Download Anti-Cancer Gold Phosphine Complexes

Rational Drug Design in
Anticancer Gold (I) Phosphine Complexes
Alexandra Nagelski
Bioinorganic Presentation
December 8, 2016
“Everything is poisonous, and nothing is harmless. The dose (amount) alone defines
whether something isn’t poison.” – Paracelsus, 1493-1541
Overview
• Background
– Medicinal Inorganic Chemistry
– Au
– Cancer cells
• 2 Classes of Anticancer Au(I) phosphines
– Linear two-coordinate complexes
• Auranofin
– Tetrahedral bis-chelated complexes
• [Au(dppe)2]Cl
• Evolution of the Research
• [Au(d2pypp)2]Cl Complex
– Reactivity
– Mechanistic insights
• Looking forward: Future Research and Implications
Medicinal Inorganic Chemistry
• Theme of chance versus design
• Key ideas in the design
– Control of toxicity
– Specificity, Targeting the metal to specific tissues,
organs or cells where activity needed
• What parts are essential for activity: M? L?
M(L)n?
• Prodrugs
Gold
• Common oxidation states: +1, +3
– Au(I) d10 ; Au(III) d8
• “Soft” metal ion
• Most stable complexes contain heavier ligands
– P>N, S>O
• Stabilized by π-acceptor ligands
• Thiolate sulfur (Cys) or selenolate selenium
(Sec)
• Aqua ion unknown
Brief Background Cancer Cells
• Thioredoxin System
– Trx
• Reduces disulfides in proteins and
peptides
• Redox active site Cys-Gly-Pro-Cys
– TrxR
• Electron donor for Trx
– NADPH
**Elevated mitochondria
membrane potential (∆Ψm)
Advantage of Au
• Not DNA-dependent
• Works for cisplatin-resistant
cancer cells
Karlenius et al. Cancers (Basel). 2010, 2(2):209-232.
Rackham et al. Biochem. Pharma. 2007, 74: 992-1002.
Linear 2-Coordinate (Class I)
Auranofin
• Rheumatoid arthritis drug
• Found to have anticancer
properties
• Forms stable adduct
through displacement of
the thiolate
• Too reactive in vivo
*Linear two-coordination Au(I):
reactivity towards thiols and
selenols
Chelated diphosphines (Class II)
• Delocalized lipophilic cations
• Nernst Equation: Eion= RT/zF * ln[ion]out/ln[ion]in
• Antitumour activity may
stem from the lipophilic,
cationic properties
• Does not undergo ligand
exchange as readily as
linear 2-coordinate Au(I)
complexes
TOXIC
Partition coefficient (P)
Lighter octanol
liquid
• Log P - Used as an indicator of
lipophilicity
Heavier water
liquid
Significance:
• Lipophilicity determines degree of protein
binding and cellular uptake
• More lipophilic, more potent, less specific
Slide figures courtesy of Dr. Mark Hilfiker (Topics in Bioorganic Chemistry)
Pyridylphosphine Analogs
• Position of N-atom
influences solvent
[Au(d2pype)2]Cl
interaction
• Intermediate lipophilicity
• 3-pyridyl, 4-pyridyl
• Significant antitumor more
activity
soluble in H2O
• Increase in potency
• Less dose limiting toxicity
(decrease in
• Higher Au concentration
in plasma
selectivity) with
and tumors
increasing lipophilicity
Log P = 1.41
Log P = -0.46 (n=2)
Log P = -1.46 (n=3)
Log P = -1.77 (n=4)
[Au(d2pypp)2]Cl
R = 2-pyridyl
Log P = -0.92
Lop P = -0.46
• Analog of (d2pype) ligand, 3carbon bridge
• Combines 2 classes of
anticancer Au(I) phosphine
complexes
• Linear: more facile ligand
exchange reactions with
thiols/selenols
• Tetrahedral: DLC properties
lead to accumulation in the
mitochondria
Bite Angle
~84.5˚
~96.4˚
Affandi et al. Dalt. Trans. 1997, 1411-1420.
