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The Coordination Chemistry of Bismuth(III) The Coordination Chemistry of Bismuth(III) Complexes and Other Heavy Metals with Biorelevant Complexes and Other Heavy Metals with Biorelevant
LigandsLigands
March 27, 2005March 27, 2005
Melanie EelmanMelanie Eelman
OverviewOverview• 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
Bismuth: 250 Years of Medicinal UseBismuth: 250 Years of Medicinal Use
P.J. Sadler, H. Li, H. Sun, Coord. Chem. Rev., 1999, 185-186, 689 G.G. Briand, N. Burford, Chem. Rev., 1999, 99, 2601.
Treatments for:Treatments for: • syphilis• bacterial infections• colitis• cancer• hypertension• diarrhea• dyspepsia• gastric/duodenal ulcers
Bismuth(III) Salts:Bismuth(III) Salts:• nitrate• oxide• salicylate• citrate• tartrate• malate• oxalate• lactate
Bismuth Pharmaceutical AgentsBismuth Pharmaceutical Agents
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
Active Ingredient of De-NolDe-Nol
OBi
O
O O
O BiO
O
OO
OO
OO
O
K
K
Dimeric in the solid stateDimeric in the solid state
Colloidal Bismuth Subcitrate(CBS)
OH
O
O
Bi
ON N
O
O
OH
OO
O
Bi
NN
O
O
OH
OO
O
Bi
J.H. Thurston, E.M. Marlier, K.H. Whitmire, Chem. Commun., 2002, 2834.
Active Ingredient of Pepto-BismolPepto-Bismol
Bismuth Subsalicylate(BSS)
• Mechanisms of bioactivity of bismuth is unknown
• Chemistry of bismuth is ill-defined• Low solubility (i.e. BSS)• Facile hydrolysis of Bi-element bonds
Developing the Coordination Developing the Coordination Chemistry of BismuthChemistry of Bismuth
Development of synthetic approaches to systematic series of bismuth compounds and
definitive characterisation
Objective:Objective:
Bismuth is thiophilic Use of ligands containing sulfur
ThiophilicityThiophilicityPreference for certain atoms (heavy metals) to form
strong bonds with sulfur
Explained by: hard-soft acid-base theory
R. G. Pearson, J.Am.Chem.Soc. 1963, 85 , 3533
En
erg
y
Hard Soft
LUMO
HOMO
LUMO
HOMO
A-B A-BA B A B
Na Cl Bi3 -SR
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 JACS 1996, 126, 895.
Dithiolate LigandsDithiolate LigandsComprehensive characterization of a series of bismuth-dithiolate compounds:Comprehensive characterization of a series of bismuth-dithiolate compounds:
Bi
Cl
Cl Cl
SHHSn
SBi
S SBi
S SBi
SS SBi
S
Cl Cl ClClS SBi
O
Cl
S
BiSS
BiS
S
SBi
X
X X
SHHS
23
SHS
HS
S SBi
S
X
2+
S
SBi
S
SS
SBi
SS
S
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.
Investigate interactions of “weak” donors (E) with bismuthInvestigate interactions of “weak” donors (E) with bismuth
SBi
S
S
E
E = OH, NMe2
Thiolate Anchored Hetero-Bifunctional LigandsThiolate Anchored Hetero-Bifunctional Ligands
SBi
S
ClEKS
S SBi
S
Cl
EKS S SBi
S
S
E = NH2, C(O)OR
E
E = OHE = OH E = NMeE = NMe22
E = NHE = NH22E = C(O)OMeE = C(O)OMe
Hetero-Bifunctional Thiolate LigandsHetero-Bifunctional Thiolate Ligands
Bi
S
Cl
E Bi
S
ES
E
Bi
S
E
E
S S
ECl
E = NR2
E = OH
Cl
E is a "weak" donor
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.
Can correlate isolated Can correlate isolated complexes to those identified complexes to those identified using ESI-MSusing ESI-MS
Bi
S
Cl
O Bi
S
OS
OBi
S
O
O
S S
OCl
Cl
OROR
RO
OR
RO
RO
E = C(O)OR; ester functional group
R = Me, EtR = Me, Et
The Importance of Electrospray Ionization The Importance of Electrospray Ionization Mass Spectrometry ‘ESI-MS’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
End PlateEnd Plate
++
+
++
+
+- -
--
-
---
+
+
-
-
-+
-+DesolvatedDesolvatedIonsIons
-
-
-- +
++
+
+
+
Desolvation
CoulombicCoulombicExplosionExplosion
--
--+++
+
--
--+++
+
Capillary
Spray ShieldSpray Shield
Liquid Flow
NeedleNeedle
Taylor ConeTaylor Cone
Electrospray Ionization (ESI)Electrospray Ionization (ESI)
Produces gaseous ionized molecules from a liquid solution by creating a spray of droplets in the presence of a strong electric field
Synthesis of the Mono(Ester-Thiolate) Synthesis of the Mono(Ester-Thiolate) Complex of BismuthComplex of Bismuth
Acid catalyzed and driven to completion by the use of excess ethanol
Transesterification occurring:
+ EtOH + MeOH
Bi
S
ClCl
O
OEt
Bi
S
ClCl
O
OMe
+BiCl3HS
OMe
O
EtOHAbsolute
+ HClBi
S
ClCl
O
OEt
methyl thioglycolate (MTG) 25% Yield
G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.
