Post on 16-Jan-2016
description
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
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
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
NH2(CH2)n
2+
NH2(CH2)nH2N NH3 Cl
Cisplatin
M50ID (L1210) = 2.4 TWI%(LX-1) = 38@4.0 mg/kg
1,1/t,t; n=6 (BBR3005)
50 ID (L1210) = 3.03 MTWI%(LX-1) = 72@3.0 mg/kg
1,0,1/t,t,t; (n = 6,6) (BBR3464)
ID50 (L1210) = 0.0094 MTWI%(LX-1) = 73@0.3 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+
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-
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
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.
[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
Formation of a 1,4- GG Interstrand Crosslink
Guanine N7
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
[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
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
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
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
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
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
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
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
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
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
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))