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

Daniil V Spector^{1

2}, Kirill G Pavlov¹, Roman A Akasov^{3

4}, Alexander N Vaneev^{1

2}, Alexander S Erofeev^{1

2}, Petr V Gorelkin², Vita N Nikitina¹, Elena V Lopatukhina², Alevtina S Semkina^{5

6}, Kseniya Yu Vlasova^{1

5}, Dmitrii A Skvortsov¹, Vitaly A Roznyatovsky¹, Nikolay V Ul'yanovskiy⁷, Ilya I Pikovskoi⁷, Sergey A Sypalov⁷, Anastasiia S Garanina², Stepan S Vodopyanov², Maxim A Abakumov^{2

5}, Yulia L Volodina⁸, Alina A Markova^{9

10}, Albina S Petrova^{11

12}, Dmitrii M Mazur¹, Dmitry A Sakharov¹³, Nikolay V Zyk¹, Elena K Beloglazkina¹, Alexander G Majouga^{1

2

13}, Olga O Krasnovskaya^{1

2}

Affiliations

¹ Chemistry Department, Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow 119991, Russia.
² National University of Science and Technology (MISIS), Leninskiy prospect 4, Moscow 119049, Russia.
³ I.M. Sechenov First Moscow State Medical University, Trubetskaya 8-2, Moscow 119991, Russia.
⁴ Federal Scientific Research Center "Crystallography and Photonics" Russian Academy of Sciences, Leninskiy Prospect 59, Moscow 119333, Russia.
⁵ Pirogov Russian National Research Medical University (RNRMU), Ostrovitianov 1, Moscow 117997, Russia.
⁶ Department of Basic and Applied Neurobiology, Serbsky National Medical Research Center for Psychiatry and Narcology, Kropotkinskiy 23, Moscow 119034, Russia.
⁷ Core Facility Center "Arktika", Northern (Arctic) Federal University, Arkhangelsk 163002, Russia.
⁸ N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Kashirskoe highway 23, Moscow 115478, Russia.
⁹ Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Kosygin Street, 4, Moscow 119334, Russia.
¹⁰ A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences (INEOS RAS), Vavilova 28, Moscow 119991, Russia.
¹¹ Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya str. 6, Moscow 117198, Russia.
¹² State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Marshal Novikov str. 23, Moscow 123098, Russia.
¹³ Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russia.

PMID: 35675651
DOI: 10.1021/acs.jmedchem.1c02136

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

Daniil V Spector et al. J Med Chem. 2022.

. 2022 Jun 23;65(12):8227-8244.

doi: 10.1021/acs.jmedchem.1c02136. Epub 2022 Jun 8.

Authors

Affiliations

¹ Chemistry Department, Lomonosov Moscow State University, Leninskie Gory 1-3, Moscow 119991, Russia.
² National University of Science and Technology (MISIS), Leninskiy prospect 4, Moscow 119049, Russia.
³ I.M. Sechenov First Moscow State Medical University, Trubetskaya 8-2, Moscow 119991, Russia.
⁴ Federal Scientific Research Center "Crystallography and Photonics" Russian Academy of Sciences, Leninskiy Prospect 59, Moscow 119333, Russia.
⁵ Pirogov Russian National Research Medical University (RNRMU), Ostrovitianov 1, Moscow 117997, Russia.
⁶ Department of Basic and Applied Neurobiology, Serbsky National Medical Research Center for Psychiatry and Narcology, Kropotkinskiy 23, Moscow 119034, Russia.
⁷ Core Facility Center "Arktika", Northern (Arctic) Federal University, Arkhangelsk 163002, Russia.
⁸ N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Kashirskoe highway 23, Moscow 115478, Russia.
⁹ Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Kosygin Street, 4, Moscow 119334, Russia.
¹⁰ A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences (INEOS RAS), Vavilova 28, Moscow 119991, Russia.
¹¹ Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya str. 6, Moscow 117198, Russia.
¹² State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Marshal Novikov str. 23, Moscow 123098, Russia.
¹³ Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow 125047, Russia.

PMID: 35675651
DOI: 10.1021/acs.jmedchem.1c02136

Abstract

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

Affiliations

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

Authors

Affiliations

Abstract

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Substances

LinkOut - more resources

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