ESI-MS of BiClESI-MS of BiCl33 and MTG in Absolute Ethanol and MTG in Absolute Ethanol
Bi
SO
O
OR
S
Bi
Cl
OS
O
RO
S
OR
OR
R = Et
Bi
S
OS
S
O
OR
OR
R = Et
O
RO
Na
BiS
O
SO
OR
ORCl
R = Et
Na
BiS
O
SO
OR
ORR = Et
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.
Bis(Methylester-Thiolato) Bismuth ComplexBis(Methylester-Thiolato) Bismuth Complex
BiS
O
SO
Cl
OMe
OMe
+ 2BiCl3 HSOMe
O
95% EtOH
+ 2HCl
methyl thioglycolate (MTG)47% Yield
G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.
Bi
SO
O
OR
S
Bi
S
OS
OO
OR
S
OR
OR
RO
Bi
S
OS
S
O
OR
OR
O
RO
Na
Bi
S
OS
O
OR
OR
Polymeric in Polymeric in solid statesolid state
Tris(Methylester-Thiolato) Bismuth ComplexTris(Methylester-Thiolato) Bismuth Complex
+3BiCl3 HSOMe
O
95% EtOH
+ 3H2O
methyl thioglycolate (MTG)
26% Yield
Bi
S
O
O
S S
O
MeO
OMeMeO
+ 3KOH
G.G. Briand, N. Burford, M.D. Eelman, T.S. Cameron, K.N. Robertson Inorg. Chem. 2003, 42, 3136.
Bi
S
OS
O
O
OMe
S
Bi
S
OS
O
O
OMe
S
OMe
OMe
OMe
MeO
OBi
O
O O
O BiO
O
OO
OO
OO
O
K
K
CBSCBS
Model of CBS!Model of CBS!
E. Asato, K. Katsura, M. Mikuriya, T. Fujii, J. Reedijk, Inorg.Chem. 1993, 32 5322-5329.
ESI-MS ofBiClESI-MS ofBiCl33 and 3 (MTG + KOH) in 95% Ethanol and 3 (MTG + KOH) in 95% Ethanol
Bi
SO
O
OR
S
Bi
S
O
S
O
O
RO
S
OR
OR
RO
R = Me
O
S
RO
K
Bi
S
OS
S
O
OR
OR
O
RO
A = K; R = MeA =Na; R = Me
A
BiS
O
SO
OR
OR
R = Me
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.
Tris(Methylthiosalicylato) Bismuth(III) ComplexTris(Methylthiosalicylato) Bismuth(III) Complex
SBi
S
S
O
OMe
O
MeO
O
MeO
+ 3BiCl3
OMe
O
SH
95% EtOH
+ 3H2O
methylthiosalicylate (MTS)
66% Yield
+ 3KOH
N. Burford, M.D. Eelman, T.S. Cameron, Chem.Commun. 2002, 1402
749.1
356.9
372.9
A = Na
Bi
SS
O
MeO
O
MeO
732.9
616.9407.1
212.0
542.9
A = K
SBi
S
S
O
OMe
O
MeO
O
MeO
A
Model of ‘BSS’Model of ‘BSS’
J.H. Thurston, E.M. Marlier, K.H. Whitmire, Chem. Commun., 2002, 2834.
N. Burford, M.D. Eelman, T.S. Cameron, Chem.Commun. 2002, 1402
OH
O
O
Bi
O
‘BSS’
SBi
S
S
O
OMe
O
MeO
O
MeO
SBi
S
S
OOMe
OMeO
O
OMe
NNO
OO
O OO
OH
OHOH
Bi
NN
OOO
OOO
HO
HO
HO
Bi
N N
O
O
OH
OO
O
Bi
NN
O
O
OH
OO
O
Bi
c.f.
