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March 27, 2005 Melanie Eelman

The Coordination Chemistry of Bismuth(III) Complexes and Other Heavy Metals with Biorelevant Ligands. March 27, 2005 Melanie Eelman. Overview. Medicinal relevance of bismuth chemistry Pepto-Bismol  De-Nol  Use of thiolate anchors on hetero-bifunctional ligands

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March 27, 2005 Melanie Eelman

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  1. The Coordination Chemistry of Bismuth(III) Complexes and Other Heavy Metals with Biorelevant Ligands March 27, 2005 Melanie Eelman

  2. Overview • Medicinal relevance of bismuth chemistry • Pepto-Bismol • De-Nol • Use of thiolate anchors on hetero-bifunctional ligands • Study interactions of bismuth with “weak” donors • Use of electrospray ionization mass spectrometry (ESI-MS) • Identify metal-ligand complexes • Characterization of interactions between bismuth and other heavy metals (e.g. lead, arsenic) and key biomolecules

  3. Bismuth: 250 Years of Medicinal Use Bismuth(III) Salts: • Treatments for: • nitrate • oxide • salicylate • citrate • tartrate • malate • oxalate • lactate • syphilis • bacterial infections • colitis • cancer • hypertension • diarrhea • dyspepsia • gastric/duodenal ulcers P.J. Sadler, H. Li, H. Sun,Coord. Chem. Rev., 1999, 185-186, 689 G.G. Briand, N. Burford,Chem. Rev., 1999, 99, 2601.

  4. Bismuth Pharmaceutical Agents Colloidal Bismuth Subcitrate (CBS) Active Ingredient of De-Nol Herrmann, Inorg. Chem., 1991, 30, 2579; Asato, Inorg. Chem., 1991, 30, 4210; Herrmann, Z. Kristallogr., 1992, 198, 25; Asato, Chem. Lett, 1992, 1967; Asato, Inorg. Chem., 1993, 32, 5322; Asato, Inorg. Chem., 1995, 34, 2447; Sadler, Dalton Trans., 1996, 2417 Bismuth Subsalicylate (BSS) Active Ingredient of Pepto-Bismol J.H. Thurston, E.M. Marlier, K.H. Whitmire,Chem. Commun., 2002, 2834. Dimeric in the solid state

  5. Mechanisms of bioactivity of bismuth is unknown Chemistry of bismuth is ill-defined Low solubility (i.e. BSS) Facile hydrolysis of Bi-element bonds Objective: Development of synthetic approaches to systematic series of bismuth compounds and definitive characterisation Bismuth is thiophilic Use of ligands containing sulfur Developing the Coordination Chemistry of Bismuth

  6. y L U M O g r e n L U M O E H O M O H O M O A A - B B A - B A B C l N a B H a r d S o f t Thiophilicity Preference for certain atoms (heavy metals) to form strong bonds with sulfur Explained by:hard-soft acid-base theory 3 i - S R R. G. Pearson, J.Am.Chem.Soc.1963, 85 , 3533

  7. + Dithiolate Ligands Comprehensive characterization of a series of bismuth-dithiolate compounds: P. Powell, J.Chem.Soc.(A)1968, 2587. L. Agocs, N. Burford, T. S. Cameron, J. M. Curtis, J. F. Richardson, K. N. Robertson, G.B. Yhard JACS1996, 126, 895.

  8. S B i E S S E = O H , N Me 2 Thiolate Anchored Hetero-Bifunctional Ligands Investigate interactions of “weak” donors (E) with bismuth E = OH E = NMe2 E = NH2 E = C(O)OMe L. Agocs, G.G. Briand, N. Burford, M.D. Eelman, N. Aumeerally, D. MacKay, K.N. Robertson, T.S. Cameron,Can. J. Chem., 2003, 81,632.

