{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T08:00:10Z","timestamp":1772611210377,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008860","name":"Wuhan University of Science and Technology","doi-asserted-by":"publisher","award":["040274"],"award-info":[{"award-number":["040274"]}],"id":[{"id":"10.13039\/501100008860","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Department of Education of Hubei Province","award":["B2022021"],"award-info":[{"award-number":["B2022021"]}]},{"name":"the Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials","award":["WKDM202304"],"award-info":[{"award-number":["WKDM202304"]}]},{"name":"Hubei Key Laboratory of Bioinorganic Chemistry &amp; Materia Medica","award":["BCMM202305"],"award-info":[{"award-number":["BCMM202305"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: To battle the side effects of anticancer Pt(II) drug cisplatin, the development of photoactivatable and\/or intracellular reduction-activatable Pt(IV) prodrugs has become a promising strategy. Methods: Herein, two novel Pt(IV) prodrugs, namely, cis,cis,trans-[PtIV(NH3)2(Cl)2(OH)(probenecid)]) (SPP) and cis,cis,trans-[PtIV(NH3)2(Cl)2(probenecid)2] (DPP) bearing mono- and di-probenecid at the axial positions of oxoplatin have been synthesized via covalently linking of carboxylate group in probenecid, which is a well-established clinic drug by inhibiting organic anion transporter 1 (OAT1) to reduce cisplatin-induced nephrotoxicity, with the axial hydroxyl group(s) in oxoplatin. The promising cytotoxicity of SPP and DPP against MCF-7, T47D breast cancer cells and the MDA-MB-231 triple-negative breast cancer cells was evaluated, and the mechanism of action of the two Pt(IV) prodrugs was investigated by apoptosis assay and Western blot assay. Results: SPP exhibits a comparable cytotoxicity to cisplatin against MCF-7 and T47D breast cancer cells, while it shows 2.1-fold higher cytotoxicity than cisplatin against MDA-MB-231 cells. DPP was shown to be more cytotoxic than SPP, and exhibits 8.7-, 7.5-, and 2.3-fold higher cytotoxicity than cisplatin against MCF-7, T47D, and MDA-MB-231 cells, respectively. Apoptosis assays revealed a similar early-apoptotic cell death mechanism to cisplatin for both SPP and DPP. The enhanced cellular and nuclear uptake of DPP compared to cisplatin contributes to its promising anticancer efficacy. DPP can bind to OAT1 in cancer cells, which may synergistically enhance the cytotoxicity of the Pt(IV) anticancer prodrugs. Conclusions: The direct conjugation of probenecid to the axial positions of oxoplatin confers the resulting Pt(IV) prodrugs a multitargeting property, significantly promoting the cytotoxicity of the resulting Pt(IV) complexes. This finding provides a practical strategy for drug design and cancer treatment based on platinum complexes.<\/jats:p>","DOI":"10.3390\/ph19030386","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:05:16Z","timestamp":1772211916000},"page":"386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multitargeting Pt(IV) Anticancer Prodrugs Bearing Mono- and Bis-Probenecid Ligands in Axial Positions: Synthesis and Evaluation of Biological Activity"],"prefix":"10.3390","volume":"19","author":[{"given":"Panxing","family":"Qiu","sequence":"first","affiliation":[{"name":"Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Dou","sequence":"additional","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqin","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silong","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0962-1260","authenticated-orcid":false,"given":"Fuyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-0395","authenticated-orcid":false,"given":"Kui","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Hubei Province for Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.cbpa.2013.01.004","article-title":"Targeted delivery of platinum-based anticancer complexes","volume":"17","author":"Butler","year":"2013","journal-title":"Curr. 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