Biotinylated Pt(IV) prodrugs with elevated lipophilicity and cytotoxicity

Daniil Spector; Alexander Erofeev; Peter Gorelkin; Dmitry Skvortsov; Alexander Trigub; Alina Markova; Vita Nikitina; Nikolay Ul'yanovskiy; Alexander Shtil’; Alevtina Semkina; Ksenia Vlasova; Nikolay Zyk; Alexander Majouga; Elena Beloglazkina; Olga Krasnovskaya

doi:10.1039/D2DT03662B

Biotinylated Pt(iv) prodrugs with elevated lipophilicity and cytotoxicity†

Daniil Spector,^ab Alexander Erofeev,

^ab Peter Gorelkin,^ab Dmitry Skvortsov,

^a Alexander Trigub,^c Alina Markova,^d Vita Nikitina,^a Nikolay Ul'yanovskiy,

^e Alexander Shtil’,^f Alevtina Semkina,^gh Ksenia Vlasova,^ah Nikolay Zyk,^a Alexander Majouga,ⁱ Elena Beloglazkina

^a and Olga Krasnovskaya

*^ab

Author affiliations

* Corresponding authors

^a Chemistry Department, Lomonosov Moscow State University, Leninskie gory 1, 3, Moscow, Russia
E-mail: Krasnovskayao@gmail.com

^b National University of Science and Technology (MISIS), Leninskiy prospect 4, Moscow, Russia

^c National Research Center “Kurchatov Institute”, Akademika Kurchatova pl., 1, Moscow, Russia

^d Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, Kosygin Street, 4, Moscow, Russia

^e Core Facility Center ‘Arktika’, Northern (Arctic) Federal University, Arkhangelsk, Russia

^f N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation, Kashirskoe highway 23, Moscow, Russia

^g Pirogov Russian National Research Medical University (RNRMU), Ostrovitianov str. 1, Moscow, Russia

^h Serbsky National Medical Research Center for Psychiatry and Narcology, Department of Basic and Applied Neuro-biology, Kropotkinskiy 23, Moscow, Russia

ⁱ Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, Moscow, Russia

Abstract

A design of Pt(IV) prodrugs with tumor cell targeting moieties leading to increased selectivity is of interest. Herein, we designed a novel Pt(IV) prodrugs with COX-inhibitor naproxen, long-chain hydrophobic stearic acid moiety and biotin as axial ligands. We have established that for Pt(IV) prodrugs with biotin and naproxen or stearate in axial position, the lipophilicity rather than biotin receptors expression is the main factor of cytotoxicity. We also monitored the reduction speed of Pt(IV) prodrug 3 with naproxen and biotin in axial positions in A549 cells using XANES and demonstrated that the prodrug gradually releases cisplatin within 20 hours of incubation.

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Biotinylated Pt(iv) prodrugs with elevated lipophilicity and cytotoxicity†

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Biotinylated Pt(IV) prodrugs with elevated lipophilicity and cytotoxicity

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