Glutathione =HO N
H
HN
OH
O O
O
O
NH2
SHTripeptide:
ESI-MS Identification of Bismuth Complexes ESI-MS Identification of Bismuth Complexes Containing L-Cysteine and GlutathioneContaining L-Cysteine and Glutathione
Cys
L-cysteine =
OH SH
O
NH2
BSS L-cysteine BiCl3 + nBi(NO3)3 glutathione
50% EtOH or H2O
n = 1-3
ESI-MS of BSS and L-Cysteine in Aqueous SolutionESI-MS of BSS and L-Cysteine in Aqueous Solution
Peak assignments confirmed by MS/MSBurford, N.; Eelman, M.D.; Mahony, D.; Morash, M. Chem. Commun. 2003, 146-147.
Bi
S
O S
O
O
O
NH3H3N
1:2S
Bi
O
O
NH2
1:1
ESI-MS of Bi(NOESI-MS of Bi(NO33))33 and Glutathione in Aqueous Solution and Glutathione in Aqueous Solution
Bi
S
O
H2N NH
O
O
Peak assignments confirmed by ESI-MS/MS
Bi
S
S
NH NH
NH NH
O
O
HO
O
OH
O
O
O
OHNH2
O
NH2
O
HO 1:2
Bi
S
H2N O
NH NH
O
O
OOH
O
1:1
Burford, N.; Eelman, M.D.; Mahony, D.; Morash, M. Chem. Commun. 2003, 146-147.
Amino Amino AcidAcid
m/zm/z Rel. Int. Rel. Int. (%)(%)
Assignment Assignment Bi:AmBi:Am
Amino Amino AcidAcid
m/zm/z Rel. Int. Rel. Int. (%)(%)
Assignment Assignment Bi:AmBi:Am
HisHis 516.9 5 1:2 CysCys 775.9 5 2:3
ThrThr 444.9 10 1:2 654.9 20 2:2
MetMet 881.7 20 2:3Na 449.0 45 1:2
859.7 40 2:3 328.0 100 1:1
710.7 10 2:2 HcysHcys 818.0 5 2:3
526.9 30 1:2Na 682.8 10 2:2
504.9 65 1:2 477.0 100 1:2
355.9 35 1:1 342.0 55 1:1
AsnAsn 471.1 5 1:2 GlnGln 498.9 10 1:2
ESI-MS Data for Mixtures of Bi(NOESI-MS Data for Mixtures of Bi(NO33))3 3 and an Amino and an Amino
Acid in 50% EtOHAcid in 50% EtOHPeak 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.
OR
Bi
O
NH2
OR
Bi
O
NH2
OR
O
H2N
OR
Bi
OHN
OR
Bi
O
H2N
OR
Bi
O
NH2O
R Bi
O
H2NO
NH2
O
R
1:1
1:2
2:2 2:3
Bi:Am Assignments: Structural PossibilitiesBi:Am Assignments: Structural Possibilities
Am = Conjugate base of the amino acid
• L-cysteine kinetically will stabilize coordination of amino acid conjugates to bismuth
Facilitating Interactions of Other Amino Acids Facilitating Interactions of Other Amino Acids With BismuthWith Bismuth
General Procedure:
Bi(NO3)3 + Cys + Am 50% EtOH
Am = Conjugate base of the amino acid
Hypothesis:Hypothesis:
Facilitating Interactions of Other Amino Acids With Bismuth Facilitating Interactions of Other Amino Acids With Bismuth Using L-CysteineUsing L-Cysteine
Amino Amino AcidAcid
m/zm/z AssignmentAssignment
Bi:Cys:AmBi:Cys:Am
Amino Amino AcidAcid
m/zm/z AssignmentAssignment
Bi:Cys:AmBi:Cys:Am
HisHis 482.9 1:1:1 HCysHCys 803.8 2:1:2
362.0 1:0:1 790.1 2:2:1
TrpTrp 859.1 2:2:1 462.9 1:1:1
532.2 1:1:1 AsnAsn 786.7 2:2:1
TyrTyr 508.9 1:1:1 459.9 1:1:1
SerSer 760.2 2:2:1 GlnGln 339.0 1:0:1
433.1 1:1:1 800.8 2:2:1
ThrThr 773.7 2:2:1 473.9 1:1:1
446.9 1:1:1 LysLys 800.7 2:2:1
MetMet 803.8 2:2:1 473.9 1:1:1
476.9 1:1:1 ArgArg 502.0 1:1:1
ProPro 443.2 1:1:1
Peak assignments confirmed by MS/MS
Amino Acids That Amino Acids That Do NotDo Not Interact Interact With BismuthWith Bismuth
H3NHC
R
C
O
O
General Structure:
Amino AcidAmino Acid -R Group-R Group
Gly -H
Ala -CH3
Val -CH(CH3)2
Leu -CH2CH(CH3)2
Ile -CH(CH3)CH(CH3)2
Phe -CH2Ph
Asp -CH2CO2H
Glu -CH2CH2CO2H
ESI-MS of Bi(NOESI-MS of Bi(NO33))33 and Glutathione in Aqueous Solution and Glutathione in Aqueous Solution
Burford, N.; Eelman, M.D.; Mahony, D.; Morash, M. Chem. Commun. 2003, 146-147.
