A snapshot of bioinorganic chemistry

Transcription

1 A snapshot of bioinorganic chemistry

2 Biological periodic table

3 Metallobiomolecules The diverse coordination chemistry of the d block elements allows metallobiomolecules to be tuned for a wide array of biological functions. Fe Cu Mg Ca, Si Zn, Hg Adapted from Fenton, D.E. Biocoordination Chemistry, xford Univ. Press, xford, UK, 1995, p. 4

4 Metalloenzymes Enzymes are proteins that catalyze chemical reactions. Zn Zn, Cu, Mg Zn, Mg Fe, Cu Fe, i Fe, Mo, V Fe, Cu Fe, Cu, Mo Fe, Cu, Mn Fe Co Adapted from Fenton, D.E. Biocoordination Chemistry, xford Univ. Press, xford, UK, 1995, p. 4

5 Heme-based oxygen carriers: hemoglobin and myoglobin C 2 - Fe C 2 - H C 2 H histidine H 2 iron protoporphyrin IX Adapted from ippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.

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

7 Crystal field splittings in lower symmetries e g d x 2-y2 d x 2-y2 d z 2 d z 2 t 2g d xy d xz d yz d xy d xz d yz M X M X M ctahedral Tetragonal Square-pyramidal Square planar

8 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 2 α chains 141 aa 2 β chains 146 aa 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; 2 is end bound with an Fe-- angle of ca. 115E Free heme complexes C 2x10 4 more tightly than 2 ; only 2x10 2 in protein Adapted in part from ippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.

9 Genetic defects in hemoglobin synthesis 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. H H H H 2 H 2 normal blood cell sickled blood cell Bottom images from and Blood, 1973, 41,653

10 Genetic defects in hemoglobin synthesis 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. Those afflicted are dependent on blood transfusions which create problems with iron overload. Chelation therapy with siderophore analogs help to reduce the problem. There is currently no cure, only treatment. Graphic from

11 on-heme oxygen carriers hemocyanin (mollusks & anthropods) hemerythrin (sea worms) Adapted from ippard and Berg, Principles of Bioinorganic Chemistry, Univ. Science Books, Mill Valley, CA, 1994.

12 Ferredoxins: Fe-S proteins for e - transport 2-, 1-3-, 2-, 1-3-, 2-3-, 2- Adapted from Wilkins and Wilkins. Inorganic Chemistry in Biology, xford Univ. Press, xford, UK, 1997, p. 41

13 Respiratory electron transport chain ADP + HP 3 2- ADP + HP 3 2- ADP + HP 3 2- e - e - Figures from Shriver & Atkins, Inorganic Chemistry, 3 rd and 4 th editions

14 Vitamin B 12 coenzyme: a naturally occurring organometallic compound CH 3 H S R H S R

15 igands for treatment of disease H 3 + H H H H H Desferrioxamine B Thalassemia (Cooley s anemia) (excess iron) Structure from Coordination chemistry and biology of chelators for the treatment of iron overload disorders Bernhardt, P.V. Dalton Trans. 2007, 3214

16 igands for treatment of disease HS H 2 H D-penicillamine Wilson s disease (excess copper) Structure of iron complex of analog of A) without the carboxyl group Deferasirox (Cooley s anemia) Exjade (orvatis) FDA approved 2005 Structure from Coordination chemistry and biology of chelators for the treatment of iron overload disorders Bernhardt, P.V. Dalton Trans. 2007, 3214

17 Metal compounds for treatment of disease A considerable part of 2 metabolized by the human organism is converted by one-electron reduction to the highly reactive superoxide radical anion, 2.-. Sources of superoxide include leaks in the cytochrome c oxidase mediated 2 -to-h 2 transformation pathway in mitochondria, various autooxidation reactions (e.g. of glutathione in red blood cells) but also the controlled production of 2.- by membranebound AD(P)H oxidase in phagocytes to support immune defense against bacterial and fungal infections. The Pharmaceutical Potential of Manganese-Based Superoxide Dismutase Mimics Roland Krämer Angew. Chem Int. Ed. 2000, 39, 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.

18 Metal compounds for treatment of disease Ph Ti Ph Ph Ti Ph Ti Ph Ph Budotitane (anticancer) 19% 21% 60% Au P(CH 2 CH 3 ) 3 S Auranofin (antiarthritis) H 3 H 3 Pt Cl Cl cis-platin (anticancer)

19 Diagnostic nuclear medicine (radiopharmaceuticals) 99m Tc - γ (140 kev) 99 4 Tc - t 4 (β, t1/2 = 2.1 x 10 5 y) 1/2 = 6 h - Tc {Tc[CCH(CH 3 ) 2 CH 3 ] 6 } H Tc99mMIBI DTPA Tc()HAM renal function brain blood flow myocardium imaging

20 HM s and UM s for CH 3 C, methylcyanide, and CH 3 C, methylisocyanide HM UM CH 3 C CH 3 C