Elsevier

Electrochimica Acta

Volume 297, 20 February 2019, Pages 452-462
Electrochimica Acta

An electrochemical study on the redox chemistry of cyclic benzimidazole derivatives with potent anticancer activity

https://doi.org/10.1016/j.electacta.2018.11.198Get rights and content

Abstract

The electrochemical behaviour of potential antitumor benzimidazole derivatives (benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles and benzimidazo[1,2-a]quinolines) bearing one or two piperazine substituents was studied at a glassy carbon electrode (GCE) using cyclic and square-wave voltammetry in a wide range of pH values and potential scan rates. The electrochemical oxidation of the studied benzimidazoles proceeded via one or two electrode reactions assigned to the oxidation of one or two piperazine substituents, respectively. The oxidation of piperazine ring involved the transfer of two electrons and one proton in a pH-dependent, kinetically controlled electrode reaction, followed by a homogenous chemical reaction (EC mechanism). Both the reactants and the products of EC reactions were strongly adsorbed on the GCE surface. The electrochemical reduction occurred in one quasireversible, pH-dependent step, followed by a chemical transformation of the electrochemically formed product. The proposed reduction mechanism was related to the cyano moiety. The assignment of electroactive sites in molecules of interest was confirmed by theoretically calculated, using the PM6 method, differences of Net atomic charges between the cation (or anion) and neutral molecule.

Introduction

Cancer is one of the most common diseases and the second leading cause of death globally. According to the WHO, in 2015 cancer was responsible for the death of 8.8 million people worldwide [1]. One of the major methods of choice in the treatment of cancer today is chemotherapy. However, existing anticancer drugs generally suffer from low specificity to cancer cells, meaning that they do not discriminate between cancer and normal cells. Besides, cancer cells have the ability to develop resistance to anticancer drugs, which leads to treatment failures [2]. There is therefore an urgent need to design new, more selective and less toxic anticancer drugs, which would improve the effectiveness of current anticancer therapies.

The benzimidazole scaffold in numerous biologically active molecules is widely explored in the development of new anticancer agents. Various substituted derivatives of benzimidazole have been reported to show remarkable antitumor activity [[3], [4], [5], [6]], in addition to numerous other biological properties (such as antimicrobial [7], antiviral [8], antihypertensive [9], anti-inflammatory [10], antioxidant activity [11,12], etc.). One important feature for their biological activities is the structural similarity of benzimidazole moiety with naturally occurring nucleotides, which enables easy interaction of these compounds with biological molecules like DNA, RNA or proteins in living systems, thus playing a crucial role in their function [13].

To date, several articles have been published on the synthesis and potent anticancer activity of different groups of benzimidazole and fused benzimidazoquinoline derivatives with amidino-, nitro- and amino-substituents at different positions [[14], [15], [16], [17]]. It was found that benzannulated benzimidazole derivatives generally exert higher antiproliferative activity than non-fused ones. These compounds most probably exert their antiproliferative activity through intercalation into double stranded DNA or RNA, which is enabled due to their highly conjugated, planar structure. Moreover, some benzimidazole derivatives acted as topoisomerases inhibitors [14,15]. Recently, the synthesis and bioactivity of alkylamino-substituted benzimidazo[1,2-a]quinolines [18,19] and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles [20] was reported. The antiproliferative activity of these compounds was tested against three human breast cancer cell lines and found to be active in low micromolar range. A structure-activity relationship (SAR) study revealed that the anticancer activity of these two groups of benzimidazoles strongly depended on the nature of an amine side chain as well as on their position on the heterocyclic skeleton. 2- and 3-piperazinyl substituted benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles, respectively, exerted the highest cytotoxicity.

Previous studies have indicated that the abovementioned compounds cause direct DNA damage by mechanisms of intercalation or minor groove binding. However, many anticancer agents and/or their metabolites may, under certain circumstances, cause cytotoxic/mutagenic effects via generation of reactive oxygen species (ROS), which ultimately may lead to DNA damage and cell death [[21], [22], [23]]. The formation of ROS via electron transfer reactions is mainly governed by the redox properties of these anticancerous compounds. To date, there have been no reports on the redox properties of the abovementioned benzimidazoles or their ability to cause oxidative DNA damage, which prompted us to perform a detailed study on the redox behaviour of several benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with piperazine substituents proven to possess prominent antiproliferative activity.

Voltammetric techniques have been successfully used for investigations of redox reactions of many bioactive compounds, since they can mimic the redox mechanisms of organisms in vitro [[24], [25], [26], [27]]. Therefore, the present study is concerned with the investigation of the electron transfer properties of benzimidazo[1,2-a]quinolines and benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles with piperazinyl substituent(s), using cyclic and square-wave voltammetry at a glassy carbon electrode. The investigation of the electrochemical oxidation and reduction mechanisms of these compounds is important since it could result in a better understanding of their physiological mechanisms of action and yield new information about the potential redox reactions that these compounds may cause in biological systems.

Section snippets

Chemicals

Compounds 18 (for chemical structures see Scheme 1) were synthesized at the Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Croatia. Stock standard solutions of compounds 18 (c = 1.0 × 10−3 mol/L) were prepared from dry pure substances in DMSO (pro analysis), purchased from Kemika (Zagreb, Croatia). The stock solutions were protected from light with aluminium foil and kept in a refrigerator. All buffer solutions (pH 1–10) were obtained

MOPAC calculations

The geometries of six benzimidazole derivatives (16) and their cations and anions in water were optimized using the MOPAC2016™ PM6 method [28]. All of the optimized structures of the neutral compounds are given in Table S1 in Supplement. The eigenvector following the (EF) optimization procedure was carried out with a final gradient norm under 0.01 kcal mol−1 Å−1. The solvent contribution to the enthalpies of formation was computed employing COSMO (Conductor-like Screening Model) calculations

Results and discussion

In this work, redox reactions of two benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazole derivatives (compounds 1 and 2) and two benzimidazo[1,2-a]quinoline derivatives (compounds 4 and 5) were studied in detail using cyclic (CV) and square-wave voltammetry (SWV). For comparison, two dipiperazinyl analogues (one analogue of benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles (compound 3) and one analogue of benzimidazo[1,2-a]quinolines (compound 6)) were studied as well, along with two analogues of

Conclusion

The redox chemistry of potential antitumor benzimidazole derivatives (benzo[b]thieno[2,3-b]pyrido[1,2-a]benzimidazoles and benzimidazo[1,2-a]quinolines) bearing one or two piperazine substituents was studied for the first time. We have shown that analysed compounds incorporate electron-transfer (ET) moieties which may play important roles in physiological responses. One of the intermediates of electrochemical oxidation of piperazinyl moiety is iminium cation, known to possess numerous

Acknowledgment

This work was supported by Croatian Science Foundation under the project (IP-2018-01-4379) and Croatian Ministry of Science and Education.

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