Research paperHuman colon cancer targeted pro-apoptotic, anti-metastatic and cytostatic effects of binuclear Silver(I)–N-Heterocyclic carbene (NHC) complexes
Graphical abstract
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
References (74)
- et al.
Complexes with protic (NH, NH and NH, NR) N-heterocyclic carbene ligands
Coord. Chem. Rev.
(2015) - et al.
Extending N-heterocyclic carbene ligands into the third dimension: a new type of hybrid phosphazane/NHC system
Chem. Sci.
(2015) - et al.
What can NMR spectroscopy of selenoureas and phosphinidenes teach us about the π-accepting abilities of N-heterocyclic carbenes?
Chem. Sci.
(2015) - et al.
Synthesis, structures, and biological studies of heterobimetallic Au (I)–Ru (II) complexes involving n-heterocyclic carbene-based Multidentate ligands
Organometallics
(2015) - et al.
Synthesis, crystal structures, characterization and biological studies of nitrile-functionalized silver (I) N-heterocyclic carbene complexes
Inorganica Chim. Acta
(2015) - et al.
Synthesis, structural characterization and in vitro anti-cancer activity of functionalized N-heterocyclic carbene platinum and palladium complexes
J. Organomet. Chem.
(1 October 2015) - et al.
Silver (I), gold (I) and gold (III)-N-Heterocyclic carbene complexes of Naphthyl substituted Annelated ligand: synthesis, structure and cytotoxicity
J. Organomet. Chem.
(15 August 2015) - et al.
Caffeine derived platinum (II) N-heterocyclic carbene complexes with multiple anti-cancer activities
J. Organomet. Chem.
(2015) - et al.
Macrophage and colon tumor cells as targets for a binuclear silver (I) N-heterocyclic carbene complex, an anti-inflammatory and apoptosis mediator
J. Inorg. Biochem.
(2015) Benzyl-substituted carbene–metal complexes: potential for novel antibiotics and anticancer drugs?
J. Organomet. Chem.
(2015)
N-Heterocyclic carbenes (NHC) with 1, 2, 4–Oxadiazole-Substituents related to natural products: synthesis, structure and potential antitumor activity of some corresponding gold (I) and silver (I) complexes
Eur. J. Med. Chem.
Characterization of HCT116 human Colon Cancer cells in an orthotopic model
J. Surg. Res.
Biologically synthesised silver nanoparticles from three diverse family of plant extracts and their anticancer activity against epidermoid A431 carcinoma
J. Colloid Iterface Sci.
Silver (I) complexes of mono-and bidentate N-heterocyclic carbene ligands: synthesis, crystal structures, and in vitro antibacterial and anticancer studies
Eur. J. Med. Chem.
Bio-synthesis of silver nanoparticles using Potentilla fulgens wall. ex hook. and its therapeutic evaluation as anticancer and antimicrobial agent
Mater. Sci. Eng. C
N-Heterocyclic carbene–silver complexes: a new class of antibiotics
Coord. Chem. Rev.
Enhanced anti-influenza a virus activity of (−)-epigallocatechin-3-O-gallate fatty acid monoester derivatives: effect of alkyl chain length
Bioorg. Med. Chem. Lett.
Synthesis and anticancer properties of gold (I) and silver (I) N-heterocyclic carbene complexes
J. Organomet. Chem.
Cytotoxic 3, 6-bis ((imidazolidinone) imino) acridines: synthesis, DNA binding and molecular modeling
Bioorg. Med. Chem.
Cytotoxic activity screening of some indigenous Thai plants
Fitoterapia
The apoptotic effect of nanosilver is mediated by a ROS-and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells
Toxicol. Lett.
Role of cell cycle events and apoptosis in mediating the anti-cancer activity of a silver (I) complex of 4-hydroxy-3-nitro-coumarin-bis (phenanthroline) in human malignant cancer cells
Eur. J. Pharmacol.
Study on potential antitumor mechanism of quinoline-based silver (I) complexes: synthesis, structural characterization, cytotoxicity, cell cycle and caspase-initiated apoptosis
Inorg. Chem. Commun.
Multiparametric staining to identify apoptotic human cells
Exp. Cell Res.
Macrophage and colon tumor cells as targets for a binuclear silver(I) N-heterocyclic carbene complex, an anti-inflammatory and apoptosis mediator
J. Inorg. Biochem.
Multicellular tumor spheroids as a model for assessing delivery of oligonucleotides in three Dimensions
Mol. Ther. Nucleic Acids
Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system
Exp. Cell Res.
N-heterocyclic carbenes. effective tools for organometallic synthesis
N-Heterocyclic carbenes
An overview of N-heterocyclic carbenes
Nature
Olefin metathesis catalyst: Stabilization effect of backbone substitutions of N-heterocyclic carbene
Org. Lett.
Stabilization of organometallic species achieved by the use of N-heterocyclic carbene (NHC) ligands
Eur. J. Inorg. Chem.
Rate and Equilibrium Constants for the addition of n-heterocyclic carbenes into Benzaldehydes: a remarkable 2-substituent effect
Angew. Chem.
Determining the ligand properties of n-heterocyclic carbenes from 77Se NMR parameters
Eur. J. Inorg. Chem.
Versatile Relay and Cooperative palladium (0) N-Heterocyclic Carbene/Copper (I) n-heterocyclic carbene catalysis for the synthesis of Tri-and tetrasubstituted alkenes
ChemCatChem
Recent advances in employing homoenolates generated by N-heterocyclic carbene (NHC) catalysis in carbon–carbon bond-forming reactions
Chem. Soc. Rev.
Cooperative catalysis of N-heterocyclic carbene and Brønsted acid for a highly enantioselective route to unprotected spiro-indoline-pyrans
Chem. Commun.
Cited by (59)
Synthesis, characterization and molecular docking of benz-imidazolium Se-adducts: Antimicrobial and anticancer studies
2024, Journal of Molecular StructureSilver(I) complexes containing N-heterocyclic carbene azole drugs: Synthesis, characterization, cytotoxic activity, and their BSA interactions
2023, Journal of Inorganic BiochemistrySynthesis, Structure and DNA-binding Property of a 14 Nuclear Silver(I) Ferrocenylacetylide Cluster
2023, Journal of Molecular StructureO-Halogen-substituted arene linked selenium-N-heterocyclic carbene compounds induce significant cytotoxicity: Crystal structures and molecular docking studies
2023, Journal of Organometallic ChemistryAroylhydrazone Cu(Ⅱ) complexes: Syntheses, crystal structures, and anticancer properties
2021, Journal of Molecular Structure