Objective
A. General background
A1:Why a COST Action for this topic
Traditionally medicinal chemistry has been concerned solely with organic chemistry. This situation arose from the belief that living things did not use inorganic chemistry, a subject once thought to be concerned only with inanimate objects (minerals). However in the last 50 or so years it has become apparent that life has an absolute requirement for a wide variety of elements (at least 25). This has led to the emergence of the subject of bioinorganic or inorganic biochemistry as a strong discipline world-wide, and within Europe this has been placed on a firm interdisciplinary footing with the establishment of the COST Action "Coordination Chemistry in the Context of Biological and Environmental Studies" and other developments described below. The success of this programme, which has included, for example, the development of advanced physical techniques for tackling bioinorganic problems and major advances in understanding the active sites of metalloproteins, opens up the way for the exploration of medicinal inorganic chemistry within Europe.
The successful application of bioinorganic chemistry to medical problems requires a concerted effort amongst European scientists in order to allow them to compete with the strong teams in the USA and Japan. There is considerable industrial interest because much of the future emphasis amongst pharmaceutical companies will lie in the discovery of truly novel rather than "me-too" drugs and diagnostic agents. Since much of the inorganic medicinal field, which includes both the essential elements and other elements in the periodic table, is unexplored, the prospects for discovery of such compounds are very high. Success in this area requires wide contacts in a number of fields including pharmacology, microbiology, virology, molecular biology and toxicology. Chemists in a large number of European countries each have a few of such contacts and the establishment of cooperation between them under a carefully-managed COST umbrella will allow them to have a major impact on world science and to pioneer advances in an area which is becoming increasingly important to health care. The COST Action focuses on the chemistry of metal ions and is named "The Chemistry of Metals in Medicine".
A2:Status of Research in the Field
The research field has been emerging strongly over the last few years, with each major bioinorganic conference, workshop and symposium devoting a section to metals in medicine. The field has attracted main-stream inorganic chemists, organic chemists (who synthesize novel ligands), physical, computational and analytical chemists. The objectives of exploration, understanding and application are all of importance in this field. Contributions to the following areas are already evident:
discovery of anticancer agents (A1, Ga, In, Ti, Ru, Pt, Au, Sn)
antimicrobial agents (Cu, Zn, Ag, Hg, Bi)
design of antiviral agents (Li, Pt, Au, W, Cu)
structures and properties of Bi antiulcer drugs
antacids (A1, Na, Mg, Ca)
mechanism of action of antihypertensive agents (Fe, Zn)
pharmacological use of metalloenzyme mimetics (Mn, Cu, Fe)
control of iron uptake and metabolism
relationships between copper uptake, excretion and diseases
role of metals in gene control (Zn)
role of mineral deposition and dissolution in disease (Ca, Fe, Sr)
contrast agents for magnetic resonance imaging (Mn, Gd, Fe)
Tc and In compounds for diagnostic radioimaging
metal compounds in radiotherapy (Re, Y, Pb)
use of metal compounds in radiosensitization for cancer therapy (Pt, Ru)
metalloporphyrins and metallochlorins for photodynamic therapy
discovery of insulin mimetics (Cr, V).
Further targets for research related to health care, discovery and design of diagnostic agents and drugs, the chemical basis of inorganic molecular pharmacology and toxicology, and the interaction of man and the environment, are:
exploration of physiologically-relevant chemistry of clinically-used drugs
design and synthesis of novel delivery systems for metal compounds
kinetic and thermodynamic speciation of metals under physiological conditions
cellular targeting of metal compounds via ligand design
use of metalloproteins, metalloenzymes and coenzymes in diagnosis and therapy
microbial chemistry of metals in relation to medical problems
exploration of the medicinal chemistry of unusual metals
metal compounds for genetic regulation
functional diagnostic agents for magnetic resonance imaging and radio-imaging
advances in computational chemistry for design and structure-activity relationships
mineral dissolution and surface chemistry related to disease and slow-release drugs.
