Rosenani A. Haque

Silver(I) complexes of mono- and bidentate N-heterocyclic carbene ligands: Synthesis, crystal structures, and in vitro antibacterial and anticancer studies

A series of benzimidazole-based N-heterocyclic carbene (NHC) proligands {1-benzyl-3-(2-methylbenzyl)-benzimidazolium bromide/hexafluorophosphate (1/4), 1,3-bis(2-methylbenzyl)-benzimidazolium bromide/hexafluorophosphate (2/5) and 1,3-bis(3-(2-methylbenzyl)-benzimidazolium-1-ylmethylbenzene dibromide/dihexafluorophosphate (3/6)} has been synthesized by the successive N-alkylation method. Ag complexes {1-benzyl-3-(2-methylbenzyl)-benzimidazol-2-ylidenesilver(I) hexafluorophosphate (7), 1,3-bis(2-methylbenzyl)-benzimidazol-2-ylidenesilver(I) hexafluorophosphate (8) and 1,3-bis(3-(2-methylbenzyl)-benzimidazol-2-ylidene)-1-ylmethylbenzene disilver(I) dihexafluorophosphate (9)} of NHC ligands have been synthesized by the treatment of benzimidazolium salts with Ag2O at mild reaction conditions. Both, NHC proligands and Ag-NHC complexes have been characterized by (1)H and (13)C{(1)H} NMR and FTIR spectroscopy and elemental analysis technique. Additionally, the structure of the NHC proligand 5 and the mononuclear Ag complexes 7 and 8 has been elucidated by the single crystal X-ray diffraction analysis. Both the complexes exhibit the same general structural motif with linear coordination geometry around the Ag centre having two NHC ligands. Preliminary in vitro antibacterial potentials of reported compounds against a Gram negative (Escherichia coli) and a Gram positive (Bacillus subtilis) bacteria evidenced the higher activity of mononuclear silver(I) complexes. The anticancer studies against the human derived colorectal cancer (HCT 116) and colorectal adenocarcinoma (HT29) cell lines using the MTT assay method, revealed the higher activity of Ag-NHC complexes. The benzimidazolium salts 4-6 and Ag-NHC complexes 7-9 displayed the following IC50 values against the HCT 116 and HT29 cell lines, respectively, 31.8 ± 1.9, 15.2 ± 1.5, 4.8 ± 0.6, 10.5 ± 1.0, 18.7 ± 1.6, 1.20 ± 0.3 and 245.0 ± 4.6, 8.7 ± 0.8, 146.1 ± 3.1, 7.6 ± 0.7, 5.5 ± 0.8, 103.0 ± 2.3 μM.

Potential of silver against human colon cancer: (synthesis, characterization and crystal structures of xylyl (Ortho, meta, &Para) linked bis-benzimidazolium salts and Ag(I)-NHC complexes: In vitro anticancer studies).

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.

Sterically tuned Ag(I)- and Pd(II)-N-heterocyclic carbene complexes of imidazol-2-ylidenes: synthesis, crystal structures, and in vitro antibacterial and anticancer studies

Unsymmetrically substituted sterically tuned Pd(II)–NHC complexes of the general formula [PdCl2(NHC)2] (NHC = 1-allyl-3-methylimidazolin-2-ylidene, 7; 1-allyl-3-butylimidazol-2-ylidene, 8; 1-benzyl-3-butyl imidazolin-2-ylidene, 9) were prepared through transmetallation from their corresponding Ag(I)–NHC complexes. The Pd complexes were structurally characterized by different spectroscopic and X-ray diffraction methods. Complexes 7 and 9 adopted a trans–anti arrangement of the NHC ligands, whereas complex 8 adopted a cis–syn arrangement. Preliminary antibiogram studies using Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria showed that Ag(I)–NHC complexes demonstrate higher activity compared with Pd(I)–NHC complexes. Furthermore, Pd(II)–NHC complexes were evaluated for their anticancer potential using the human colorectal cancer cell line. A higher anticancer activity was observed for complexes 8 and 9, with 26.5 and 6.6 mM IC50 values, respectively.

Design, synthesis and structural studies of meta-xylyl linked bis-benzimidazolium salts: potential anticancer agents against 'human colon cancer'.

