Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position

We report herein the design, synthesis, and biological investigation of a series of novel Pt­(IV) prodrugs with non-steroidal anti-inflammatory drugs naproxen, diclofenac, and flurbiprofen, as well as these with stearic acid in the axial position. Six Pt­(IV) prodrugs 5–10 were designed, which showe...

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Published inJournal of medicinal chemistry Vol. 65; no. 12; pp. 8227 - 8244
Main Authors Spector, Daniil V., Pavlov, Kirill G., Akasov, Roman A., Vaneev, Alexander N., Erofeev, Alexander S., Gorelkin, Petr V., Nikitina, Vita N., Lopatukhina, Elena V., Semkina, Alevtina S., Vlasova, Kseniya Yu, Skvortsov, Dmitrii A., Roznyatovsky, Vitaly A., Ul’yanovskiy, Nikolay V., Pikovskoi, Ilya I., Sypalov, Sergey A., Garanina, Anastasiia S., Vodopyanov, Stepan S., Abakumov, Maxim A., Volodina, Yulia L., Markova, Alina A., Petrova, Albina S., Mazur, Dmitrii M., Sakharov, Dmitry A., Zyk, Nikolay V., Beloglazkina, Elena K., Majouga, Alexander G., Krasnovskaya, Olga O.
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 23.06.2022
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
IN-VITRO
CISPLATIN
MODELS
DNA-DAMAGE
NANOPARTICLE DELIVERY
AGENTS
PLATINUM(IV) COMPLEXES
CYTOTOXICITY
CYCLOOXYGENASE INHIBITORS
TUMOR MICROENVIRONMENT
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Summary:We report herein the design, synthesis, and biological investigation of a series of novel Pt­(IV) prodrugs with non-steroidal anti-inflammatory drugs naproxen, diclofenac, and flurbiprofen, as well as these with stearic acid in the axial position. Six Pt­(IV) prodrugs 5–10 were designed, which showed superior antiproliferative activity compared to cisplatin as well as an ability to overcome tumor cell line resistance to cisplatin. By tuning the drug lipophilicity via variation of the axial ligands, the most potent Pt­(IV) prodrug 7 was obtained, with an enhanced cellular accumulation of up to 153-fold that of cisplatin and nanomolar cytotoxicity both in 2D and 3D cell cultures. Pt2+ species were detected at different depths of MCF-7 spheroids after incubation with Pt­(IV) prodrugs using a Pt-coated carbon nanoelectrode. Cisplatin accumulation in vivo in the murine mammary EMT6 tumor tissue of BALB/c mice after Pt­(IV) prodrug injection was proved electrochemically as well. The drug tolerance study on BALB/c mice showed good tolerance of 7 in doses up to 8 mg/kg.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.1c02136