MetalBased Drugs: Novel Targets

1

Metal-Based Drugs Novel Targets
Bulk elements
Trace elements
Possibly essential
Metallopharmaceuticals
H
He
Anti- Depressive
Li
Be
B
C
N
O
F
Ne
Na
Mg
Al
Si
P
S
Cl
Ar
K
Ca
Sc
Ti
V
Cr
Mn
Fe
Co
Ni
Cu
Zn
Ga
Ge
As
Se
Br
Kr
Rb
Sr
Y
Zr
Nb
Mo
Tc
Ru
Rh
Pd
Ag
Cd
In
Sn
Sb
Te
I
Xe
Cs
Ba
Ln
Hf
Ta
W
Re
Os
Ir
Pt
Au
Hg
Tl
Pb
Bi
Po
At
Rn
Fr
Ra
Ac
Th
Pa
U
Antiulcer
Diagnostic Agents X-ray, MRI
Anticancer
Antiinfective
Radiopharmaceuticals
Antiarthritic
2
Metal-Based Drugs New targets

• Current ARC funded projects
• Kinetics and mechanism of binding of platinum
  anticancer drugs to DNA
• Development of metal-based antimitochondrial
  antitumour agents

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DNA Interactions of platinum anticancer drugs
University of Western Australia Prof
Sue Berners-Price Dr Junyong (June) Zhang Don
Thomas Joe Moniodis Virginia Commonwealth
University, USA Prof Nick Farrell (Network
International Advisory panel USA)
Funding ARC Discovery (2002-4), ARC Linkage
Int (2002-4) NIH, NSF, Am Cancer
Soc. Facilities UWA NMR Facility (600, 500 MHz
Spectrometers)
4
2
Cisplatin
1,1/t,t n6 (BBR3005)
5
1H NMR 14-mer DNA duplex
1.6 mM
15N-
T-CH3
(4 h 25 oC)
Pt-NH2
imino
Pt-NH3
0
2
4
6
8
10
12
14
d/ppm
6
1H, 15N NMR 14-mer DNA duplex
1.6 mM 15N-
(4 h 25 oC)
Pt-NH2
(H2O)
End Groups
-48
? 15N
-46
-44
Linker
4.6
5.4
5.2
5.0
4.8
? 1H
7
1,4- and 1,6-GG Interstrand Crosslink Formation
Cox et al J. Am. Chem. Soc. 123, 1316-1326
(2001) Hegmans et al. J. Am. Chem. Soc. (2004) in
press.
8
Kinetics of formation of 1,6- and 1,4-
Interstrand Crosslinks
Y/Y
Cl/Cl
G/G
G/G
Cl/Cl
Pt2 (mM)
G/Cl
G/Cl
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Formation of a 1,4- GG Interstrand Crosslink
Guanine N7
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Metal-Based Drugs New targets

• Current ARC funded projects
• Kinetics and mechanism of binding of platinum
  anticancer drugs to DNA
• Development of metal-based antimitochondrial
  antitumour agents

11
Au(dppe)2Cl Antitumour Activity

• Active against a spectrum of mouse tumour
  models (4 i.p. tumours 3 s.c. tumours)
• Active in a cisplatin-resistant subline of P388
  leukaemia
• Acts synergistically with cisplatin against
  moderately advanced P388 leukaemia

Berners-Price at. al. (1986) Cancer Research 46,
5486
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Metal complexes of bidentate pyridyl phosphines

13
Cytotoxic potency against human ovarian tumours
vs partition coefficient
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Relative
Tumour
Volume
Antitumour activity vs log kw
Colon 38 mouse tumour model
Au(dppe)2Cl (R Ph)
R 2-pyridyl
R 4-pyridyl
100
10
1
Time (days)
McKeage et al. Cancer Chemother. Pharmacol.
2000, 46, 343
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Mitochondrial Control of Apoptosis
Cytoplasm
inhibits apoptosis, binds ICE proteins
and suppresses release of cytochrome c and AIF

-
ICE

CED-4
Bcl2
-
accumulate within mitochondria
Antitumour Lipophilic Cations
?
Mitochondria
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Mitochondrial Permeability Transition Pore Complex
Voltage Dependent Anion Channel
Hexokinase
Benzodiazepin receptor
å
Bax, Bak
Bcl-2
Intermembrane space
Creatine Kinase
Adenine Nucleotide Translocase
Cyclophilin-D
Matrix
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Mitochondrial Permeability Transition Pore Complex
Inducers Ca2, ROS
Inducers PBR ligands
å
InducersBH3 peptides
Bax, Bak
Bcl-2
Intermembrane space
Inducers Ca2, ROS, NO thiol oxidation Inhibitor
thiol reduction
InhibitorCyclosporin A
Matrix
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Targeting mitochondrial cell death pathways in
chemotherapy

• More than 20 cytotoxic drugs are now known to
  induce cell death by permeabilizing mitochondrial
  membranes
• (demonstrated in a cell-free system)
• e.g.
• Etoposide, Paclitaxel,
• PBR ligands (PK11195)
• ANT ligands Ionidamine, Arsenite, CD437

See Debatin, Poncet, Kroemer, Oncogene, 2002 21
8786-8803
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Antimitochondrial activity of Auranofin

• At submicromolar concentrations Auranofin induces
  mitochondrial permeability transition (requires
  Ca2, cyclosporin-A sensitive)
• Attributed to inhibition of mitochondrial
  thioredoxin reductase
• Au(I) binds to active site selenocysteine

Rigobello, Bindoli et al. Br. J. Pharmacol.
(2002) 136 1162
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Antimitochondrial activity
Absorbance
I
II
Time (min)
mg Au/mg protein
IV
III
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University of Western Australia Prof
Sue Berners-Price Prof David Day A/Prof Murray
Baker A/Prof George Yeoh Dr Peter
Barnard James Hickey Funding ARC
Discovery (Berners-Price, Baker 2004-6) Gold
Phosphine and Carbene Complexes as Potential
Antimitochondrial Agents Design,Synthesis and
Biological Chemistry Collaborators A/Prof Mark
McKeage, Bruce Baguley (Auckland) Prof Peter
Sadler (Edinburgh) (Network International
Advisory panel (EU))