Research paper
Human colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver(I)–N-Heterocyclic carbene (NHC) complexes

https://doi.org/10.1016/j.ejmech.2015.11.034Get rights and content

Highlights

  • Synthesis of two new binuclear Ag(I)–N-Heterocyclic Carbene (NHC) Complexes.

  • Screening against a panel of cancer cell lines and normal cell lines.

  • A detailed study of the most active complex for cell death mechanism.

  • Highly lypophilic binuclear Ag(I)–NHC complexes may induce enhanced cell death.

Abstract

The current mechanistic study was conducted to explore the effects of increased lipophilicity of binuclear silver(I)–NHC complexes on cytotoxicity. Two new silver(I)–N-Heterocyclic Carbene (NHC) complexes (3 and 4), having lypophilic terminal alkyl chains (Octyl and Decyl), were derived from meta-xylyl linked bis-benzimidazolium salts (1 and 2). Each of the synthesized compounds was characterized by microanalysis and spectroscopic techniques. The complexes were tested for their cytotoxicity against a panel of human cancer c as well normal cell lines using MTT assay. Based on MTT assay results, complex 4 was found to be selectively toxic towards human colorectal carcinoma cell line (HCT 116). Complex 4 was further studied in detail to explore the mechanism of cell death and findings of the study revealed that complex 4 has promising pro-apoptotic and anti-metastatic activities against HCT 116 cells. Furthermore, it showed pronounced cytostatic effects in HCT 116 multicellular spheroid model. Hence, binuclear silver(I)–NHC complexes with longer terminal aliphatic chains have worth to be further studied against human colon cancer for the purpose of drug development.

Introduction

N-Heterocyclic Carbenes (NHCs) have become a well known class of organometallic ligands [1], [2], [3], [4], [5]. The versatility of NHCs greatly depends on the ring size and substitutions over the ring [6], [7], [8]. Recently, Se–NHC adducts have been studied to determine the effect of ring size and substitutions on the donor abilities of NHCs [9], [10]. Apart from the chemical properties of NHCs, a huge work has been done on catalytic and biological applications of NHC based organometallic compounds [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Considering the biological applications, herein we will focus on the anticancer properties of silver(I)–NHC complexes. Since the first report [21] of cytotoxic properties of silver(I)–NHC complex (Chart 1A) against cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116), a number of new silver(I)–NHC complexes were synthesized and screened against several carcinoma cell lines [18], [22], [23], [24], [25], [26], [27]. However, there are very few reports which describe the anticancer properties of silver(I)–NHC complexes in detail [28], [29]. For example, after screening against a panel of cancer cell lines, complex B (Chart 1) was tested in detail for DNA assay, albumin binding assay, CAKI-1 xenograft model, and in vivo zebrafish assay [28]. Although, the complex B showed good in vitro results against several cancer cell lines and also proved to have a strong DNA binding capacity, however it showed negative in vivo results. No significant inhibition in tumor growth was observed during in vivo assays. Furthermore, Eloy and co-workers screened several complexes against the proliferation of cancer cells and selected complexes (C–D) for apoptotic study [29]. It can be noticed that silver(I)–NHC complexes studied in detail are mononuclear in nature. Since, our previous studies indicated that increasing silver centres in a complex increased the biological efficacy of silver(I)–NHC complexes [30]. Hence, the current report describes a detailed anticancer study of binuclear silver(I)–NHC complexes (3 and 4), Scheme 1.

Section snippets

Material and methods

All chemicals and solvents were obtained from commercial sources and were of analytical grade and were used without further purifications. The benzimidazole, Ag2O, octyl bromide, decyl bromide, and 1,3-dibromomethyl benzene were purchased from Sigma–Aldrich. N-octyl, N-decyl benzimidazoles were prepared according to the literature [31] method with slight modifications. The FT-IR spectra of the compounds were recorded in potassium bromide disks using a Perkin Elmer 2000 system spectrometer in

Silver complexes showed cytotoxic activities against a variety of human cancer cell lines

Silver in various forms (nanoparticles, coordination complexes and organometallic compounds) is now being focussed due to its significant effect against cancer cells [23], [39], [40], [41], [42], [43], [44]. Since time immortal, silver has been used for the treatment of a variety of ailments [45], [46], [47]. In the present study complexes (Scheme 1) were prepared and their characteristic patterns were compared with the previous reports having comparable chemical structures [34]. Prior studies

Conclusion

In the present study, two new silver(I)–NHC complexes (3 and 4) were derived from meta-xylyl linked bis-benzimidazolium salts (1 and 2) and were screened for their cytotoxic potential against a panel of human cancer cell lines. Among the complexes tested, 4 showed more selective cytotoxicity against cancer cell lines specially against HCT 116, U-937 and PANC-1 which might be due to its longer terminal chain. Selectivity index value points that 4 was selectively toxic towards HCT 116 compared to

Conflict of interest

The authors declare no conflict of interest.

Author's contribution

Asif, M and Iqbal, MA conducted the experiments under the supervision of rest of the authors. All the authors have equal contribution to this work.

Acknowledgement

The authors would like to acknowledge Institute of Postgraduate Studies, Universiti Sains Malaysia for providing USM Fellowship [PF-D0009/12(R)] and Universiti Sains Malaysia (USM) for Research University Grant (RUT 1001/PFARMASI/851001) to support this project. Dr. Muhammad Adnan Iqbal is thankful to USM for postdoctoral fellowship in research. Dr. Muhammad Adnan Iqbal is also thankful to university of Agriculture, Faisalabad, Pakistan for TTS appointment as Assistant Professor at department

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