{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T03:24:36Z","timestamp":1792553076198,"version":"4.5.0"},"reference-count":33,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Salinomycin and its derivatives display promising anti-proliferating activity against bloodstream forms of Trypanosoma brucei. The mechanism of trypanocidal action of these compounds is due to their ionophoretic activity inducing an influx of sodium cations followed by osmotic water uptake, leading to massive swelling of bloodstream-form trypanosomes. Generally, higher trypanocidal activities of salinomycin derivatives are associated with higher cell swelling activities. Although ironomycin (C20-propargylamine derivative of salinomycin) and salinomycin showed identical cell swelling activities, ironomycin was 6 times more trypanocidal than salinomycin, and the 50% growth inhibition (GI50) values were 0.034 \u03bcM and 0.20 \u03bcM, respectively. However, when bloodstream-form trypanosomes were incubated with ironomycin in the presence of vitamin E and ammonium ferric citrate, the trypanocidal activity of the compound was reduced to that of salinomycin (GI50 = 0.21 \u03bcM vs. GI50 = 0.20 \u03bcM). In addition, vitamin E was found to decrease the trypanocidal activity of ironomycin much more than ammonium ferric citrate (GI50 = 0.18 \u03bcM vs. GI50 = 0.042 \u03bcM). Moreover, ironomycin caused a reduction in the uptake of the iron-carrier protein transferrin mediated by a downregulation of the transferrin receptor and led to the accumulation and sequestering of iron(II) in the parasite\u2019s lysosome, triggering an increase production of reactive oxygen species (ROS). These results suggest that the increased trypanocidal activity of ironomycin can be mainly attributed to an increased ROS production and, to a lesser extent, an impairment in iron uptake.<\/jats:p>","DOI":"10.3390\/molecules29235597","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T08:17:42Z","timestamp":1732695462000},"page":"5597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased Trypanocidal Activity of the Salinomycin Derivative Ironomycin Is Due to ROS Production and Iron Uptake Impairment"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0050-7771","authenticated-orcid":false,"given":"Dietmar","family":"Steverding","sequence":"first","affiliation":[{"name":"Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Rushworth","sequence":"additional","affiliation":[{"name":"Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina R.","family":"Hurle","sequence":"additional","affiliation":[{"name":"BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0877-1726","authenticated-orcid":false,"given":"Micha\u0142","family":"Antoszczak","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Pozna\u0144skiego 8, 61-614 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6127-9621","authenticated-orcid":false,"given":"Micha\u0142","family":"Sulik","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Pozna\u0144skiego 8, 61-614 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4770-215X","authenticated-orcid":false,"given":"Adam","family":"Huczy\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Pozna\u0144skiego 8, 61-614 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0647-8158","authenticated-orcid":false,"given":"Kevin M.","family":"Tyler","sequence":"additional","affiliation":[{"name":"BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Franco, J.R., Priotto, G., Paone, M., Cecchi, G., Ebeja, A.K., Simaroo, P.P., Sankara, D., Metwally, S.B.A., and Argaw, D.D. 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