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Metal-Based Drugs: Novel Targets Antiulcer Bulk elements Trace elements Possibly essentia 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 C l Ga In Tl Ge Sn Pb As Sb Bi Se Te Po Br I At He Ne Ar Kr Xe Rn Metallopharmaceuticals Anti- Depressi ve Insulin Mimetic agnostic Agents: X-ray, MRI Radiopharmaceuticals Anticancer Antiarth ritic Antiinfective

Metal-Based Drugs: Novel Targets

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Insulin Mimetic. 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. - PowerPoint PPT Presentation

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Page 1: Metal-Based Drugs: Novel Targets

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

Page 2: Metal-Based Drugs: Novel Targets

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

Page 3: Metal-Based Drugs: Novel Targets

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

Page 4: Metal-Based Drugs: Novel Targets

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+

Page 5: Metal-Based Drugs: Novel Targets

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-

Page 6: Metal-Based Drugs: Novel Targets

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

Page 7: Metal-Based Drugs: Novel Targets

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.

Page 8: Metal-Based Drugs: Novel Targets

[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

Page 9: Metal-Based Drugs: Novel Targets

Formation of a 1,4- GG Interstrand Crosslink

Guanine N7

Page 10: Metal-Based Drugs: Novel Targets

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

Page 11: Metal-Based Drugs: Novel Targets

[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

Page 12: Metal-Based Drugs: Novel Targets

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

Page 13: Metal-Based Drugs: Novel Targets

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

M

Partition coefficient

IC50

(M)[Au(dppe)2]+

0.0

0.1

1

10

100

1000

0.01 0.1 1 10 100

Page 14: Metal-Based Drugs: Novel Targets

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

Page 15: Metal-Based Drugs: Novel Targets

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

Page 16: Metal-Based Drugs: Novel Targets

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

Page 17: Metal-Based Drugs: Novel Targets

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

Page 18: Metal-Based Drugs: Novel Targets

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

Page 19: Metal-Based Drugs: Novel Targets

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

Page 20: Metal-Based Drugs: Novel Targets

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

Page 21: Metal-Based Drugs: Novel Targets

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))