Chelation and Stability of Metal Ligand Complexes

• Chelation


  The formation of a metal-ligand complex where the ligand attaches to the metal ion at two or more points, forming a ring structure
• Stability of metal-ligand complexes

  The strength of the bond between the metal ion and the ligand(s)
• Equilibrium for metal-ligand complex formation


  Metal ion + Ligand ⇌ Metal-ligand complex

  
• Adding more ligand gives another equilibrium
• Water is in big excess and has a constant concentration (solvent) so is eliminated from the equation
• Stepwise stability constants


  Equilibrium constants for each step of ligand addition to the metal ion

  
• Overall stability constant (β)


  The product of the stepwise stability constants, representing the overall stability of the metal-ligand complex

  
• Large values of β indicate that the concentration of the complex is much greater than the concentration of its constituents
• A value of β ≈ 108 means the complex is thermodynamically stable
• Stable complexes have logβ ≥ 1 (ΔG is negative), indicating no further substitution

  
• Unstable complexes have logβ < 1 (ΔG is positive)

  
• Trend in stepwise stability constants (K)

  • K1 > K2 > K3 > ... > Kn (if no changes in geometry)
  • Exceptions occur when there are changes in geometry
• Chelate effect


  Chelate complexes are more stable, having higher K and β values
• Requirements for a suitable agent for chelation therapy


  • Drug and its metabolites must be non-toxic
  • Must be orally active
  • Must form kinetically and thermodynamically stable complexes with the target metal ion
  • Must be selective for the target metal
  • Must contain suitable functional groups (HSAB theory)
  • Selectivity may be obtained on the basis of size of the cation
  • Metal-drug complexes must be excreted and not cause re-distribution of the metal around the body
  • Drug must contain hydrophilic groups to facilitate renal excretion of the metal
  • Must be economic to produce

  
• Immediate treatment of acute metal poisoning

  1. Identify a drug that binds the toxic metal more strongly than naturally occurring ligands

  2. The complex formed must be hydrophilic and excreted in the urine
• Treatment of chronic heavy metal poisoning

  1. Drug must be lipophilic to reach tissues where metal is deposited

  2. Drug must then form a lipophilic complex to be transferred back to plasma

  3. Complex in plasma must be hydrophilic to facilitate excretion and not cause redistribution
• Synergistic therapy


  • First drug is a lipophilic agent that mobilises metal from tissues into blood plasma
  • Second drug is a hydrophilic agent with higher affinity for the toxic metal, forming a hydrophilic complex that is excreted

  
• Dithiols (e.g. BAL)

  • Lipid-soluble, can mobilise tissue-bound metal
  • Complexes may be sufficiently water-soluble to be excreted in the urine
  • Disadvantages: lower LD50, susceptible to oxidation, side effects

  
• Water-soluble derivatives of BAL


  Less toxic but can only mobilise extracellular metal
• Aminopolycarboxylic acids (EDTA and DTPA)

  • Contain oxygen and nitrogen donor groups, form 5-membered chelate rings
  • Undergo little metabolic change, have modest toxicity
  • Lack specificity, chelate a wide range of metal ions
  • Must be given intravenously as poorly absorbed from GI tract
  • Rapidly excreted in urine without significant metabolism
• EDTA


  • Initially developed to treat lead poisoning
  • Must be given as Na2CaEDTA to prevent calcium depletion
  • Hydrophilic, only removes extracellular metal
• DTPA


  Chelates the same metals as EDTA but with higher stability constants, often more effective
• 1. Penicillamine (DPen)


  • Has 3 different donor groups (NH2, SH, COOH), a more general chelating agent
  • Orally active, but only about 50% intestinal absorption
  • Low toxicity but limited clinical use due to side effects, enhances nephrotoxicity of cadmium
• Triethylenetetramine (Trien or Trientine)


  • Has 4 amine donor groups, tetradentate
  • Shows high affinity for copper, used to treat Wilson's disease when D-penicillamine is not tolerated
  • Side effects include skin rash, anaemia, and (occasionally) fever
• Hard and soft acid-base theory


  Useful to predict which donor groups are likely to show affinity for a particular metal ion, particularly when designing chelating agents to remove and complex metal ions
• HSB theory

  Allows us to predict if the bond between the Ligand and metal's stable or not
• Hard acids


  • Metal cations that are relatively small with a relatively high charge
  • Less polarisable
• Soft acids


  • Large metal ions
  • More polarisable
  • Have large electron clouds that can exhibit more polarisable
• Hard bases


  • Small ligands with quite a big charge compared to their size
  • Charge is highly localised on a singular, small atom
• Soft bases


  • Big ligands with a small charge compared to their size
  • Charge is diffuse, distributed around a larger molecular volume or on an atom with a large radius
• Hard acids


  Have a higher charge density and form bonds that are more ionic in nature
• Soft acids


  Have a lower charge density and form bonds that are more covalent in nature
• Early transition metals with valence electrons in the 3d subshell are hard acids
• Bases derived from electronegative elements (N, O and F) in the n=2 will be hard bases, even if they're part of a molecular or polyatomic ion
• Hard acids interact best with hard bases


  Soft acids interact best with soft bases
• Soft acids are usually having charges of 1+ or 2+, due to their larger size and polarisability
• There are plenty of species that qualify as having intermediate hardness/softness, not leaning heavily in either direction: they have intermediate size, charge and polarisability
• If a reaction goes to the right-hand side

  It makes a more stable complex, as the bond is stronger than the M-L bond
• This can be used to rank ligands based on binding ability, depending on the nature of M and L