The above list of topics illustrates that many important developments are likely to be stimulated by research in this field. These are of high economic, industrial, social and educational value. Understanding the chemistry of metal ions is central to this programme and is therefore given prominence in this plan for Action.
A3:Relationship with other European Programmes and Activities
Existing COST projects "New chelating systems for Tc and Re for medical application" and "Studies towards novel platinum antitumour compounds" within Actions B3 and D1 are complementary to the new Action.
On a world-wide scale there has been an important development during the last decade as illustrated by a number of international meetings:
The biannual series on Bioinorganic Chemistry (ICBIC) began in 1983 in Italy (400 participants), followed by Portugal in 1985 (450 participants), the Netherlands in 1987 (500 participants), Boston in 1989 (500 participants), Oxford in 1991 (950 participants), San Diego in 1993 (800 participants), and L_beck, Germany in 1995.
The activities in Europe on this scale have been limited so far. A small series of international symposia "Metal Ions in Biology and Medicine" held in France 1990, Greece 1992 and Montreal 1994 has been available up to now.
In Europe the topic "Metals in Medicine" has only been partially addressed at general bioinorganic meetings. To be mentioned are the following:
The biannual European Bioinorganic Chemistry Conference (EUROBIC) began in the UK (Newcastle) in 1992 and attracted about 300 participants. EUROBIC II was held in Italy (Florence) in 1994 (420 participants), and EUROBIC III and IV are scheduled for the Netherlands (Noordwijkerhout) in 1996, and Spain (Sevilla) in 1998.
Biannual joint meetings of Italian, Portuguese and Spanish chemists feature work on Metals in Medicine and attract over 250 participants (1991 Spain, 1993 Portugal, 1995 Italy). The ESF programme "Chemistry of Metals in Biological Systems" has provided a very successful two-week training course in Louvain-la-Neuve each year since 1992 for a total of over 380 young scientists from across Europe, as well as yearly workshops, and is organizing EURESCO conferences in 1994 (Albufeira, Portugal) and 1995 (San Miniato, Italy). In addition, the RSC (London) Discussion Group "Inorganic Biochemistry" has a total membership of about 350 and includes workers from several European countries.
The European Confederation of the Upper Rhine Universities (EUCOR) has established a postgraduate training programme in "Metal Complexes in Medicine" (MECOM) supported by the EC COMETT program. A new journal "Metal-Based Drugs" has arisen through contacts within the HCM programme and has a European Editor and several European members on the Editorial Board.
Given these scattered regional activities in Europe it is evident that there is now a need for a concerted European activity on the "Chemistry of Metals in Medicine".
B. Objectives of the Action and Scientific Content
B1:Main Objective
The main objective of this COST Action is to explore the chemistry of metals in medicine and to apply the knowledge and experience gained for the development of novel drugs, novel diagnostic agents, more effective diagnosis and therapy and improvements in health care. The objective has close connections with the existing COST Action D1 for which secondary objectives include synthetic analogues of the active centres of metalloproteins, the development of new metal-containing drugs, specific synthesis of organic compounds and molecular recognition of metal ions and ligands. Action D1 has allowed many European workers to make initial contacts in fields related to the new COST Action.
B2:Secondary Objectives
1. To study and explore the physiologically-relevant chemistry of metallodrugs in clinical use within Europe. This will include anticancer (Pt, Ti), antiarthritic (Au), antimicrobial (Ag, Hg, Zn, Bi), antacids (Mg, Al, Ca), mineral supplements, psychotic agents (Li).
2. To support research on radiopharmaceuticals and imaging agents related to both diagnosis and therapy, especially the development of functional agents.
3. To establish a programme for investigation of the medicinal chemistry of metallo-proteins, -enzymes and -prosthetic groups (coenzymes) relating to the detection and treatment of diseases.
4. To set up a programme for the study of the speciation of metal compounds of medicinal importance. This will include investigations of thermodynamic and kinetic stabilities in both aqueous and non-aqueous media relevant to cells and tissues, and in physiological media, also minerals formed in vivo and used as slow-release drugs.
