metal-based drugs: novel targets antiulcer bulk elementstrace elementspossibly essential h li na k...
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Metal-Based Drugs: Novel Targets
Antiulcer
Bulk elements Trace elements Possibly essential
H
Li
Na
K
Rb
Cs
Fr
Be
Mg
Ca
Sr
Ba
Ra
Sc
Y
Ln
Ac
Ti
Zr
Hf
Th
V
Nb
Ta
Pa
Cr
Mo
W
U
Mn
Tc
Re
Ru
Os
Fe Co
Rh
Ir
Ni
Pd
Pt
Cu
Ag
Au
Zn
Cd
Hg
B C N O F
Al Si P S Cl
Ga
In
Tl
Ge
Sn
Pb
As
Sb
Bi
Se
Te
Po
Br
I
At
He
Ne
Ar
Kr
Xe
Rn
Metallopharmaceuticals
Anti-Depressive
Insulin Mimetic
Diagnostic Agents: X-ray, MRI
Radiopharmaceuticals
Anticancer
Antiarthritic
Antiinfective
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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
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University of Western Australia Prof Sue Berners-PriceDr Junyong (June) ZhangDon ThomasJoe Moniodis
Virginia Commonwealth University, USA Prof Nick Farrell (Network International Advisory panel USA)
FundingARC Discovery (2002-4), ARC Linkage Int (2002-4)NIH, NSF, Am Cancer Soc.
FacilitiesUWA NMR Facility (600, 500 MHz Spectrometers)
DNA Interactions of platinum anticancer drugs
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NH2(CH2)n
2+
NH2(CH2)nH2N NH3 Cl
Cisplatin
M50ID (L1210) = 2.4 TWI%(LX-1) = [email protected] mg/kg
1,1/t,t; n=6 (BBR3005)
50 ID (L1210) = 3.03 MTWI%(LX-1) = [email protected] mg/kg
1,0,1/t,t,t; (n = 6,6) (BBR3464)
ID50 (L1210) = 0.0094 MTWI%(LX-1) = [email protected] mg/kg
Cl
PtH3N
H3N Cl
Pt
H3N
Cl NH3 ClPt
H3N
H2N NH3
Pt
H3N
Cl NH3 NH2(CH2)nPt
H3N NH3Pt
H2N
H3N
4+
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02468101214
imino
1H NMR : 14-mer DNA duplex
T-CH3
Pt-NH3
Pt-NH2
+ 1.6 mM
(4 h 25 oC)
Pt
NH2(CH2)6H3N
Cl NH3 NH2(CH2)6Pt
H3N
H2N NH3
NH3Pt
H2N
H3N Cl
4+
aromatic(G H8)
/ppm
15N-
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5.4 5.2 5.0 4.8
-44
-46
-48
1H
15N
[1H, 15N] NMR : 14-mer DNA duplex
+ 1.6 mM 15N- (4 h 25 oC)Pt
NH2(CH2)6H3N
Cl NH3 NH2(CH2)6Pt
H3N
H2N NH3
NH3Pt
H2N
H3N Cl
4+
Pt-NH2
-60
-62
-64
4.6 4.4 4.2 4.0
Pt-NH3
EndGroups
Linker
EndGroups
Linker
(H2O)
4.6
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1,4- and 1,6-GG Interstrand Crosslink Formation
Pt
PtCl
Cl
GT
AC G
TA
CTA
AT
GT
AC G
TA
CTA
AT
Pt
PtCl
GT
AC G
TA
CTA
AT
Pt
PtOH2
Pt
Pt
Cl
OH2
+
G
C GT
AC
TA
AT
APt
PtT
kH kk
k
k
-H
2
1
3
Cox et al J. Am. Chem. Soc. 123, 1316-1326 (2001)Hegmans et al. J. Am. Chem. Soc. (2004) in press.