  9. O R O R O R R O S S S O O O O C l B i B i B i S S S C l C l O O R O R O E = C ( O ) O R ; e s t e r f u n c t i o n a l g r o u p R = Me, Et Hetero-Bifunctional Thiolate Ligands Can correlate isolated complexes to those identified using ESI-MS L. Agocs, G.G. Briand, N. Burford, T.S. Cameron, W. Kwiatkowski, K.N. Robertson Inorg. Chem. 1997, 36, 2855. G.G. Briand, N. Burford, T.S. Cameron, W. Kwiatkowski, J.Am.Chem.Soc. 1998, 120, 11374. G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.

  10. The Importance of Electrospray Ionization Mass Spectrometry ‘ESI-MS’ • Bismuth compounds hard to characterize • NMR • EI-MS • Advantages of ESI-MS • Dilute solutions • Can handle ill-defined reaction mixtures: “in situ ESI-MS” • Intact metal-ligand complexes Electrospray Ionization (ESI) Desolvation Spray Shield - + Produces gaseous ionized molecules from a liquid solution by creating a spray of droplets in the presence of a strong electric field - + - Needle + - + + - + - + - + + Capillary + - - Liquid Flow + - - - - + + + - + - - + + + - - + + - + - + - - + + - Taylor Cone - + Coulombic Explosion Desolvated Ions End Plate

  11. BiCl3 + + HCl methyl thioglycolate (MTG) 25% Yield Synthesis of the Mono(Ester-Thiolate) Complex of Bismuth Transesterification occurring: Acid catalyzed and driven to completion by the use of excess ethanol G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.

  12. ESI-MS of BiCl3 and MTG in Absolute Ethanol Peak assignments confirmed by MS/MS G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.

  13. Bis(Methylester-Thiolato) Bismuth Complex BiCl3 + 2 + 2HCl methyl thioglycolate (MTG) 47% Yield Polymeric in solid state G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.

  14. Tris(Methylester-Thiolato) Bismuth Complex BiCl3 + 3KOH +3 + 3H2O methyl thioglycolate (MTG) 26% Yield Model of CBS! CBS G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136. E. Asato, K. Katsura, M. Mikuriya, T. Fujii, J. Reedijk,Inorg.Chem.1993, 32 5322-5329.

  15. ESI-MS ofBiCl3 and 3 (MTG + KOH) in 95% Ethanol Peak assignments confirmed by ESI-MS/MS G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.

  16. Tris(Methylthiosalicylato) Bismuth(III) Complex BiCl3 + 3 + 3KOH + 3H2O methylthiosalicylate (MTS) 66% Yield • N. Burford, M.D. Eelman, T.S. Cameron, Chem.Commun.2002, 1402

  17. ‘BSS’ c.f. Model of ‘BSS’ • N. Burford, M.D. Eelman, T.S. Cameron, Chem.Commun.2002, 1402 J.H. Thurston, E.M. Marlier, K.H. Whitmire,Chem. Commun., 2002, 2834.

  18. BSS L-cysteine BiCl3 + n Bi(NO3)3 glutathione Cys n = 1-3 ESI-MS Identification of Bismuth Complexes Containing L-Cysteine and Glutathione Tripeptide:

  19. 1:1 1:2 ESI-MS of BSS and L-Cysteine in Aqueous Solution Peak assignments confirmed by MS/MS Burford, N.; Eelman, M.D.; Mahony, D.; Morash, M. Chem. Commun.2003, 146-147.

  20. 1:1 1:2 ESI-MS of Bi(NO3)3 and Glutathione in Aqueous Solution Peak assignments confirmed by ESI-MS/MS Burford, N.; Eelman, M.D.; Mahony, D.; Morash, M. Chem. Commun.2003, 146-147.

  21. ESI-MS Data for Mixtures of Bi(NO3)3 and an Amino Acid in 50% EtOH Peak assignments confirmed by MS/MS Burford, N.; Eelman, M.D.; LeBlanc, W.G. Can. J. Chem. 2004, 82, 1254-1259. Briand, G.G.; Burford, N.; Eelman, M.D.; Aumeerally, N.; Chen, L.; Cameron, T.S.; Robertson, K.N. Inorg. Chem. 2004, 43, 6495.

