Metales en Medicina y su Aplicación en Diagnóstico y Terapia

CURSO QUÍMICA BIOINORGÁNICA
UNAM Noviembre 12, 2012
[email protected]
Metales en Medicina y su Aplicación en Diagnóstico y Terapia
cis-Pt and related complexes; metallo drugs; MRI agents
B. ROSENBERG, L. VAN CAMP, T.
KRIGAS (1965) Nature, 205, 698 - 699
1
Metales y Vida: la Química de Coordinación de la
Naturaleza
“The application of metals to treat human ailments dates back at
least to the fifth century B.C., and the study and mimicry of
metals in biology is a vibrant subject today”….
Stephen Lippard, J Am Chem Soc (2010), 132, 141689-14693
2
El cerebro es un órgano especializado que
concentra iones metálicos
Bush (2000), Current Opinion in Chemical Biology, 4, 184-191
3
Artículos que introducen
Orvig, Abrams (1999), Chem. Reviews, 99, 2201 - 2203
Guo and Sadler (1999), Angew. Chem. Int. Ed., 38, 1512 - 1531
Thompson, Orvig (2003), Science 300, 936 – 939
Frederickson, Koh, Bush (2005), NATURE REVIEWS, 6, 449 – 462
Que, Domaille, Chang (2008), Chem. Reviews, 108, 1517–1549
Cobb, Surewicz (2009), Biochemistry, 48, 2574–2585
Scott, Orvig (2009), Chem. Reviews, 109, 4885-4910
Sun, Tsang and Sun (2009) , METALLOMICS, 1, 25 -31
http://faculty.virginia.edu/metals/cases/east2.html
http://chemwiki.ucdavis.edu/xApproaches/ChemCases/Cisplatin%3A_The_Inve
ntion_of_an_Anticancer_Drug
4
The elements/metals of life
H
Li
He
www.webelements.com
Be
B
C
N
O
F
Ne
Na Mg
Al
Si
P
S
Cl
Ar
Cu Zn Ga Ge As Se Br
Kr
K
Ca Sc Ti
Rb Sr
Y
Zr
Cs Ba La Hf
Ca: 1.2 kg
K: 150 g
Na: 70 g
Mg: 20-30 g
V
Cr
Mn Fe Co Ni
Nb Mo Tc
Ta
W
Ru Rh Pd Ag Cd In
Re Os Ir
Essential
Transition Metals
Fe: 4.5 g
Zn: 2.3 g
Cu: 72 mg
Mo: 9 mg
Pt
Au Hg Tl
Sn Sb Te
Pb Bi
I
Po At
Xe
Rn
Transition metals (ions) are
under strict control within the
living cell; usually bound to
proteins, peptides, or other
molecules.
In CHEMISTRY we call this a
TRANSITION METAL COMPLEX
5
Metals in Medicine
H
Li
He
Be
B
C
N
O
F
Ne
Na Mg
Al
Si
P
S
Cl
Ar
Cu Zn Ga Ge As Se Br
Kr
K
Ca Sc Ti
Rb Sr
Y
Zr
Cs Ba La Hf
F-block:
Gd
V
Cr
Mn Fe Co Ni
Nb Mo Tc
Ta
W
Ru Rh Pd Ag Cd In
Re Os Ir
Pt
Au Hg Tl
Sn Sb Te
Pb Bi
I
Po At
Xe
Rn
Uses in therapy : Pt anticancer drugs
Au antiarthritic drugs
Bi antiulcer drugs
Uses in diagnostics: “Barium meal” ; contrast agent for X-ray
99mTc: Radioimaging
Gd3+ complexes as MRI contrast agents
6
Bertrand Diagram
Dose-Function Relationship
7
Prokaryotes and Eukaryotes - cell structure
Nucleolus
• Eukaryotes:
– All higher organisms, such
as plants and animals
– Fungi
– Algae
– ...