BackgroundBenzimidazole derivatives are structurally bioisosteres of naturally occurring nucleotides, which makes them compatible with biopolymers of living systems. This property gives benzimidazole a biological and clinical importance. In the last decade, this class of compounds has been reported to possess anti-allergic, anti-diabatic, anti-HIV, anti-hypertensive, anti-inflammatory, anti-mycobacterial, anti-oxidant, anti-protozoal, and anti-viral properties. The researchers are now interested to explore their potential as anti-cancer agents. In the present study, an effort was made to further explore this area of research. Furthermore, in order to increase the solubility and efficacy of these heterocycles, the interest is now shifted to the salts of these compounds. With this background, we planned to synthesize a series of meta-xylyl linked bis-benzimidazolium salts to assess their anti-proliferation efficacy on human colon cancer cell line (HCT 116).ResultsA number of N-alkylbenzimidazoles were synthesized by reactions of benzimidazole with alkyl halides (i-PrBr, PrBr, EthBr, Pent-2-ylBr, BuBr, BenzCl, HeptBr). The subsequent treatment of the resulting N-alkylbenzimidazoles with 1,3-(bromomethylene)benzene afforded corresponding bis-benzimidazolium salts. All synthesized compounds were characterized by spectroscopic techniques (Additional file 1: NMR & FT-IR) and microanalysis. Molecular structures of selected compounds were established through single crystal x-ray diffraction studies. All the compounds were assessed for their anti-proliferation test on human colorectal cancer cell line (HCT 116). Results showed that the compounds exhibited dose dependent cytotoxicity towards the colon cancer cells with IC50 ranges between 0.1 to 17.6 μM. The anti-proliferation activity of all compounds was more pronounced than that of standard reference drug 5-flourouracil (IC50 =19.2 μM).ConclusionsAll the synthesized bis-benzimidazolium salts showed potential anticancer activity. Out of them, some of these salts showed IC50 value as low as 0.1–0.2 μM. Based on the results it can be concluded that, the bis-benzimidazolium salts could probably be the potential source of chemotherapeutic drugs.

Macrophage and colon tumor cells as targets for a binuclear silver(I) N-heterocyclic carbene complex, an anti-inflammatory and apoptosis mediator.

Chronic inflammation intensifies the risk for malignant neoplasm, indicating that curbing inflammation could be a valid strategy to prevent or cure cancer. Cancer and inflammation are inter-related diseases and many anti-inflammatory agents are also used in chemotherapy. Earlier, we have reported a series of novel ligands and respective binuclear Ag(I)-NHC complexes (NHC=N-heterocyclic carbene) with potential anticancer activity. In the present study, a newly synthesized salt (II) and respective Ag(I)-NHC complex (III) of comparable molecular framework were prepared for a further detailed study. Preliminarily, II and III were screened against HCT-116 and PC-3 cells, wherein III showed better results than II. Both the compounds showed negligible toxicity against normal CCD-18Co cells. In FAM-FLICA caspase assay, III remarkably induced caspase-3/7 in HCT-116 cells most probably by tumor necrosis factor-alpha (TNF-α) independent intrinsic pathway and significantly inhibited in vitro synthesis of cytokines, interleukin-1 (IL-1) and TNF-α in human macrophages (U937 cells). In a cell-free system, both the compounds inhibited cyclooxygenase (COX) activities, with III being more selective towards COX-2. The results revealed that III has strong antiproliferative property selectively against colorectal tumor cells which could be attributed to its pro-apoptotic and anti-inflammatory abilities.

Dinuclear silver(I)-N-heterocyclic carbene complexes of N-allyl substituted (benz)imidazol-2-ylidenes with pyridine spacers: synthesis, crystal structures, nuclease and antibacterial studies

The synthesis, structures and antibacterial studies of silver complexes of N-heterocyclic carbene (NHC) ligands are reported. The NHC precursors, 2,6-bis(3-allylimidazol-1-ylmethyl) pyridine hexafluorophosphate (1) and 2,6-bis(3-allylbenzimidazol-1-ylmethyl)pyridine dibromide (2) were treated with Ag2O to yield 2,6-bis(3-allylimidazol-1-ylmethyl)pyridine disilver bis(hexafluorophosphate) (3) and 2,6-bis(3-allylbenzimidazolium-1-ylmethyl)pyridine disilver bis(hexafluorophosphate) (4). All four compounds were characterized by physico-chemical and spectroscopic techniques and by single-crystal X-ray diffraction. The compounds were screened for their antibacterial activities against Staphylococcus aureus (ATCC 12600) as a Gram-positive and Escherichia coli (ATCC 11303) as a Gram-negative bacteria. Compounds 1 and 2 showed no inhibition while 3 and 4 inhibited the growth of these bacteria. The nuclease activities of the compounds were evaluated by gel electrophoresis, and the results indicate that complexes 3 and 4 can degrade both DNA and RNA.

