{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:39:23Z","timestamp":1785425963663,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003336","name":"National Science Fund of Bulgaria","doi-asserted-by":"crossref","award":["K\u03a0-06-H59\/9"],"award-info":[{"award-number":["K\u03a0-06-H59\/9"]}],"id":[{"id":"10.13039\/501100003336","id-type":"DOI","asserted-by":"crossref"}]},{"award":["K\u03a0-06-H59\/9"],"award-info":[{"award-number":["K\u03a0-06-H59\/9"]}],"id":[{"id":"https:\/\/ror.org\/05eg49r29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Among the non-classical platinum complexes, Pt(IV) prodrugs are most promising as versatile scaffolds for structural modification and fine tuning of their activation-by-reduction mechanism of action and the resulting anticancer activity. Herein, four new asymmetrically disubstituted pyrenebutyrate complexes of Pt(IV) (2\u20135) were synthesized and thoroughly studied. In this series, the second axial ligand was derived from dicarboxylic acids of different length\u20144 and 5 C-atoms, or replacement of the C-atom in the middle with either O- or S-atom. The structural effects on reduction kinetics, lipophilicity and cellular internalization of the complexes were monitored by NMR, HPLC, fluorescence and ICP-MS measurements. Their cytotoxicity was tested on a panel of cancer cell lines and mechanistic insights were obtained from proteome analysis and microscope imaging. The data indicate that all complexes, especially complex 3, represent a promising class of Pt(IV) prodrugs, exhibiting significantly higher cytotoxic activity than cisplatin in all tested models, including a cisplatin-resistant line. This was explained with a stronger and more integrated apoptotic response than cisplatin: pronounced Bax upregulation (3.6-fold), maximal cleaved caspase-3 (4-fold), activation of both intrinsic and extrinsic pathways, and effective p53 Ser15\/Ser46 phosphorylation. The consistent rank order of potency (3 &gt; 4 &gt; 5 \u2248 2 \u226b cisplatin) suggests that subtle ligand modifications can substantially enhance efficacy, possibly by improving cellular uptake or altering DNA binding.<\/jats:p>","DOI":"10.3390\/molecules31132336","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T07:59:47Z","timestamp":1783065587000},"page":"2336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Asymmetrically Disubstituted Pyrenebutyrate Complexes of Pt(IV) as Cisplatin Prodrugs with Improved Anticancer Activity"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-0730","authenticated-orcid":false,"given":"Rositsa","family":"Mihaylova","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Medical University\u2014Sofia, 2 Dunav Street, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Mihaylova","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier blvd., 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"Burdzhiev","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier blvd., 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9775-3222","authenticated-orcid":false,"given":"Ivo D.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier blvd., 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4101-7036","authenticated-orcid":false,"given":"Zhanina","family":"Petkova","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl. 9, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-7089","authenticated-orcid":false,"given":"Georgi","family":"Momekov","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University\u2014Sofia, 2 Dunav Street, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-6761","authenticated-orcid":false,"given":"Denitsa","family":"Momekova","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Medical University\u2014Sofia, 2 Dunav Street, 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6288-648X","authenticated-orcid":false,"given":"Anife","family":"Ahmedova","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry and Pharmacy, Sofia University, 1, J. Bourchier blvd., 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8276139","DOI":"10.1155\/2018\/8276139","article-title":"Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands","volume":"2018","author":"Li","year":"2018","journal-title":"Bioinorg. Chem. Appl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111353","DOI":"10.1016\/j.jinorgbio.2020.111353","article-title":"Platinum(IV) anticancer agents; are we en route to the holy grail or to a dead end?","volume":"217","author":"Gibson","year":"2021","journal-title":"J. Inorg. 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