Metal Drugs and Therapy

1. Metal Drugs and Therapy Metal containing drugs are important for a number of medical applications: I. Diagnosis radiopharmaceuticals MRI contrast agents II. Treatment cancer inflammation ulcers arthritis antibiotics chelation therapy

2. Drug Structures Which of these commonly used drugs is active as a metal complex?

3. Drug Structures Looking at the structures of drugs designed for different treatments Which of these commonly used drugs is active as a metal complex?

4. Some important inorganic drugs While most drugs are organic compounds, there are a large number of drugs where a metal ion is a key component of its pharmacological activity So, we have examples of some unusual metal ions (Pt, Au, Tc) playing important roles in the structures of useful drugs

5. Medical applications of unusual elements Metals have played an important role in a wide range of medical applications The list of metals that have been involved in different medical uses is quite extensive Technicium Radioactive imaging

7. “Metabolism” of cisplatin The toxicity of cis-platin comes from binding to plasma proteins and from binding to the DNA of normal cells Second and third generation metal anticancer drugs These Pt compounds have more favorable distribution profiles and better stability

8. Iron-Bleomycin Bleomycin is an anticancer drug that acts by induction of DNA strand breaks in cancer cells Arrows indicate the Fe binding ligands DNA cleavage by bleomycin requires the presence of oxygen and bound Fe(III) Oxygen binds to the iron and produces superoxide and hydroxyl radicals that cleave DNA

10. Tagamet (cimetidine) Histamine antagonist used in the treatment of heartburn and peptic ulcers This drug is most active as a copper complex

11. Suprofen Non-steroidal anti-inflammatory drug Again, the copper complex is the active form

12. Copper Anti-cancer drugs Cancer cells are more sensitive to apoptosis-inducing stimulation Inhibitors of proteosome degradation induce apoptosis There are copper-containing drugs that inhibit proteosomal degradation Both the NCI drug and a copper-binding peptide (LLnL) show effective concentration dependent inhibition of proteosomal chymotrypsin activity Biochem. Pharmacol. 67, 1139 (2004)

13. Sulfonamides (sulfa drugs) Antibacterial sulfonamides act as competitive inhibitors of an enzyme that catalyses a key step in folate synthesis Folate is necessary for the cell to synthesize nucleic acids In the absence of folate cells are unable to divide Folate is not synthesized in mammalian cells, but is a dietary requirement, explaining the selective toxicity of sulfonamides to bacterial cells Sulfonamides are active inhibitors as metal ion complexes Two different structures have been proposed as the active forms The most likely form depends on the pH, with structure II favored at low pH

14. Zinc antibiotics Many commonly used topical antibiotics are actually active as the zinc complex Polymyxin B is bactericidal and active against Pseudomonas aeruginosa and other gram-negative bacteria Bacitracin, a polypeptide antibiotic, is bactericidal against gram-positive organisms Neomycin, another topical antibiotic, is used to prevent or treat bacterial skin infections

15. Gold containing drugs Au(I) is a soft metal and prefers to bind to soft donor atoms Several gold complexes with sulfur-containing ligands have found use as clinical drugs

16. Gold containing drugs Gold(I) drugs used for treatment of rheumatoid arthritis (1) aurothiomalate (2) aurothioglucose (3) auranofin Gold(III) has the same 4-coordinate square planar geometry as Pt(II) Several complexes have been examined as potential anticancer drugs

17. Gold Anticancer Drugs Gold drugs have been used for the treatment of rheumatoid arthritis since the mid 20th century With the advent of new therapies gold drugs are now used infrequently Since the introduction of auranofin in 1985 there has been no new clinically approved gold drug In spite of this apparent lack of progress there has been a great deal of interest in the use of gold compounds for cancer therapy Toxicity (IC50 in µM) of Au(III) complexes towards different tumor cell lines Lower values indicate greater potency The clinical anticancer drug cisplatin is shown for comparison purposes

18. Radiopharmaceuticals A number of different radioactive elements (radionuclides) have been used as diagnostic agents Different carriers are used to transport radionuclides to various target organs Once a radionuclide is distributed an imager is used to get a non-invasive picture of internal organs Xenon gas or a technicium aerosol is used to image the lungs Most other carriers involve metal ion complexes, where the complex acts as the delivery agent

19. Properties of Radiopharmaceuticals For radiopharmaceuticals to be useful them must decay to produce reasonable energy emission and they must have a lifetime that is long enough to image but not too long to persist in the patient These radionuclides each meet these criteria

20. Technetium Radiopharmaceuticals Technicium is among the most useful of the radionuclides because it is generated from stable Mo by neutron capture This generates a radionuclide with a half-life of 6 hours that slowly decays by gamma emission to produce another Tc isotope 99Tc is essentially stable (half-life of >200,000 years), undergoes only weak β when it does decay, and is excreted A number of different Tc complexes are used for radioimaging

21. Technetium Radiopharmaceuticals Tc is also used to tag a variety of biomolecules Different complexes are used to direct Tc to different organs

22. Properties of Other Radionuclides While Tc is the most commonly used radionuclide, there are isotopes of other elements that are also useful imaging agents There are applications where either a shorter or a longer half-life would be advantageous

23. Magnetic Resonance Imaging Contrast Agents Magnetic resonance imaging (MRI) relies on the difference in relaxation rates of water protons to image structures Compounds with unpaired electrons (paramagnetic) will dramatically shorter proton relaxation rates for waters in the immediate vicinity The selective introduction of paramagnetic metal complexes has been used to enhance MRI signals Comparison of an X-ray scan (left) and an MRI scan (right) of a brain tumor The MRI scan can give superior images without subjecting the patient to ionizing radiation

24. Magnetic Resonance Imaging Contrast Agents A variety of gadolinium-based contrast agents are in clinical use The most commonly used Manganese-based contrast agent

25. Metal Chelation Therapy Chelation therapy is use to lower abnormally high levels of essential metals or to treat acute exposure to highly toxic metals Different chelators have been used to selectively remove toxic metals

26. Treatment of acute iron poisoning Exposure to high levels of iron requires an immediate response to prevent long term, irreversible damage Iron chelation therapy requires compounds with a number of important properties

27. Iron chelating agentsfailed human trials There are a number of factors in addition to high affinity that must be considered for a clinically effective iron chelator Most chelators fail human trials either because they are toxic at the levels administered or because they are ineffective in enhancing the excretion of iron despite having high affinity for iron in isolated binding studies

28. Toxicity of Chelators There is a wide range in the toxicity of different metal ion chelators Compounds with the lowest LD50 values are the most toxic In some cases the toxicity arises from compounds binding to and interfering with some essential biomolecules In other cases the toxicity is caused by the non-selective chelation of other essential metal ions This can be minimized by introducing the essential metal ion along with the chelator to compensate for any losses

29. Examples of potential iron chelators Hydroxamate based chelators Other microbial and synthetic chelators low toxicity i.v. use only highly toxic

30. Summary • A number of drugs contain metal ions as essential components • Pt complexes function as anticancer drugs • Fe-bleomycin is also an anticancer drug • Cu complexes are anti-inflammatory and anticancer drugs • Zn complexes serve as topical antibiotics • Au complexes are used to treat arthritis and as experimental anticancer drugs • Tc complexes are used for radioimaging • Gd and Mn complexes serve as MRI contrast agents • Chelators are used for treatment of chronic and acute toxic metal overloads