• Prokaryotes: Bacteria
– Usually unicellular, but
can be in larger assemblies
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Metales en Medicina – Aplicaciones
“Uno de los desafíos de diseñar medicinas basadas en el metal es equilibrar la
toxicidad potencial de una formulación activa con el impacto positivo sustancial
de estos recursos terapéuticos y diagnósticos cada vez más comunes”
K.H. Thompson, C. Orvig (2003) Science 300, 936-939
9
Cis-Platin and related complexes
10
S.J. Lippard, MIT
National Medal of Science, 2006
11
Nuevo desarrollo – Complejos de Ruthenium
12
DNA structure: The Double Helix
• Note major
and minor
grooves
http://fig.cox.miami.edu/~cmallery/150/chemistry/organic.htm
13
Superficie electrostática de ADN
Minor groove
Major groove
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Bases y sus sitios de unión Metálicos
7
N
N
N
O
N
N
Thymine
O
N
O
Uracil
N
3
N
N
3
N
Adenine
7
O
3
N
N
O
N
N
Guanine
N
N
N
O
Cytosine
15
Gold Complexes - Arthritis
16
Diagnosis with radioactive Technetium-99
17
MRI – Magnetic Resonance Imaging
http://www.howstuffworks.com/mri.htm
This image shows a tumor growth in a
female's brain. MRI systems can
distinguish between blood flow and
tissue by using a contrast injection.
18
Magnetic Resonance Imaging (MRI)
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Published in: Emily L. Que; Dylan W. Domaille; Christopher J. Chang; Chem. Rev. 2008, 108, 1517-1549.
DOI: 10.1021/cr078203u
Copyright © 2008 American Chemical Society
20
MRI Contrast Agents
21
MRI – Contrast Agents
22
NO Imaging – Strategies
M.D. Pluth, M.R. Chan, L.E. McQuade, S.J. Lippard (2011), Inorg. Chem., 50, 9385-9392
23
In vivo NO Imaging by Fluorescence
M.D. Pluth, M.R. Chan, L.E. McQuade, S.J. Lippard (2011), Inorg. Chem., 50, 9385-9392
24
Cu/Fe Homeostasis
Link to Neurodegenerative diseases
• L. Gehrig‘s disease/SOD (McCabe et al., PNAS,
1995; Amyotrophic Lateral Sclerosis)
• Fe uptake (Stearman et al., Science, 1996)
• Alzheimer‘s disease (Multhaup et al., Science,
1996)
• Cu transport in cells (J. Selverstone Valentine et
al., Science, 1997)
• Cu binding to prion proteins (D.R. Brown et al.,
Nature, 1997)
• Cu chaperone for SOD (Rae et al., Science, 1999;
Harrison et al., TIBS, 2000)
25
Cu trafficking in cells (Cu(I) is transported)
26
Un modelo esquemático para Zn(2+) neuronal homeostasis
List of abbreviations: AMPAR-C, AMPA receptor-gated channel; MT3, metallothionein-3; Na/Ca Ex, Na +/Ca 2+
exchanger; NMDAR-C, NMDA receptor-gated channel; VGCC, voltage-gated calcium channel; Vglut1, vesicular
glutamate transporter-1; ZIP, zrt/irt-like proteins; ZnT, zinc transporter protein.
Published in: Emily L. Que; Dylan W. Domaille; Christopher J. Chang; Chem. Rev. 2008, 108, 1517-1549.
DOI: 10.1021/cr078203u
Copyright © 2008 American Chemical Society
27
Alzheimer‘s – Aß Protein Plaque
28
Location of Aβ1−42 region within the larger transmembrane protein APP. Cu2+ binding sites both on APP and within the
Aβ1−42 fragment are indicated, and putative Cu2+-binding residues within Aβ1−42 are highlighted. Adapted with permission
from Wiley-Blackwell Publishing, ref 94, copyright 2005.
Published in: Lauren E. Scott; Chris Orvig; Chem. Rev. 2009, 109, 4885-4910.
DOI: 10.1021/cr9000176
Copyright © 2009 American Chemical Society
29
Sensing Cu(1+) and Cu(2+)
E.L. Que, D.W. Domaille, C.J. Chang (2008), Chem. Reviews, 108, 1517-1549
30
Biological Chelate: Siderophores
Extremely stable complex of Enterobactin/Fe3+ K~ 1049
Release of Fe through a) degradation of ligand, or b) protonation
and reduction to Fe2+ which binds much weaker to the siderophore.
31
A selection of pyridoxal isonicotinoyl hydrazone (PIH)
derivatives demonstrating good Fe removal and low toxicity
Published in: Lauren E. Scott; Chris Orvig; Chem. Rev. 2009, 109, 4885-4910.
DOI: 10.1021/cr9000176
Copyright © 2009 American Chemical Society
32
Desferrithiocin and deferitrin, orally active Fe3+ chelators
Published in: Lauren E. Scott; Chris Orvig; Chem. Rev. 2009, 109, 4885-4910.
DOI: 10.1021/cr9000176
Copyright © 2009 American Chemical Society
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Metales en Medicina - Una Área de investigación
importante para Químicos Inorgánicos
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