Ateneo - UPO

The course aims to provide knowledge on the role of inorganic elements in biological systems, including their therapeutic uses. In the first part of the course (Metals in biological systems, 3 credits) the chemical properties and biological functions of the elements that bind to biomolecules, the mechanisms of metal uptake, transport systems and insertion in the final sites, the mechanisms of action for some classes of metalloproteins and the involvement of metals in some diseases will be studied. In the second part (Metals in Medicine, 3 credits) the course deals with metal complexes used in medicine, such as Pt complexes as antitumor agents, Au complexes for rheumatoid arthritis, Bi complexes for peptic ulcer disease, nitroprusside for hypertensive emergency, vanadyl derivatives for diabetes, nuclear medicine (drugs for radiotherapy and diagnostics), metal compounds for tropical diseases, metal complexes for diagnosis (MRI in particular).

The course slides (in English) will be made available on DIR. The following texts are recommended:
Wolfgang Kaim, Brigitte Schwederski, Axel Klein, "Bioinorganic Chemistry - Inorganic Elements in the Chemistry of Life: An Introduction and Guide", 2nd Edition, Wiley, 2013
Rosette M. Roat-Malone, "Bioinorganic Chemistry: A Second Short Course", Wiley Interscience, 2007
Ivano Bertini, Harry B. Gray, et al., "Biological Inorganic Chemistry", University Science Books, 2007
Stephen J. Lippard, Jeremy M. Berg, Principles of Bioinorganic Chemistry", University Science Books, 1994
James C. Dabrowiak, “Metals in Medicine”, Wiley;
C. Jones and J. Thornback, “Medicinal Applications of Coordination Chemistry”, RSC Publishing.
Scientific articles for in-depth studies will be also provided.

The main aim of the course is the acquisition of the essential knowledge to understand the role of metals in biological systems and the chemical processes in which they are involved. The student should be also able to understand the properties of transition metal and rare earth metal complexes as chemotherapeutic and/or diagnostic agents. He will also develop the ability to apply the theory in the discussion of case studies. The students will be able to use a suitable chemical vocabulary in relation to the topics described in the course and will develop the ability in making judgements, drawing conclusions, and autonomously deepening a subject related to those of the course.

For the Bioinorganic chemistry course it is recommended to have good basic knowledge in inorganic chemistry (coordination compounds) and biochemistry.

Teaching in lecture halls with theoretical lessons and collective discussion of case studies autonomously studied in-depth by the students and chosen among those suggested by the teachers that will give them suitable scientific articles to read.

The in itinere learning will be verified with collective discussion.

The final judgement will consist in a written exam of 2 hours for the whole 6-CFU course, consisting of 5 theoretical open questions (max 6 points each). For the students of "LM Biologia” who attend only one part of the course (3 CFU), the final judgement will consist in a written exam of 1.5 hours, consisting of 3 theoretical open questions (max 10 points each).
For all the students one question will be about the subject chosen by the student for an autonomous learning.
Two questions will be about the “Metals in biological systems” part and will be chosen so that the entire program is covered (in turn the subjects will be the mechanisms of metal uptake, transport systems and insertion in the final sites, the mechanisms of action for some classes of metalloproteins, the role of metal deficiency and excess in some diseases).
Two questions will be about the “Metals in medicine” part and will be chosen so that the entire program is covered (in turn the subjects will be platinum antitumor complexes, antitumor antibiotics, radiotherapy and radiodiagnostics, photodynamic therapy, metal complexes for diabetes, ulcer or rheumatoid arthritis, tropical diseases, etc.) and the student can demonstrate that they know and understand the basic concepts.
The difficulty level of the exam corresponds to the program and the reference texts indicated. The written test will be passed with the knowledge of the basic concepts corresponding to a sum of the scores not less than 18 points (18/30). The highest grade will be obtained showing the acquisition of all the knowledge and abilities/capacities indicated. This kind of exam verify the theoretical knowledges of bioinorganic chemistry and their applications, the ability to use a suitable scientific language and the learning skills.