• Leads to increased reactivity due to increased chelate
ring size (L exchange reactions)
Biological
Biological Activity
Ac vity
Breast cancer
cancer cells
cells
Breast
PP
22
PP
22
Au
Au
Cl
Cl
PP
PP
22
22
[Au(dppe)22]Cl
]Cl
[Au(dppe)
Log P = 1.41
Cite this
this figure
figure
Cite
R
P
R
P
2
2
P
R
P
R
2
2
A
u
A
u
R
P
R
P
2
2
Normal cells
cells
Normal
R=
C
C
ll R=
P
R
P
R
2
2
N
N
R
=
R
=
2
p
y
r
d
y
P
h
2
p
y
r
ii
d
y
ll
P
h
[
A
u
(
d
2
p
y
p
p
)
]
C
l
[
A
u
(
d
2
p
y
p
p
)
]
C
l
2
2
R
=
2
p
y
r
i
d
y
R
=
2
p
y
r
i
d
ll
Ny
N
N
N
Lop P = -0.46
Rackham et al. Biochem. Pharma. 2007, 74: 992-1002.
Mechanism
• [Au(d2pypp)2]+
selectively potent to
breast cancer cells
• Leads to programmed
cell death mediated
via mitochondria
• Problematic nature of
TrxR enzyme
– Complex structure
– Catalytic mechanism
unknown
Rackham et al. Biochem. Pharma. 2007, 74: 992-1002.
Future Research & Implications
• Trx/TrxR
– Mechanism
– Structure
– Luminescence techniques
• Gold (I) Complexes
– Au(PPh3)(alkynyl)
– Au(I) NHC
– Nano-carriers
• Techniques
– High resolution mass spectroscopy
• Other metals?
References
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Humphreys, A. S.; Filipovska, A.; Berners-Price, S. J.; Koutsantonis, G. A.; Skelton, B. W.; White, A. H. “Gold(I) chloride adducts of 1,3-bis(di-2pyridylphosphino)propane: synthesis, structural studies and antitumour activity” Dalt Trans. 2007, 4943-4950.
P F Smith, G D Hoke, D W Alberts, P J Bugelski, S Lupo, C K Mirabelli and G F Rush. “Mechanism of toxicity of an experimental bidentate phosphine gold complexed
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S Alvarez. “Distortion Pathways of Transition Metal Coordination Polyhedra
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Storr T. Ligand Design in Medicinal Inorganic Chemistry. Wiley 2004, 1: 230-259.
Rigobello MP, Folda A, Scutari G, Bindoli A. “The modulation of thiol redox state affects the production and metabolism of hydrogen peroxide by heart
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Rigobello MP, Folda A, Baldoin MC, Scutari G, Bindoli A. “Effect of auranofin on the mitochondrial generation of hydrogen peroxide. Role of thioredoxin reductase.”
Free Radic. Res. 2005, 39(7): 687-95.
Xiaodong C, Huanjiao JZ, Qunhua H, Lin L, Wang M. “Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3dependent lymphangiogenesis” Anticancer Agents Med. Chem. 2016, 14(7): 946-954.
Roder C, Thomson MJ. “Auranofin: Repurposing an Old Drug for a Golden New Age” Drugs R. D. 2015, 15(1):13-20.
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in vivo” Cell Death and Disease. 2014 5.
Bhabak KP, Bhuyan BJ, Mugesh G. “Bioinorganic and medicinal chemistry: aspects of gold(I)-protein complexes” Roy. Soc. Chem. 2011, 40: 2099-2111.
Naggar ME, Shehadi I, Abdou HE, Mohamed AA. “Gilded Hope for Medicine” Inorganics 2015, 3(2), 139-154.
Ye XQ, Wang GH, Huang GJ, Bian XW, Gian GS, Yu SC. “Heterogeneity of Mitochondrial Membrane Potential: A Novel Tool to Isolate and Identify Cancer Stem Cells
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