent drugs (i.\u2009e., 5\u2010FU and an imidazole\u2010based HO\u20101 inhibitor) were connected through an easily cleavable succinic linker. Experimental hydrolysis rate, and <jats:italic>in silico<\/jats:italic> ADMET predictions were indicative of good drug\u2010likeness and pharmacokinetic properties. Novel hybrids significantly reduced the viability of prostate DU145 cancer cells compared to the parent compounds 5\u2010FU and HO\u20101 inhibitor administered alone or in combination. Interestingly, both compounds showed statistically significant lower toxicity, than 5\u2010FU at the same dose, against non\u2010tumorigenic human benign prostatic hyperplasia (BPH\u20101) cell line. Moreover, the newly synthesized mutual prodrugs inhibited the HO\u20101 activity both in a cell\u2010free model and <jats:italic>in\u2005vitro<\/jats:italic>, as well as downregulated the HO\u20101 expression and increased the reactive oxygen species (ROS) levels.<\/jats:p>","DOI":"10.1002\/cmdc.202300047","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T05:31:18Z","timestamp":1675920678000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Discovery of SI 1\/20 and SI 1\/22 as Mutual Prodrugs of 5\u2010Fluorouracil and Imidazole\u2010Based Heme Oxygenase 1 Inhibitor with Improved Cytotoxicity in DU145 Prostate Cancer Cells"],"prefix":"10.1002","volume":"18","author":[{"given":"Loredana","family":"Salerno","sequence":"first","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Sorrenti","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Pittal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"},{"name":"Department of Molecular Medicine College of Medicine and Medical Sciences Princess Al Jawhara Centre for Molecular Medicine Arabian Gulf University  Manama 329 Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Consoli","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria N.","family":"Modica","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Romeo","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Marrazzo","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Giuliano","sequence":"additional","affiliation":[{"name":"Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) University of Palermo  Via del Vespro 129 90127 Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Zajdel","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry Jagiellonian University Medical College  9 Medyczna Str. 30-688 Krak\u00f3w Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Vanella","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-1745","authenticated-orcid":false,"given":"Sebastiano","family":"Intagliata","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences University of Catania  viale A. Doria 6 95125 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,24]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"J. Ferlay M. Ervik F. Lam M. Colombet L. Mery M. Pi\u00f1eros A. Znaor I. Soerjomataram F. Bray Available from: https:\/\/gco.iarc.fr\/today accessed 08 March 20222020."},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2020-045343"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0257420"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.3314"},{"key":"e_1_2_8_6_1","unstructured":"\u00a0"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.107.07104"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111703"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5675"},{"key":"e_1_2_8_10_1","unstructured":"M.\u2005D. Maines Curr. Protoc. Toxicol.2001 Chapter\u20059 Unit 9 1."},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.1.99"},{"key":"e_1_2_8_12_1","unstructured":"\u00a0"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26133860"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2019.10.008"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2018.02.030"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2017.04.076"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1659"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00633"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox6020029"},{"key":"e_1_2_8_20_1","first-page":"23","volume":"22","author":"Podkalicka P.","year":"2018","journal-title":"Contemp. Oncol. (Pozn)."},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1074"},{"key":"e_1_2_8_22_1","unstructured":"\u00a0"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2019.37.7_suppl.319"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010396710"},{"key":"e_1_2_8_25_1","unstructured":"\u00a0"},{"key":"e_1_2_8_26_2","first-page":"33","volume":"13","author":"Macdonald J. S.","year":"1999","journal-title":"Oncology (Williston Park)"},{"key":"e_1_2_8_27_2","doi-asserted-by":"publisher","DOI":"10.1081\/CBI-120002597"},{"key":"e_1_2_8_28_1","unstructured":"\u00a0"},{"key":"e_1_2_8_29_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568011023354146"},{"key":"e_1_2_8_30_2","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.7-4-288"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202100473"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.05.068"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00128"},{"key":"e_1_2_8_34_1","unstructured":"\u00a0"},{"key":"e_1_2_8_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo971076p"},{"key":"e_1_2_8_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/js9702574"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2021.1928111"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.02.007"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci500588j"},{"key":"e_1_2_8_40_1","first-page":"418","author":"Lee S. K.","year":"2003","journal-title":"in EuroQSAR 2002 Designing Drugs and Crop Protectants: Processes, Problems and Solutions (Blackwell Publishing)"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(00)00129-0"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008130001697"},{"key":"e_1_2_8_43_1","unstructured":"\u00a0"},{"key":"e_1_2_8_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.103777"},{"key":"e_1_2_8_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21061923"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.3109\/10715761003667554"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0384-2"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2005"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.04.003"},{"key":"e_1_2_8_50_1","first-page":"917","volume":"11","author":"Sorrenti V.","year":"2021","journal-title":"Biomol. Eng."}],"updated-by":[{"DOI":"10.1002\/cmdc.202400510","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000}}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202300047","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202300047","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202300047","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T13:35:34Z","timestamp":1760276134000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202300047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,24]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,4,17]]}},"alternative-id":["10.1002\/cmdc.202300047"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202300047","archive":["Portico"],"relation":{"correction":[{"id-type":"doi","id":"10.1002\/cmdc.202400510","asserted-by":"object"}]},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,24]]},"assertion":[{"value":"2023-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202300047"}}