Post on 16-Oct-2018
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B. ROSENBERG, L. VAN CAMP, T.
KRIGAS (1965) Nature, 205, 698 - 699
CURSO QUÍMICA BIOINORGÁNICA
UNAM Noviembre 12, 2012
peter.kroneck@uni-konstanz.de
Metales en Medicina y su Aplicación en Diagnóstico y Terapia cis-Pt and related complexes; metallo drugs; MRI agents
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
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El cerebro es un órgano especializado que
concentra iones metálicos Bush (2000), Current Opinion in Chemical Biology, 4, 184-191
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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
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The elements/metals of life www.webelements.com
Ca: 1.2 kg
K: 150 g
Na: 70 g
Mg: 20-30 g
Essential
Transition Metals
Fe: 4.5 g
Zn: 2.3 g
Cu: 72 mg
Mo: 9 mg
H He
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 Ge As Se Br Kr
Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe
Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At 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
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Metals in Medicine H He
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 Ge As Se Br Kr
Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe
Cs Ba La Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn
Gd F-block: 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
Bertrand Diagram
Dose-Function Relationship
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Prokaryotes and Eukaryotes - cell structure
• Eukaryotes:
– All higher organisms, such
as plants and animals
– Fungi
– Algae
– ...
• Prokaryotes: Bacteria
– Usually unicellular, but
can be in larger assemblies
Nucleolus
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
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Cis-Platin and related complexes
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S.J. Lippard, MIT National Medal of Science, 2006
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Nuevo desarrollo – Complejos de Ruthenium
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DNA structure: The Double Helix
• Note major
and minor
grooves
http://fig.cox.miami.edu/~cmallery/150/chemistry/organic.htm
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Superficie electrostática de ADN
Minor groove Major groove
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Bases y sus sitios de unión Metálicos
N N
NN
N
N N
NN
O
N
N
N
O
O
N
N
O
N
N
N
O
O
Adenine Thymine Uracil
Guanine Cytosine
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7
3 3
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Gold Complexes - Arthritis
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Diagnosis with radioactive Technetium-99
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MRI – Magnetic Resonance Imaging http://www.howstuffworks.com/mri.htm
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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.
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
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MRI – Contrast Agents
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NO Imaging – Strategies M.D. Pluth, M.R. Chan, L.E. McQuade, S.J. Lippard (2011), Inorg. Chem., 50, 9385-9392
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In vivo NO Imaging by Fluorescence M.D. Pluth, M.R. Chan, L.E. McQuade, S.J. Lippard (2011), Inorg. Chem., 50, 9385-9392
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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)
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Cu trafficking in cells (Cu(I) is transported)
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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
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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
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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.
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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
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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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