title: 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).
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  N-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.
  
  
  CONCLUSIONS
  All 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.
authors: The School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia. rosenani@usm.my.
authors: Muhammad Adnan
authors: MA
authors: Iqbal
authors: Rosenani A
authors: RA
authors: Haque
authors: Siti Fatimah
authors: SF
authors: Nasri
authors: Ams Abdul
authors: AA
authors: Majid
authors: Mohamed B Khadeer
authors: MB
authors: Ahamed
authors: Elham
authors: E
authors: Farsi
authors: Tabinda
authors: T
authors: Fatima
references: J Am Chem Soc. 2011 Nov 9;133(44):17594-7
references: 21981727
references: Acta Crystallogr Sect E Struct Rep Online. 2012 Jun 1;68(Pt 6):o1635
references: 22719436
references: Chem Cent J. 2012 Jul 27;6(1):73
references: 22839208
references: Dalton Trans. 2004 Nov 7;(21):3756-64
references: 15510303
references: J Med Chem. 2004 Feb 12;47(4):973-7
references: 14761198
references: Chem Cent J. 2012 Jul 18;6(1):68
references: 22809051
references: Chem Soc Rev. 2013 Jan 21;42(2):755-73
references: 23147001
references: Bioorg Med Chem. 2012 Nov 1;20(21):6208-36
references: 23031649
references: Dalton Trans. 2010 Sep 21;39(35):8113-27
references: 20593091
references: Br J Nurs. 2005 Oct 27-Nov 9;14(19):S22, S24, S26 passim
references: 16301917
references: Acta Crystallogr Sect E Struct Rep Online. 2012 Apr 1;68(Pt 4):o924-5
references: 22589990
references: Angew Chem Int Ed Engl. 2006 Feb 20;45(9):1348-52
references: 16447297
references: Chem Rev. 2005 Nov;105(11):3978-4008
references: 16277368
references: Dalton Trans. 2009 Sep 21;(35):6894-902
references: 20449127
references: J Med Chem. 2011 Jul 28;54(14):5245-9
references: 21671598
references: Acta Crystallogr Sect E Struct Rep Online. 2011 Jul 1;67(Pt 7):o1814-5
references: 21837184
references: J Med Chem. 2011 Jan 13;54(1):3-25
references: 21077686
references: Acta Crystallogr Sect E Struct Rep Online. 2012 Mar 1;68(Pt 3):o573
references: 22412490
references: Angew Chem Int Ed Engl. 2011 Jan 24;50(4):804-5
references: 21246674
references: Chem Commun (Camb). 2011 Jul 21;47(27):7830-2
references: 21647511
references: Acta Crystallogr Sect E Struct Rep Online. 2011 Feb 16;67(Pt 3):o643
references: 21522396
references: Acta Crystallogr Sect E Struct Rep Online. 2011 Aug 1;67(Pt 8):o1931
references: 22090975
references: CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
references: 15761078
references: Nature. 1965 Feb 13;205:698-9
references: 14287410
references: ChemMedChem. 2012 May;7(5):805-14
references: 22383263
references: Metallomics. 2012 Jan;4(1):23-32
references: 22027962
references: Acta Crystallogr Sect E Struct Rep Online. 2012 Feb 1;68(Pt 2):o466-7
references: 22347075
references: Eur J Med Chem. 2011 Jun;46(6):2274-9
references: 21439689
references: Dalton Trans. 2013 Mar 14;42(10):3269-84
references: 23223752