Bi
S
O
H2N NH
O
O Bi
S
S
NH NH
NH NH
O
O
HO
O
OH
O
O
O
OHNH2
O
NH2
O
HO 1:2
Bi
S
H2N O
NH NH
O
O
OOH
O
1:1
-Glu
The First Bismuth Complex Containing a The First Bismuth Complex Containing a BiomoleculeBiomolecule
Bi(NO3)3.5H2O +OH SH
O
NH2
+N N
50% EtOH
N NBi
H2OO
S
OO
H3N
O
N
O
O
N O
O
Yield: 31%
Ligand StabilisationLigand Stabilisation
Briand, G.G.; Burford, N.; Eelman, M.D.; Aumeerally, N.; Chen, L.; Cameron, T.S.; Robertson, K.N. Inorg. Chem. 2004, 43, 6495.
Dianionic
Monoanionic
Neutral
S O
NH2
O
S OH
NH2
O
Monocationic
HS O
NH2
O
S O
NH3
O
HS OH
NH2
O
HS O
NH3
O
S OH
NH3
O
H2S OH
NH2
O
HS OH
NH3
O
HS OH2
NH2
O
H+-H+
H+-H+
H+-H+
Equilibria and Tautomerism for CysteineEquilibria and Tautomerism for Cysteine
Bi
O
S
NH2Cl
O
c.f.
Herrmann, 1993Herrmann, 1993
N NBi
H2OO
S
OO
H3N
O
N
O
O
N O
O
Comparison with a Derivative of a Comparison with a Derivative of a Bismuth-Amino Acid ComplexBismuth-Amino Acid Complex
Bi(Cys)(Phen)(NOBi(Cys)(Phen)(NO33))22HH22OO
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!
Consider the Other Heavy MetalsConsider the Other Heavy Metals
= toxic = toxic
How do the other heavy metals interact with the amino acids?
= bioactive= bioactive
AsAs
BiBi
SbSb
PbPbTlTlHgHg
CdCd
Identification of Lead-Amino Acid Adducts Identification of Lead-Amino Acid Adducts by ESI-MSby ESI-MS
Same ESI-MS method used for bismuth-amino acid mixtures
Pb forms kinetically stable complexes with all of 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, 1:6 and Pb:Am ratios
Burford, N.; Eelman, M.D.; LeBlanc, W.G.; Cameron, T.S.; Robertson, K.N. Chem. Commun. 2004, 332.
ESI-MS of Pb(NOESI-MS of Pb(NO33))2 2 and L-Threonine in 50% EtOHand L-Threonine in 50% EtOH216.9
282.1
648.9854.9
973.7
1:2 3:2
3:3
Peak assignments confirmed by MS/MS
970.8 976.8
975.8974.8
973.7
972 .8
971.8
977
976975
974
973972
971
3:3
326.0
1:1
Synthesis of the First Lead-Amino Acid Synthesis of the First Lead-Amino Acid ComplexComplex
Pb(NO3)2 +OH
O
NH2
50% EtOH
Yield: 55%
Zwitterionic valinesZwitterionic valines
Pb
OH2
OH2
O O
O
O
N
O
H3N
OO
H3N
NO3
# amino acids# amino acids
7: 7: His, Thr, Met, Cys, Hcys, Asn, GlnHis, Thr, Met, Cys, Hcys, Asn, Gln
2121
Identification of Interactions Between Heavy Identification of Interactions Between Heavy Metals and Amino Acids Using ESI-MSMetals and Amino Acids Using ESI-MS
MetalMetal
BiBi3+3+
PbPb2+2+
AsAs3+ 3+ 5: 5: Ser, Thr, Cys, Asn, GlnSer, Thr, Cys, Asn, Gln SbSb3+ 3+ 4: 4: His, Cys, Glu, GlnHis, Cys, Glu, Gln
TlTl+ + 2121
HgHg2+ 2+ 2121
CdCd2+ 2+ 2121
SummarySummary• ESI-MS offers 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
AcknowledgmentsAcknowledgmentsDr. Neil BurfordDr. Neil Burford
Wes LeBlancWes LeBlanc
The Burford GroupThe Burford Group
Dr. T.S. Cameron and Dr. K.N. Robertson (DALX)Dr. T.S. Cameron and Dr. K.N. Robertson (DALX)
Maritime Mass Spectrometry LaboratoriesMaritime Mass Spectrometry Laboratories
Canada Research Chairs ProgramCanada Research Chairs Program
Nova Scotia Research and Innovation Trust FundNova Scotia Research and Innovation Trust Fund