  22. Bi:Am Assignments: Structural Possibilities Am = Conjugate base of the amino acid

  23. L-cysteine kinetically will stabilize coordination of amino acid conjugates to bismuth Facilitating Interactions of Other Amino Acids With Bismuth Hypothesis: General Procedure: Am = Conjugate base of the amino acid

  24. Facilitating Interactions of Other Amino Acids With Bismuth Using L-Cysteine Peak assignments confirmed by MS/MS

  25. Amino Acids That Do Not Interact With Bismuth

  26. 1:1 1:2 ESI-MS of Bi(NO3)3 and Glutathione in Aqueous Solution Burford, N.; Eelman, M.D.; Mahony, D.; Morash, M. Chem. Commun.2003, 146-147.

  27. The First Bismuth Complex Containing a Biomolecule Ligand Stabilisation Yield: 31% Briand, G.G.; Burford, N.; Eelman, M.D.; Aumeerally, N.; Chen, L.; Cameron, T.S.; Robertson, K.N. Inorg. Chem. 2004, 43, 6495.

  28. Equilibria and Tautomerism for Cysteine

  29. Comparison with a Derivative of a Bismuth-Amino Acid Complex c.f. Herrmann, 1993 Bi(Cys)(Phen)(NO3)2H2O Bi(Cys)(Phen)(NO3)2H2O is more viable in acidic media and is a closer model of the potential interaction of bismuth with cysteine in the gastric environment!

  30. = toxic Consider the Other Heavy Metals How do the other heavy metals interact with the amino acids? As Cd Sb Bi Hg Tl Pb = bioactive

  31. Same ESI-MS method used for bismuth-amino acid mixtures Pb forms kinetically stable complexes with allof the essential amino acids All amino acids:1:1, 1:2, 2:2 and 2:3 Pb:Am ratios Thr, Met, Asp:3:2 Pb:Am ratios Ala, Val, His, Glu, Arg, Pro: Form Pb:Am complexes containing H2O or NO3 Arg:1:1, 1:2, 1:4, 1:5, 1:6and Pb:Am ratios Identification of Lead-Amino Acid Adducts by ESI-MS Burford, N.; Eelman, M.D.; LeBlanc, W.G.; Cameron, T.S.; Robertson, K.N. Chem. Commun. 2004, 332.

  32. ESI-MS of Pb(NO3)2 and L-Threonine in 50% EtOH Peak assignments confirmed by MS/MS

  33. N H 2 O P b ( N O ) + 3 2 O H 5 0 % E t O H Synthesis of the First Lead-Amino Acid Complex Yield: 55% Zwitterionic valines

  34. As3+ 5: Ser, Thr, Cys, Asn, Gln Sb3+ 4: His, Cys, Glu, Gln Tl+ 21 Hg2+ 21 Cd2+ 21 Identification of Interactions Between Heavy Metals and Amino Acids Using ESI-MS Metal Bi3+ Pb2+ # amino acids 7: His, Thr, Met, Cys, Hcys, Asn, Gln 21

  35. ESI-MSoffers a powerful new technique in understanding heavy metal bio-incorporation Study interactions of other small and larger biomolecules with all heavy metals by virtue of their distinctive m/z values The solid state structures of a bismuth-cysteine and lead-valine complexes are the first examples involving amino acids for both Consistent with assignments of ESI-MS data Insight into the coordination mode for cysteine in the acidic gastric environment Summary

  36. Dr. Neil Burford Wes LeBlanc The Burford Group Dr. T.S. Cameron and Dr. K.N. Robertson (DALX) Maritime Mass Spectrometry Laboratories Canada Research Chairs Program Nova Scotia Research and Innovation Trust Fund Acknowledgments

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