Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position,Journal of Medicinal Chemistry

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Pt(IV) Prodrugs with Non-Steroidal Anti-inflammatory Drugs in the Axial Position
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-08 , DOI: 10.1021/acs.jmedchem.1c02136
Daniil V Spector _{1,

2} , Kirill G Pavlov ₁ , Roman A Akasov _{3,

4} , Alexander N Vaneev _{1,

2} , Alexander S Erofeev _{1,

2} , Petr V Gorelkin ₂ , Vita N Nikitina ₁ , Elena V Lopatukhina ₂ , Alevtina S Semkina _{5,

6} , Kseniya Yu Vlasova _{1,

5} , Dmitrii A Skvortsov ₁ , Vitaly A Roznyatovsky ₁ , Nikolay V Ul'yanovskiy ₇ , Ilya I Pikovskoi ₇ , Sergey A Sypalov ₇ , Anastasiia S Garanina ₂ , Stepan S Vodopyanov ₂ , Maxim A Abakumov _{2,

5} , Yulia L Volodina ₈ , Alina A Markova _{9,

10} , Albina S Petrova _{11,

12} , Dmitrii M Mazur ₁ , Dmitry A Sakharov ₁₃ , Nikolay V Zyk ₁ , Elena K Beloglazkina ₁ , Alexander G Majouga _{1,

2,

13} , Olga O Krasnovskaya _{1,

2}

Affiliation

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

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.

中文翻译：

轴向位置含有非甾体抗炎药的 Pt(IV) 前药

我们在此报告了一系列新型 Pt(IV) 前药与非甾体类抗炎药萘普生、双氯芬酸和氟比洛芬的设计、合成和生物学研究，以及这些在轴向位置具有硬脂酸的药物。设计了六种 Pt(IV) 前药5-10，与顺铂相比，它们显示出优异的抗增殖活性以及克服肿瘤细胞系对顺铂耐药的能力。通过改变轴向配体来调节药物的亲脂性，获得了最有效的 Pt(IV) 前药7，其在 2D 和 3D 细胞培养物中的细胞积累高达顺铂的 153 倍，并且具有纳摩尔的细胞毒性。铂²⁺在使用 Pt 涂层碳纳米电极与 Pt(IV) 前药孵育后，在 MCF-7 球体的不同深度检测到物种。在 Pt(IV) 前药注射后，顺铂在 BALB/c 小鼠的鼠乳腺 EMT6 肿瘤组织中的体内积累也被电化学证明。对 BALB/c 小鼠的药物耐受性研究显示，在高达 8 mg/kg 的剂量下对7具有良好的耐受性。

更新日期：2022-06-08

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