SWOSU 26th May 2009
Metals in Medicine
Dr Steve Archibald
Department of Chemistry
University of Hull
• 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
O
O
O
O
O
O
+
O
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.
Topics
1. Preventing heart injuries
2. Imaging the body
3. Anti-cancer drugs
–
–
Radiation emitters
DNA binders
4. Anti-HIV drugs
1. Preventing heart injuries
Heart attackhow is the tissue damaged?
The majority of tissue damage is
actually caused after a heart
attack.
O2-.
O2 + Mn2+
+ Mn3+
H++ HO2. + Mn2+
H2O2 + Mn3+
Superoxide is a radical anion
and is quite toxic
Normally SOD enzymes destroy it
(Superoxide Dismutase)
H
N
H
Cl N
Mn
NH
N
H
Cl
N
H
Pentaazamacrocycle Mn2+ complexes act as therapeutic SOD mimics
Riley, Nature Reviews Drug Discovery, 2002, 367-374.
2.
DiagnosisImaging 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
DRUG
radiopharm
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
-OOC
COON
N
N
-OOC
-OOC
-OOC
N
COO-
-OOC
N
N
N
COOCOO-
DTPA
DOTA
1,4,7,10-tetraazacyclododecane
-1,4,7,10-tetraacetic acid
diethylene triamine pentaacetic acid
O
N
N
NO
O O
OH2
Gd
O
O
N O
O
Gd(DOTA)-
3. Anti-cancer drugs
Curing cancer with radioactive metals
Chelator
Biomolecule
Radiometal
Covalent Linkage
Drugs for delivery of therapeutic doses of
radiation to specific disease sites.
“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 Bcell 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.
cisplatin
cisplatin
carboplatin
carboplatin
What’s new with cisplatin?
We know much more about why it works!
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
Why doesn’t the DNA damage get repaired?
4. Anti-HIV drugs
Blocking virus attack
Drug
Receptor
signalling
protein
Cell
AMD3100 = Plerixafor = Mozobil
H
H
N
N
N
N
N
N
N
N
H
H
H
H
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?
NH
I
Y
P
C
S I G E M -NH2
N
NH HN
N
HN
NH HN
CHO
T S D N Y T E E
M
G
E K M S D Y D G S
K Q G C
I
D D A
E
Y F G
R
I
E
F
W
A
Y
E
N
Y PN
E
N
N
F
I
L
F
D
V
F
A
N
D R
L
N
L
L C
N
W
ExtraT
V
K
I
A
V
H V K
A
cellular F I
K C
S F D
V
D
V
L
V
W
F
I
V A
P
171 F F Q
W A
I S
V H
262 I
F I
I T
I S
Q
I
P F
Y
H
I G
E T
P D
L
T Y V
I
Y
I S
I
T
A
M
Y
T
I
I
L
V
P
F
L
N
A
G
F
F V
Y L
T L
L L A
WL C
I L L
S
H F C
G
L L
A
S
I
P
D
V
V
I
P
C
F
A
G
F
L
L
V
I
I
N
N G
V W
L A
P
V
L S
L G
A L
V G
I
L I Y
L I
L H
V
I F
I L
S
R
V Y
A
Y
S
V
C
L I
V
T
F
Y
K
L
V
K
L
C
T
G
I
K
R D
A E
G M
D
IntraL
Y
I I S
KA
K A
L
T
F
L
cellular Y
L K
Q
L
K R
K
M
S
A
Q
K
S
H
K
T
I
K L R
H
S A QH
S
R
V
K G
P
H
V
R
A
S E S E T S
T N SQ
S
F R E E N
S
F H S S -COOH
Gerlach et al., 2001
47
H
N
N
N
Zn2+
H
N
N
H
Zn2+
N
H
H
N
N
H
Molecular shape
H
N
H
N
N
NH
H
trans-I
trans-II
trans-III
trans-IV
trans-V
cis-V
Bosnich, B.; Poon, C. K.; Tobe, M. L. Inorg. Chem.,1965, 4,1102
49
Restrict to one configuration
N
H
N
N
H
N
R
N
N
N
trans-II
N
NH
Only trans-II
H
N
N
X
X
N
R
Only cis V
50
Me
NN
N
N
NN
N
H
NN
N
N
N
N
H
N
N
Me
Lewis, E. A.; Hubin, T. J.; Archibald, S.J. Patent WO2005121109, 2005.
% inhibition of antibody binding
Residence time, Cu-Cross Bridged
100
90
Copper 3
80
AMD3100
70
60
Copper AMD3100
50
40
30
20
10
0
1
24
48
72
96
hours
G. McRobbie, A. Khan, G. Nicholson, L. Madden, J. Greenman C. Pannecouque, E. De Clercq, T. J.
Hubin and S. J. Archibald, J. Am. Chem. Soc, 2009, 3416.
52
• 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!