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[Pt2](mM)
0 10 20 30 40 50Time (h)
0.00
0.50
1.50
2.00
1.00
0 10 20 30 40 50Time (h)
0.00
0.40
0.80
1.20
1.60
2.00
Kinetics of formation of 1,6- and 1,4- Interstrand Crosslinks
5'-d(A-T-A-T-G-T-A-C-A-T-A-T)3'-d(T-A-T-A-C-A-T-G-T-A-T-A)
(1,4-GG)
5'-d(T-A-T-G-T-A-T-A-C-A-T-A)3'-d(A-T-A-C-A-T-A-T-G-T-A-T)
(1,6-GG)
G/G G/GCl/Cl Cl/Cl
G/Cl G/Cl
Y/Y
PtH3N NH2
NH3H2NPtNH3
NH2H3N
Y 4+
PtH2N NH3
H3N Y
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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
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[Au(dppe)2]Cl: 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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M = Au(I), Ag(I), Cu(I)
P
Ar
Ar
PAr
+
M
P
Ar
ArAr
Ar
Ar
PP P
R
R
R
R
1
2
3
4
R1-R4
N
2-pyridylN
3-pyridyl
N
4-pyridyl
or or
Metal complexes of bidentate pyridyl phosphines
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Cytotoxic potency against human ovarian tumours vs partition coefficient
X SKOV-3 CH 1/ -cisR/ 41 M/ -cisR/
P P
+
P PR´
R´
R
R
R´
R´
R
R
M
Partition coefficient
IC50
(M)[Au(dppe)2]+
0.0
0.1
1
10
100
1000
0.01 0.1 1 10 100
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0 5 10 15 20 0 5 10 15 20 0 5 10 15 20
Antitumour activity vs log kw
Colon 38 mouse tumour model
Time (days)
100
10
1
100
10
1
100
10
1
RelativeTumourVolume
R = 2-pyridylR = 4-pyridyl
log Kw
5.4log Kw
2.2log Kw
2.9
[Au(dppe)2]Cl (R = Ph)
McKeage et al. Cancer Chemother. Pharmacol. 2000, 46, 343
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Apoptosis
released frommitochondria byapoptotic stimuli
accumulatewithinmitochondria
inhibits apoptosis, bindsICE proteins and
suppresses release of cytochrome c and AIF
Mitochondrial Control of Apoptosis
Antitumour
LipophilicCations
cytochrome c
AIF
Bcl2
CED-4
ICE
?
+
-
+
-
Mitochondria
Cytoplasm
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Mitochondrial Permeability Transition Pore Complex
å
Bax,Bak
Bcl-2
Cyclophilin-D
Adenine Nucleotide Translocase
Benzodiazepin receptorHexokinase
Voltage Dependent Anion Channel
Creatine KinaseIntermembrane
space
Matrix
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å
Bax,Bak
Bcl-2
Inhibitor:Cyclosporin A
Inducers: Ca2+, ROS, NOthiol oxidation
Inhibitor: thiol reduction
Inducers: PBR ligands Inducers:BH3 peptides
Inducers: Ca2+, ROS
Intermembranespace
Matrix
Mitochondrial Permeability Transition Pore Complex
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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
O
H
AcO
H
AcO
H
H
OAcHS
OAc
Au PEt3
Rigobello, Bindoli et al. Br. J. Pharmacol. (2002) 136 1162
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Antimitochondrial activity
0 5 10 150
1
2
3
4
5IIII
II
IV
0 5 100.5
1.0
1.5
I
IIIII
IV
N
N
N
NN
N
N
N
Au
Au
2
N
N N
N N
NN
NAu
Au
2+
N
N
N
N
NN
N
NN
NAu
Au
2+
N
N
N N N N
NNNN
Au Au
2+
I II
IVIII
Abs
orba
nce
Time (min)
g A
u/m
g pr
otei
n
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University of Western Australia Prof Sue Berners-Price Prof David DayA/Prof Murray Baker A/Prof George YeohDr Peter BarnardJames Hickey
FundingARC Discovery (Berners-Price, Baker 2004-6)Gold Phosphine and Carbene Complexes as Potential Antimitochondrial Agents: Design,Synthesis and BiologicalChemistry
CollaboratorsA/Prof Mark McKeage, Bruce Baguley (Auckland)Prof Peter Sadler (Edinburgh)(Network International Advisory panel (EU))