Original research articleBiological approach of anticancer activity of new benzimidazole derivatives
Introduction
Hypoxia is the leading targeting in cancer therapy. The poor oxygen concentration, which is characteristic for solid tumors affects many processes such as angiogenesis, erythropoiesis and alteration of cellular metabolism at tumor cells [5]. Hypoxia, for sure, can influence the survival of tumor cells by different changes in the gene expression that reduce apoptosis and increase autophagy, vasculogenesis, metastasis, immune reactivity and activity of receptor tyrosine kinase. Generally tumor cells under hypoxia lose genomic stability by generating the reactive oxygen species (ROS) and suppress regulation of DNA repair pathways [8], [10], [21], [23], [25].
In order to minimize those survival effects of tumor cells, scientists conduct research into targeted therapy with the use of specific substances which have a bioreductive mechanism of action at hypoxia conditions [1], [6], [13]. This concept of approaching new chemical classes of pro-drugs activated to selective cytotoxins, was started by using derivatives of aniline nitrogen mustard as the first class of bioreducive prodrugs. Now different chemical bonds such as nitro group, quinones, heterocyclic N-oxides (CB 1954, tirapazamina, AQ4N) are currently radical prodrugs useful for cancer therapy (Fig. 1) [11], [12], [14], [20]. The mechanisms of the metabolic activation of bioreductive prodrugs were shown at Scheme 1 [25]. The common feature of all these new chemical compounds is their ability to generate cytotoxic agents for DNA damage. A new group of benzimidazole derivatives, i.e. potential new agents of the DNA destruction, should be particularly paid attention to [2], [3], [4]. These compounds are intensively being worked on as they might have new anticancer properties [7], [16], [17], [22], [24]. It was the reason for initiating our experiments in the group of new benzimidazole derivatives and N-oxide benzimidazole derivatives. Therefore, we analyzed a series of benzimidazole derivatives (1–12) to elucidate their contribution to the antyproliferation activity at normoxia and hypoxia conditions. The particularly selective activity of N-oxide benzimidazole derivatives into hypoxia was very interesting for us. Additionally we determined their cytotoxic activity by necrosis or apoptosis. The main reason for our experiments concerned their effect of DNA damage at hypoxia and normoxia cancer cells.
Section snippets
Cell culture
A549 (human lung adenocarcinoma) cell line was purchased from Health Protection Agency Culture Collections (ECACC, Salisburg, UK), were cultured in F12K medium (HyClone, UK) supplemented with 10% heat-inactivated fetal bovine serum (FBS), penicillin (10,000 U/ml) and streptomycin (10,000 μg/ml) in 5% CO2 at 37 °C.
Hypoxic cells were created by culture of A549 cells in hypoxic incubator in 1% O2 and 5% CO2 at 37 °C for 24 h before treatment.
DNA damage assay
The effect of compounds on DNA damage was determined based on
Chemistry
The structure of the new benzimidazole derivatives and N-oxide benzimidazole derivatives is shown in Fig. 2. The cyclocondensation of diamine with aldehydes was prepared according to the known and described in literature method [9], [18], [19]. We worked out the conditions for obtaining new benzimidazole derivatives and N-oxide benzimidazole derivatives as we described earlier [26]. Structure of new benzimidazole derivatives was established by X-ray crystal structure analysis [6].
Biological activities
Human lung
Discussion
From our screening tests, we found that compounds 1 and 7 were the most effective in the inhibition of the cell growth in normoxic as well as in hypoxic A549 cells. But their cytotoxic activity at hypoxia drew attention too. The compounds 2 and 8 were more potent to specifically inhibit cell viability of hypoxic cancer cells while they were less effective in normoxic cells. Moreover, hypoxic/aerobic cytotoxicity coefficient of compound 8 was 4.75 while for tirapazamine was 5.59. This parameter
Funding
Synthetical and biochemical research is supported by Medical University of Łódź, Poland (503-3015-1, Grant No. 507-13-052).
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