Novel cis-Pt(II) Complexes with Alkylpyrazole Ligands: Synthesis, Characterization, and Unusual Mode of Anticancer Action.

Jana Kasparkova,Hana Kostrhunova,Tatiana A Podrugina,Viktor V Temnov,Alexey A Nazarov,Аlexey A Logvinov,Viktor Brabec,Nataliya E Borisova,Lenka Markova,Pavel Starha,Vojtech Novohradsky,Franc Perdih

doi:10.1155/2022/1717200

Abstract

One concept of improving anticancer effects of conventional platinum-based antitumor drugs consists of conjugating these compounds with other biologically (antitumor) active agents, acting by a different mechanism. Here, we present synthesis, physicochemical characterization, biological effects, and mechanisms of action of four new analogs of conventional cisplatin, namely, cis-Pt(II) complexes containing either methyl or ethyl pyrazole N-donor ligands and chlorido or iodido ligands. It is noteworthy that while chlorido complexes display activity in a variety of cancer cell lines comparable to cisplatin, iodido complexes are considerably more potent due to their enhanced hydrophobicity and consequently enhanced cellular accumulation. Moreover, all of the studied Pt(II) alkylpyrazole complexes display a higher selectivity for tumor cells and effectively overcome the acquired resistance to cisplatin. Further results focused on the mechanism of action of the studied complexes and showed that in contrast to cisplatin and several platinum-based antitumor drugs, DNA damage by the investigated Pt(II)-alkylpyrazole complexes does not play a major role in their mechanism of action. Our findings demonstrate that inhibition of the tubulin kinesin Eg5, which is essential for forming a functional mitotic spindle, plays an important role in their mechanism of antiproliferative action.

Highlights

Cisplatin, carboplatin, and oxaliplatin are the only worldwide approved metal-based antitumor drugs [1–4]
Cis-Pt(II) iodido complexes have long been predominantly used as intermediates in synthesizing target platinum chlorides and carboxylates, by the Dhara method or its modifications [17, 18]
Synthesis and Chemical Characterization. e ligands mepz and etpz were prepared by alkylation of the commercially available unsubstituted 1H-pyrazole. e platinum(II) diiodido complexes 1a,b (Figure 1) were prepared using methods reported by Reedijk with a minor modification [35]

Summary

Introduction

Carboplatin, and oxaliplatin are the only worldwide approved metal-based antitumor drugs [1–4]. The search for new antitumor Pt drugs followed the rules established based on knowledge of the mechanism of action of cisplatin and its direct analogs. This search is shifting to the greater structural diversity of platinum complexes, including nonclassical structures [5–16]. Cis-Pt(II) iodido complexes have long been predominantly used as intermediates in synthesizing target platinum chlorides and carboxylates, by the Dhara method or its modifications [17, 18]. Cis-Pt(II) diiodides containing 7-azaindole and its derivatives were significantly more active than cisplatin in several cancer cell lines [19]

Methods

Results

Conclusion