Metals in MedicineMetals in Medicine

Dr Steve Archibald

Department of Chemistry

University of Hull

SWOSU 26th May 2009

• Periodic table with elements highlighted

Concepts you need to know!

Metals and ligands.

How does nature use metals?

Metal + Ligand

Control of the properties properties of the metal through the use of new metal/ligand combinations

OO

O

O

O

OO

O

O

O+

Metals in disease

There are a number of diseases that can be cured by the administration of metals.

Diseases can also be caused by the lack of metal ions.

Topics1. Preventing heart injuries

2. Imaging the body

3. Anti-cancer drugs – Radiation emitters– DNA binders

4. Anti-HIV drugs

1.1. Preventing heart injuriesPreventing heart injuries

Heart attack-

how is the tissue damaged?

The majority of tissue damage is actually caused after a heart attack.

+ O2 +

+ H2O2 +

O2-.

HO2.H++

Mn3+

Mn3+

Mn2+

Mn2+

Superoxide is a radical anion and is quite toxic

Normally SOD enzymes destroy it(Superoxide Dismutase)

NN

N

N

N

Mn

Cl

Cl

H H

H

H

H

Pentaazamacrocycle Mn2+ complexes act as therapeutic SOD mimicsRiley, Nature Reviews Drug Discovery, 2002, 367-374.

2.2. Diagnosis-Diagnosis-Imaging the bodyImaging the body

Radiation emitters and MRI agents

Types of metal drugs:

Radiopharmaceutical 0.0001 mmol

MRI contrast 0.1 mmol

Metal isotopes that emit radiation are used (short half life!).

High energy radiation required.

The ligand can direct the metal to specific areas of the body.

Targeted Imaging

radiopharmDRUG

Magnetic resonance imaging

Analysing the water in the tissues of the body.

Humans are approx. 70% water. 

The patient is placed within a large superconducting magnet and pulsed with radiowaves and the resulting signals analysed by computer.

Do you need a metal?

No… but it helps.

Gadolinium is used because of its unique properties.

However it is toxic!

The magnetism of the Gd disrupts the signal from the water resulting in an improved image.

None

Contrast agent used

N N N

-OOC

-OOCCOO-

COO--OOC

DTPA

N

NN

NCOO-

COO--OOC

-OOC

DOTA

O

O

N

N

N

GdO

ON

O

O

OH2O

O

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

diethylene triamine pentaacetic acid

Gd(DOTA)-

3. 3. Anti-cancer drugsAnti-cancer drugs

Curing cancer with radioactive metals

Drugs for delivery of therapeutic doses of radiation to specific disease sites.

Biomolecule Radiometal

Chelator

Covalent Linkage

“The first dose uses 111In (indium-111) ibritumomab for imaging. Indium-111 emits gamma radiation, which can be picked up by the gamma camera. A scan is done to assess biodistribution of the drug. This test dose is used to determine that no excess amounts go to the marrow, liver, etc. in this particular patient.

If the gamma scan shows no altered biodistribution, then the second dose is given, using 90Y (yttrium-90) ibritumomab as the actual treatment. Yttrium-90 emits the cell-killing beta radiation.” http://en.wikipedia.org/wiki/Zevalin

Tiuxetan chelator

Most expensive drug!!

Uses an antibody to target the cancer taking a radioactive payload with it.

 

Zevalin- licensed (US) in 2002.

Can cost as much as $24,000 for treatment

Zevalin

 Utilised to combat B-cell non-hodgkins lymphoma.

Antibody utilised for targeting.

 Ibritumomab mouse antibody

Killing cancer cells by binding to DNA

DNA double helix

History

Platinum containing drug.

 1978 cisplatin was proven

and used in the clinic to treat cancer

patients.

NH3

NH3

NH3

NH3

PtCl

Cl

PtO

O

O

O

cisplatin carboplatincisplatin carboplatin

What’s new with cisplatin?We know much more about why it works!

Why doesn’t the DNA damage get repaired?

Following administration, one of the chloride ligands is slowly displaced by water (an aqua ligand), in a process termed aquation. The aqua ligand in the resulting [PtCl(H2O)(NH3)2]+ is itself easily displaced, allowing the platinum atom to bind to bases. Of the bases on DNA, guanine is preferred. Subsequent to formation of [PtCl(guanine-DNA)(NH3)2]+, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. http://en.wikipedia.org/wiki/Cisplatin

PtCl

ClNH3

NH3

4.4. Anti-HIV drugsAnti-HIV drugs

Blocking virus attack

Cell

DrugReceptor signalling protein

N N

N N

NN

NN

H

H H

H

HH

AMD3100 = Plerixafor = Mozobil

Where is my metal?

The drug is not adminstered with a metal ion.

New studies have shown that binding of a metal makes the drug work better.

Where does the metal come from?

N N

N N

NN

NN

H

H H

H

HH

Zn2+Zn2+

N

NN

NN

NN

N

Me Me

N N

N N

NN

NNH H

Lewis, E. A.; Hubin, T. J.; Archibald, S.J. Patent WO2005121109, 2005.

• Periodic table with elements highlighted

Where now?

Lots of new drugs and new possibilities for metals in medicine.

There is much research to be done!

Back to the laboratory!