Synthesis of Platinum(II) Complexes with Some 1-Methylnitropyrazoles and In Vitro Research on Their Cytotoxic Activity.

Henryk Mastalarz,Magdalena Milczarek,Agnieszka Mastalarz,Andrzej Regiec,Andrzej Kochel,Joanna Wietrzyk

doi:10.3390/ph13120433

Abstract

A series of eight novel platinum(II) complexes were synthesized by the reaction of the appropriate 1-methylnitropyrazole derivatives with K2PtCl4 and characterized by elemental analysis, ESI MS spectrometry, 1H NMR, 195Pt NMR, IR and far IR spectroscopy. Thermal isomerization of cis-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 1 to trans-dichloridobis(1-methyl-4-nitropyrazole)platinum(II) 2 has been presented, and the structure of the compound 2 has been confirmed by X-ray diffraction method. Cytotoxicity of the investigated compounds was examined in vitro on three human cancer cell lines (MCF-7 breast, ES-2 ovarian and A-549 lung adenocarcinomas) and their logP was measured using a shake-flask method. The trans complex 2 showed better antiproliferative activity than cisplatin for all the tested cancer cell lines. Additionally, trans-dichloridobis(1-methyl-5-nitropyrazole)platinum(II) 4 has featured a lower IC50 value than reference cisplatin against MCF-7 cell line. To gain additional information that may facilitate the explanation of the mode of action of tested compounds cellular platinum uptake, stability in L-glutathione solution, influence on cell cycle progression of HL-60 cells and ability to apoptosis induction were determined for compounds 1 and 2.

Highlights

Since the discovery of cisplatin cytostatic properties, platinum complexes have been widely used in modern medicine for the treatment of various solid tumors
Using 1-methylated ligands allowed us to avoid the troublesome formation of additional isomers caused by the ring N–H tautomerism and should enhance the bioavailability of synthesized Pt complexes due to higher lipophilicity
Considering unsatisfactory yield (10%) of most active compound 2 during the standard procedure, we carried out an additional route of its synthesis through highly efficient thermal2020, isomerization ofREVIEW

Summary

Introduction

Since the discovery of cisplatin cytostatic properties, platinum complexes have been widely used in modern medicine for the treatment of various solid tumors. Three of these compounds, namely cisplatin, oxaliplatin and carboplatin, are in clinical use as anti-cancer drugs. The anticancer activity of cisplatin is believed to arise from its interaction with DNA. Several cellular pathways are activated in response to this interaction, including recognition by repair enzymes, translation synthesis by polymerases, and induction of apoptosis. All these processes are suspected to Pharmaceuticals 2020, 13, 433; doi:10.3390/ph13120433 www.mdpi.com/journal/pharmaceuticals

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