the coordination chemistry of bismuth(iii) complexes and other heavy metals with biorelevant ligands...

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


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


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


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


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


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


m/zm/z AssignmentAssignment

Bi:Cys:AmBi:Cys:Am


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


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


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

the coordination chemistry of bismuth(iii) complexes and other heavy metals with biorelevant ligands...

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