Synthesis, crystal structures, in vitro anticancer, and in vivo acute oral toxicity studies of bis-imidazolium/benzimidazolium salts and respective dinuclear Ag(I)-N-heterocyclic carbene complexes

The synthesis, spectral (FT-IR and NMR), and structural studies of 1,1′-methylene linked 3,3′-2-cyanobenzyl bis-imidazolium salt (L1) and respective dinuclear Ag(I)-NHC complex (C1) are reported. The structures of both compounds were established through single-crystal X-ray diffraction. C1 has a short Ag–Ag separation of 3.16 Å. Both L1 and C1 were tested for potential against leukemia (k562) cell line. For comparison, para-xylyl linked bis-benzimidazolium salts (L2–L4) and their dinuclear Ag(I)-NHC complexes (C2–C4) were synthesized and tested against the same cell line (K562). The IC50 values proved that L2–L4 and C2–C4 are many fold more active than L1 and C1. The mechanism of action and structure activity relationship are discussed. In vivo oral acute toxicity study (sighting study) was carried out which depicts that 2000 mg/kg dose of selected compounds is an appropriate and safe dose for conducting main study on animals.

A new dinuclear Ag(I)–N-heterocyclic carbene complex derived from para-xylyl linked bis-imidazolium salt: synthesis, crystal structure, and in vitro anticancer studies

This manuscript describes synthesis, spectral (FT-IR and NMR), and structural studies of a new para-xylyl linked bis-imidazolium salt (1) and the dinuclear Ag(I)–N-heterocyclic carbene complex (2). Both 1 and 2 were tested for their potential against human colon cancer (HCT 116) and breast cancer (MCF-7) cell lines. According to cell viability measurements using MTT assay, the test compounds showed dose-dependent cytotoxic activities against both cell lines. The complex displayed significant activity (IC50 = 20.9 μM for HCT 116 and 2.4 μM for MCF-7) compared to their respective imidazolium salt (IC50 > 200 μM for HCT 116 and  = 137 μM for MCF-7). The photomicrographs of the cells treated with 2 revealed that the cytotoxic efficacy of 2 is mainly by deposition of silver in the cytoplasm of the affected cells since clear signs of black silver deposits in the cytoplasm of the affected cells were observed.

A new binding geometry for an ortho-xylylene-linked bis(NHC)cyclophane: a ruthenium(II) complex with a chelating (η1-NHC)2:η6-arene ligand

Using two different reaction procedures, a Ru(II) complex has been isolated that contains an ortho-xylylene-linked bis(NHC)cyclophane (NHC = N-heterocyclic carbene) that binds to the Ru centre through two carbene carbons and one of the arene rings in an eta(6)-mode.

Crystal Structure Elucidation and Anticancer Studies of (-)-Pseudosemiglabrin: A Flavanone Isolated from the Aerial Parts of Tephrosia apollinea

Tephrosia apollinea is a perennial shrublet widely distributed in Africa and is known to have medicinal properties. The current study describes the bio-assay (cytotoxicity) guided isolation of (-)-pseudosemiglabrin from the aerial parts of T. apollinea. The structural and stereochemical features have been described using spectral and x-ray crystallographic techniques. The cytotoxicity of isolated compound was evaluated against nine cancer cell lines. In addition, human fibroblast was used as a model cell line for normal cells. The results showed that (-)-pseudosemiglabrin exhibited dose-dependent antiproliferative effect on most of the tested cancer cell lines. Selectively, the compound showed significant inhibitory effect on the proliferation of leukemia, prostate and breast cancer cell lines. Further studies revealed that, the compound exhibited proapoptotic phenomenon of cytotoxicity. Interestingly, the compound did not display toxicity against the normal human fibroblast. It can be concluded that (-)-pseudosemiglabrin is worthy for further investigation as a potential chemotherapeutic agent.