Abstract
BackgroundSince the first successful synthesis of Ag(I)-N-heterocyclic carbene complex in 1993, this class of compounds has been extensively used for transmetallation reactions where the direct synthesis using other metal ions was either difficult or impossible. Initially, silver(I)-NHC complexes were tested for their catalytic potential but could not get fame because of lower potential compare to other competent compounds in this field; however, these compounds proved to have vital antimicrobial activities. These encouraging biomedical applications further convinced researchers to test these compounds against cancer. The current work has been carried out with this aim.ResultsN-ipropylbenzimidazole was synthesized by reaction of benzimidazole with ipropyl bromide. The subsequent treatment of the resulting N-alkylbenzimidazole with ortho/meta/para-(bromomethylene) benzene afforded corresponding bis-benzimidazolium bromides (5-7). The counter anion (Br-) of each salt was replaced by hexaflourophosphate (PF6-) for the ease of handling and further purification (8-10). Each salt (Ligand), in halide form, was further allowed to react with Ag2O with stirring at room temperature for a period of two days to synthesize dinuclear Ag(I)-NHC complexes (11-13). All synthesized compounds were characterized by spectroscopic techniques and microanalysis. Molecular structures of compounds 5, 9 &10 were established through single crystal x-ray diffraction technique. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116). Results showed that the ligands (5-10) showed mild to negligible cytotoxicity on HCT 116 cells whereas respective silver complexes (11-13) exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 9.7 to 44.5 μM. Interestingly, the complex 13 having para-xylyl spacer was found the most active (IC50 9.7 μM) that verifies our previously reported results.ConclusionsAll the bis-benzimidazolium salts (8-10) were found inactive whereas after bonding with silver cations, the Ag(I)-NHC complexes (11-13) showed a dose dependent cytotoxic activity. This proved that silver practice an important role in death of cancer cells. Also, the N-alkyl/aryl substitutions and ortho/metal/para xylyl units regulate the cytotoxicity.
Highlights
Since the first successful synthesis of Ag(I)-N-heterocyclic carbene complex in 1993, this class of compounds has been extensively used for transmetallation reactions where the direct synthesis using other metal ions was either difficult or impossible
Inspiring from our previous research on anticancer potential of benzimidazole based ligands and respective dinuclear Ag(I)-N-heterocyclic carbene (NHC) complexes [26,27,28], in this research, N-ipropyl substituted ortho/meta/para xylyl linked bisbenzimidazolium salts were synthesized either with bromide or hexaflourophosphate counter anions and were further bonded with silver metal ions in order to test their potential against cancer cells
In the case when product settled as a sticky brownish fluid at the bottom of flask, the upper layer was decanted and product was washed with fresh 1,4-dioxane (3 × 5ml)
Summary
Ag(I)-NHC complexes were found relatively active compared to the respective ligands indicating that silver cations play a vital role against cancer cells. Single crystals suitable for xray diffraction study were obtained by slow evaporation of saturated solution of title compound in methanol/ water (3:1) at room temperature. Synthesis of 3,3'-[(1,3-phenylenebis(methylene)]bis(1-ipropylbenzimidazolium) bis-hexaflourophosphate (6/9) Compound 6 was prepared according to the same procedure for 5; N-ipropyl benzimidazole (3.20 g, 0.02 mol) and 1,4-dibromomethyl benzene (2.36 g, 0.01 mol). Crystals suitable for x-ray diffraction study were obtained by slow evaporation of saturated solution of title compound in methanol/water (3:1) at room temperature. Synthesis of Ag-NHC Complexes (11-13) Synthesis of 3,3'-[1,2-phenylenebis(methylene)]bis(1-ipropylbenzimidazolium) disilver (I) bis(hexaflourophosphate) (11) Compound 5 (1.68 g, 0.002 mol) was dissolved in methanol (100 mL) alongwith Ag2O (0.7 g, 0.003 mol) with excluion of light by enveloping flask with aliminum foil. Synthesis of 3,3'-[1,4-phenylenebis(methylene)]bis(1-ipropylbenzimidazolium) disilver (I) bis(hexaflourophosphate) (13) Compound 13 was synthesized by following the same procedure for 8; Compound 7 (1.23 g, 0.002 mol) and Ag2O (0.7 g, 0.003 mol).
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