A snapshot of bioinorganic chemistry

Biological periodic table

The diverse coordination chemistry of the d block elements allows metallobiomolecules to be tuned for a wide array of biological functions.

Metallobiomolecules

Fe

CuMgCa, SiZn, Hg

Adapted from Fenton, D.E. Biocoordination Chemistry, Oxford Univ. Press, Oxford, UK, 1995, p. 4

Metalloenzymes

Enzymes are proteins that catalyze chemical reactions.

Fe, CuFe, Cu, Mo

Fe, Cu, Mn

Fe, Mo, VFe, NiFe, Cu Fe

Co

Zn, MgZn, Cu, MgZn

Adapted from Fenton, D.E. Biocoordination Chemistry, Oxford Univ. Press, Oxford, UK, 1995, p. 4

Heme-based oxygen carriers: hemoglobin and myoglobin

N

NN

N

Fe

CO2-

CO2-

iron protoporphyrin IX

N

N CO2H

NH2

H

histidine

Adapted from Lippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.

Comparison of crystal field splittings for octahedral, square planar and tetrahedral

ligand fields

Crystal field splittings in lower symmetries

eg

t2g dxydxz dyz

dx -y 2 2

dz2

L

M

L

L L

LL

X

M

X

L L

LLM

L L

LL

Octahedral Square planarTetragonal

dx -y 2 2

dz2

dxydxz dyz

Square-pyramidal

Schematic structure of myoglobin• Hemoglobin consists of 4 similar

subunits

• Hemoglobin takes dioxygen from the air (lungs) and transports it via blood to myoglobin in tissue

• In resting state the iron atom is five-coordinate and is located ca. 0.4 D above the plane of the macrocyclic ligand

• In the oxy-form the iron is in the plane; O2 is end bound with an Fe-O-O angle of ca. 115E

• Free heme complexes CO 2x104

more tightly than O2; only 2x102

in proteinAdapted in part from Lippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.

2 α chains – 141 aa

2 β chains – 146 aa

Sickle cell anemia – genetic disorder in which the sixth amino acid in the β chain of the normal protein, glutamate, is substituted by valine. This results in severe distortion of the red blood cells under conditions of oxygen stress. Imparts malaria resistant to carriers.

HO OH

OO

NH2

OH

NH2

O

Bottom images fromhttp://en.wikipedia.org/wiki/Sickle-cell_diseaseand Blood, 1973, 41,653

Genetic defects in hemoglobin synthesis

normal blood cell

“sickled” blood cell

Thalassemia (Cooley's anemia) – genetic disorder that results in reduced or even no production of the β protein chain in hemoglobin, which means limited production of functional adult hemoglobin. This results in severe distortion of the red blood cells under conditions of oxygen stress.

Genetic defects in hemoglobin synthesis

• Those afflicted are dependent on blood transfusions which create problems with iron overload.

• Chelation therapy with siderophoreanalogs help to reduce the problem.

• There is currently no cure, only treatment.

Graphic fromhttp://en.wikipedia.org/wiki/Sickle-cell_disease

Non-heme oxygen carriers

hemocyanin(mollusks & anthropods)

hemerythrin(sea worms)

Adapted from Lippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.

Ferredoxins: Fe-S proteins for e- transport

2-, 1-

3-, 2-

3-, 2-, 1-

3-, 2-

Adapted from Wilkins and Wilkins. Inorganic Chemistry in Biology, Oxford Univ. Press, Oxford, UK, 1997, p. 41

Respiratory electron transport chainADP + HOPO3

2- ADP + HOPO32- ADP + HOPO3

2-

e- e-

Figures from Shriver & Atkins, Inorganic Chemistry, 3rd and 4th editions

Vitamin B12 coenzyme: a naturally occurring organometallic compound

HO SR

O O

CH3

HOS

R

O

O

Ligands for treatment of disease

Desferrioxamine BThalassemia (Cooley’s anemia)(excess iron)

H3N+ NN

O

OOH

H

NHOONN

O

OH

O

H

Structure from “Coordination chemistry and biology of chelators for the treatment of iron overload disorders”Bernhardt, P.V. Dalton Trans. 2007, 3214

Ligands for treatment of disease

Deferasirox (Cooley’s anemia)

Exjade® (Norvatis)

FDA approved 2005

HS OH

NH2

O

D-penicillamineWilson’s disease(excess copper)

Structure from “Coordination chemistry and biology of chelators for the treatment of iron overload disorders”Bernhardt, P.V. Dalton Trans. 2007, 3214

Structure of iron complex of analog of A) without the carboxyl group

“A considerable part of O2 metabolized by the human organism is converted by one-electron reduction to the highly reactive superoxideradical anion, O2

.-. Sources of superoxide include leaks in the cytochrome c oxidase mediated O2-to-H2O transformation pathway in mitochondria, various autooxidation reactions (e.g. of glutathione in red blood cells) but also the controlled production of O2

.- by membrane-bound NAD(P)H oxidase in phagocytes to support immune defense against bacterial and fungal infections.”

“The Pharmaceutical Potential of Manganese-Based SuperoxideDismutase” Mimics Roland Krämer Angew. Chem Int. Ed. 2000, 39,4469.

The enzyme superoxide dismutase has been used to treat arthritis, inflammation and the side-effects of radiation treatment. Superoxide dismutase mimics have been developed for the treatment of many diseases which involve an excess of superoxide.

Metal compounds for treatment of disease

Metal compounds for treatment of disease

PtH3N Cl

ClH3N

cis-Platin(anticancer)

O

Ti

O

O O

OO

Ph

Ph

O

Ti

O

O O

OO

Ph

Ph

O

Ti

O

O O

OO

Ph

Ph

19% 21% 60%Budotitane(anticancer)

Au P(CH2CH3)3

O S

OO

O

O

O

OO

O

Auranofin (antiarthritis)

Diagnostic nuclear medicine (radiopharmaceuticals)

N

N N

N

O H O

TcO

N

N

N

O

O-

O-O O O-O-O O -O

DTPA Tc(O)HAMO

99mTcO4- 99TcO4

- (β, t1/2 = 2.1 x 105 y)γ (140 keV)

t1/2 = 6 h

{Tc[CNCH(CH3)2OCH3]6}+

Tc99mMIBI

brain blood flowrenal function myocardium imaging

HOMO’s and LUMO’s for CH3CN, methylcyanide, and CH3NC, methylisocyanide

CH3CN

CH3NC

HOMO LUMO