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The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)\/toxicity properties, by a multi- and transdisciplinary <jats:italic>in silico<\/jats:italic>, <jats:italic>in vitro<\/jats:italic>, and <jats:italic>in vivo<\/jats:italic> approach. Doxorubicin was used as the reference compound. The <jats:italic>in silico<\/jats:italic> profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. <jats:italic>In vitro<\/jats:italic> data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME\/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings.<\/jats:p>","DOI":"10.3389\/fphar.2022.831791","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T06:56:34Z","timestamp":1646636194000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors"],"prefix":"10.3389","volume":"13","author":[{"given":"Petko","family":"Alov","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merilin","family":"Al Sharif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denitsa","family":"Aluani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantin","family":"Chegaev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jelena","family":"Dinic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Divac Rankov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel X.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Fusi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso T.","family":"Garc\u00eda-Sosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Risto","family":"Juvonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Kondeva-Burdina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 M.","family":"Padr\u00f3n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilza","family":"Pajeva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Pencheva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adri\u00e1n","family":"Puerta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannu","family":"Raunio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Riganti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivanka","family":"Tsakovska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Tzankova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yordan","family":"Yordanov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Saponara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1093\/bib\/bbz103","article-title":"Computational\/In Silico Methods in Drug Target and Lead Prediction","volume":"21","author":"Agamah","year":"2019","journal-title":"Brief Bioinform"},{"key":"B2","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/j.bcp.2005.06.018","article-title":"Expression of the Drug Transporters MDR1\/ABCB1, MRP1\/ABCC1, MRP2\/ABCC2, BCRP\/ABCG2, and PXR in Peripheral Blood Mononuclear Cells and Their Relationship with the Expression in Intestine and Liver","volume":"70","author":"Albermann","year":"2005","journal-title":"Biochem. 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