The course deals with:
“Metals in biological systems”: 1. Coordination Chemistry for Biologists / 2. Biochemistry for Chemistry / 3. A Brief Overview of Molecular Biology / 4. Biological Functions of Inorganic Elements / 5. Biological Ligands for Metal Ions (amino acids; proteins; macrocycles; nucleobases) / 6. Metal Assimilation and Pathways. Sodium and potassium (ion channels; ion pumps; cotransport; homeostasis); Magnesium and Calcium (adsorption and homeostasis); Iron (assimilation; storage; homeostasis); Copper (assimilation; homeostasis); Zinc (assimilation; homeostasis) / 7. Cobalamin and cobalt proteins (introduction; reactivity; enzyme classes, deficiency) / 8. Metals at the center of photosynthesis (magnesium) (introduction; light absorption; exciton transport; why Mg2+?; magnesium at the centre of PCR) / 9. The O2 Molecule: Uptake; Transport and Storage of an Inorganic Natural Product (story of the O2 molecule; hemoglobin and myoglobin; O2 transport; a lesson from Nature; delivery; hemoglobin; a cheating husband!; when something goes wrong; how to measure O2 in vivo; the oxygen paradox; other heme and iron containing systems) / 10. Copper-containing Proteins: An Alternative to Biological Iron (introduction; copper proteins type 1-3) / 11. The Bioinorganic Chemistry of the Quintessentially Toxic Metals (introduction; aluminium; chromium; lead; cadmium; mercury; arsenic; gadolinium; brief histories of toxic metals) / 12. Metal chelation in medicine (introduction; ligands and their properties; treatment for heavy metal intoxication; iron diseases; copper disease; a story of metal chelation) / 13. Biomineralization (introduction; nucleation and crystal growth; bone formation; bone regulation; teeth; gravity- or inertia-sensitive receptors).

“Metals in Medicine”: introduction to inorganic medicinal chemistry, a brief account of pharmacokinetics and pharmacodynamics, general information about cancer and cancer chemotherapy strategy. Alkylating agents will be studied in detail and, in particular, metal complexes as electrophiles: mechanism of action, toxicity Pt complexes in the clinic practice, SAR rules and design of new drugs. Organometallic complexes: titanocene and arene-dichloride-ruthenium (RAPTA). Chemoresistance. Complexes activated in the tumour acidic or reductive milieu (prodrugs). Pt(IV) derivatives. Application of the concepts of "drug targeting and delivery" to Pt compounds. Active and passive targeting. EPR effect. Liposomes and lipoplatin. DNA intercalators. The triplet / singlet oxygen and ROS (reactive oxygen species): metal complexes causing oxidative damage to DNA (bleomycin activated by iron cations) and photosensitizers for photodynamic therapy (metal - porphyrins). Photoactivatable Pt(IV)-azide complexes. Metal complexes for different therapies: Au(I) as an antirheumatic; Bi(III) as anti-ulcer, complexes for rapid release of nitric oxide (NO) (e.g. sodium nitroprusside) for anti-hypertensive emergencies, vanadyl derivatives as insulin mimetics for the treatment of diabetes. Malaria and ferroquine; metal compounds for tropical diseases. Basics of radiochemistry. Nuclear medicine: drugs for radiotherapy and radiodiagnostics. SPECT and 99-m Technetium. Formation, reduction and speciation of technetium. Iodine radioisotopes and thyroid. PET and fluoroglucose. BNCT and boranes. Mention to MRI.

Knowledge and understanding: knowledge of the biological properties of metals and metal complexes, and of their applications in the living systems and medicine.
Applying knowledge and understanding: ability to apply the theory in the discussion of case studies.
Making judgments: skill to critically evaluate the concepts learnt; skill to critically analyze the proposed case studies.
Communication skills: ability to describe subjects of bioinorganic chemistry with a suitable language.
Learning skills: ability to use the teaching material for a critical and reasoned study; skill to autonomously in-depth study a subject related to the course and to analyze data (even though not personally obtained) based on the assimilated knowledge.