FPDA1: Chelating Agents
So to be able to chelate Pb2+, how many donor atoms does it require?
4; (charge (2) x 2)
What size "rings" does this form?
5 and 6 membered intramolecularly; not 4
How many points of interaction are there between deferexamine and Fe3+?
6; But it does it in a 1:1 complex.
What is 2,3 dimercapto-1propanesulphonic acid (DMPS)?
A mercury chelatory; more effective Hg chelator than DMSA
What is a chelating agent?
A molecule that forms a complex with a metal ion
What is a bronsted base?
A proton acceptor
What is a bronsted acid?
A proton donor
So what is a hydrogen bond?
A specific type of dipole dipole where the +H bonds with a negative dipole; can be intermolecular or intramolecular
What can deferiprone cause?
Agranulocytosis and neutropenia; Plus its given tid. So reserved for people with thalassemia syndromes when current chelation treatment is inadequate
What is deferiprone?
Also an iron chelator; But requires 3:1 complex; bidentate
What is trientine?
Also used to treat wilson's disease; Also Fe and Zn
What is a lewis acid?
An electron pair acceptor
What is a lewis base?
An electron pair donor
What is deferoxamine?
An iron chelating agent; given IM, IV or SQ; can also chelate Al
What is deferasirox?
An oral iron cehlator. Cehlates iron (Fe3+) in a 2:1 complex; tridentate
Why can't you take fluroquinolones or tetracyclines with milk, dairy, antacids, or iron containing products within a few hours?
Because they can chelate the Ca, Fe, Mg, Al and form insoluble chelates and you get less absorption
What is penicillamine?
Chelates Cu, Hg, Pb, As; Indicated for Wilson's disease which is inability to eliminate copper
What is dimercaprol?
Created to chelate As2+, Pb2+, Hg2+, Au;
What is ethambutol?
Drug used in treatment of tuberculosis; forms intramolecular hydrogen bonds
So what is the equation for chelation?
E (lewis base) + M (lewis acid) <-> EM
What are properties of ligands?
Every ligand has at least one unshared pair of valence electrons. They are either polar molecules or anions.
What is the problem with this?
If you get a biological ligand that is a better lewis base than water, then the metal can bind with the biological ligand and this can be toxic
So what does the chelating agent do?
It's a better lewis base than the biological agent, so it bonds to the metal and then it can be excreted
So what does the chelating agent do?
It's a polydentate ligand that grapss the metal ion between two or more donor atoms
What is the problem?
It's an oil for injection, has low solubility and has a noxious smell
The ability to form EM (chelate) is dependent on what?
Kf
So are chelating agents lewis acids or bases?
Lewis bases
What are polydentate ligands?
Ligands with two or more donor atoms that can simultaneously coordinate to a metal ion; Bidentate=2, tridentate=3, etc.
What are ligands?
Molecules that bind to a metal ion
What are the most common donor atoms?
N, O and S
What is EDTA?
Nonselective chelating agent; highest Kf for Pb2+; used to treat lead poisoning
S o it was modified to create what?
Succimer (DMSA); Has increased water solubility, odorless, and comes as an oral tablet
What are other examples of drugs that do this?
Tetracycline (antibiotic) and fluroquinolones (antibacterials)
Why are these intramolecular hydrogen bonds important?
That usually tells you that you can form a chelate with a metal. The metal just bonds in place of the hydrogen
What is the donor atom?
The atom of the ligand bound directly to the metal ion
So does the water act as the lewis base or acid?
The base; the metal is always the lewis acid
What was the problem with just using EDTA?
There were myocardial problems due to the EDTA chelating Calcium also
What happens to metal ions in the body?
They are immediately surrounded by water
So what'd they do to fix it?
They gave it as calcium disodium versenate (EDTA with calcium already chelated). Then It would still chelate lead because of the higher Kf, but it wouldn't remove the bodies calcium
Are metal ions lewis acids or bases?
They have empty valence orbitals, so they can act as lewis acids (e- pair acceptors)
How do ligands bond to metal ions?
Through unshared pair of electrons (lone pairs of e-) on the donor atom and functions as a lewis base (e- pair donor)
What is the goal of chelation therapy?
To remove metal ions in toxicity situations
So what makes a chelating agent?
When it can form intramolecular hydrogen bonds
Are chelating agents ligands?
Yes
So what does deferexamine treat?
acute iron toxicity (eating ferrous sulfate), overload secondary to RBC transfusions
So what are some characteristics of a successful chelating drug?
high affinity for the toxic metal, low affinity for the essential metals, minimal toxicity itself
So if we have a high Kf, does that mean it's more or less likely for a chelate to forM?
the higher the Kf, the more easily the chelate forms