5. To establish a programme for the design and synthesis of metallodrugs, to include relevant areas of computational chemistry and molecular modelling, structure-activity relationships, use of unusual metal ions (e.g. lanthanides) and targeting features within ligands.
C.Organization Management and Responsibilities
C1:Management
The objectives described under section B2 are a selection of very important sub-topics which are already stimulated in several European member countries and which are very promising for concertation at the European level.
C2:Responsibilities
The Management Committee has responsibilities for:
(1)drawing up the inventory during the first year, organization of workshops and start of the activity; existing contacts (see section A3) will be used which should greatly facilitate this task;
(2)coordinating the joint activities with other COST Actions; joint meetings are likely to result from this activity;
(3)exploring the possibilities for wider participation and exchange of information with EC-specific programmes, ESF, etc;
(4)planning the intermediate report, final report and concluding symposium.
The respective participants will also provide reports on the progress of each of the projects in their own countries within the framework of existing programmes.
C3:Evaluation of Progress
The progress of the programme will be monitored by means of brief annual reports from each of the participating scientists which will describe the results of research obtained through concertation. A mile-stone report will be prepared by the Management Committee after 3 years of joint activities. The report will be presented to the COST Technical Committee for Chemistry for their review.
A final report will be published to inform non-participating scientists and research workers interested in the results about the scientific achievements of the Action. It is expected that some reviews by participants which describe the progress made and state of the field will be published in International Journals. To conclude the COST Action, a symposium will be held after 5 years which will be accessible to other scientists.
D.Time-table
The programme will cover five years and consist of four stages:
Stage 1: After the first meeting of the Management Committee a detailed inventory of on-going research and existing plans of the participating groups to begin joint projects will be made. This will result in a discussion document which will allow further planning to occur.
Stage 2: It will be evident which projects are closely related and would benefit from joint activities. Researchers (and co-workers) will set-up (and continue) joint collaborative projects and exchange their recent research results. It may be appropriate to explore wider collaboration with other European countries during this stage.
Stage 3: An intermediate progress report will be prepared after three years for review by the COST Technical Committee for Chemistry and by the COST Senior Officials Committee.
Stage 4: This final phase will begin after four years and will involve the evaluation of the results obtained. It may include the organization of a symposium for all the participants and co-workers.
E.Duration of the Action
The Action will last for five years: 1996-2001.
F.Economic dimension of the Action
The economic dimension of the Action (initial estimate of total costs = personnel + operational + running + Commission costs) is 37 MECU.
In total, activities in at least one of the five sub-topics are on-going in most of the COST member countries. The total human effort in the area of "The Chemistry of Metals in Medicine" as described in this document, amounts to 755 man-years, being equivalent to 32 MECU.
1. Personnel costs
Estimates of personnel costs (research + administration) are as follows:
Sub-topic 1:in about 18 countries a total of 178 man-years, totalling to 7,6 MECU;
Sub-topic 2:in about 11 countries a total of 125 man-years, totalling to 5,3 MECU;
Sub-topic 3:in about 11 countries a total of 59 man-years, totalling to 2,4 MECU;
Sub-topic 4:in about 15 countries a total of 152 man-years, totalling to 6,4 MECU;
Sub-topic 5:in about 18 countries a total of 241 man-years, totalling to 10,2 MECU.
2. Operational and running costs
The estimate of the total operational and running costs including costs of instruments and materials is 5 MECU.
3. Coordination costs
The costs for coordination to be covered by the COST budget are estimated to be 60 MECU per year.
Current status
The scientific programme of the Action will be focused on the following five sub-topics :
- metallodrugs in clinical use;
- radiopharmaceuticals and imaging agents;
- metallo-proteins, -enzymes and -prosthetic groups (coenzymes);
- speciation of metals compounds;
- design and synthesis of metallodrugs.
Nineteen countries (A, B, CH, CZ, D, DK, E, F, FIN, GR, H, I, IRL, N, NL, P, S, UK, and the Ukraine) have signed the Memorandum of Understanding of the COST Action D8.
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1049 Brussels
Belgium