Natural Products as a Source for Discovery, Synthesis, and Application of New Pharmaceuticals

Obiettivo

A. GENERAL BACKGROUND

A1: Why a COST Action on this topic?

The search for biologically active natural products for the development of new drugs has a long tradition. Most such compounds were isolated from plants, animals, fungi, and microorganisms like bacteria, which exist in great variety on earth. Total synthesis is playing a major role in the drug discovery process since it allows exploration in chemical biology through molecular design and mechanistic study.

Natural products are the most consistently successful source of drug leads and continue to provide greater structural diversity than standard combinatorial chemistry. They offer major opportunities for finding novel low molecular weight lead structures that are active against a wide range of assay targets.

Current commercial evidence also supports this statement. More than 60% of the available anti-cancer drugs were either directly based on or developed from natural products.

Natural products play a major role in anti-cancer drugs (see study NCI, USA). The majority of these medicines are related to natural products. A similar picture has been demonstrated in other important diseases where the majority of the available lead structures is based on natural products too.

Available anti-Cancer Drugs until 1994; Ref. NCI, USA

A Directly Based on Natural Sources
B Synthesised from Natural Sources (e.g. semi-synthetic)
C Fully Synthetic
D Synthetic, but Based on Natural Products

A very important example of plant derived drugs, taxol(r), originally isolated from the bark of the pacific yew tree, was subsequently synthesised and has recently been released for cancer therapy by Bristol-Myers-Squibb in the U.S. An example of a previously ignored group of organisms is the myxobacteria. Also known as gliding bacteria, these are common but unusual soil bacteria that can form fruiting bodies. Many diverse structures have been isolated from myxobacteria, including the epothilones, macrolides that show a taxol-like effect on tubulin. The epothilones are superior over taxol being active on multi-drug-resistant cells (MDR). Epothilone B and analogues are right now under clinical development in phases one and two.

Many other compounds of microbial origin are already in use: e.g. as agents such as antibiotics in human and veterinary health care, as feeding additives for animals, and as insecticides or herbicides for agricultural use.

There is both general and industrial interest in further searches for new secondary metabolites. In addition, the development of new and elegant synthetic methods is required to synthesise target molecules by novel and efficient strategies that make economic use of feedstock, energy and produce less waste. This COST action focuses on target-orientated discovery of novel compounds with the special emphasis on multi-drug-resistant cells. In addition, strategies for the total synthesis of biologically active natural products are a major subject of this action. This provides flexible entries to a variety of analogues in order to find the common pharmacophoric model. In light of that there is a demand for such a COST action on: "Natural Products as a Source for Discovery, Synthesis, and Application of New Pharmaceuticals", in order to coordinate research efforts on target orientated total synthesis of biologically active natural products. In addition, laboratories with expertise in the target-orientated discovery of new structures with an important biological profile (e.g. active against MDR cell lines) will be included. The development of strategies to synthesise these compounds will combine research efforts.

Finally, an enormous interest of pharmaceutical companies such as CIBA, Novartis, AstraZeneca, Pharmacia Inc. and Degussa in this action and their collaboration with research groups from academia on the development of new leads for clinical development is expected. This is evident from some other COST Chemistry actions (e.g. the D12 action) where several working groups have established fruitful collaborations with companies. This action on discovery and total synthesis of biologically active natural products will further increase and affirm this type of collaboration.

A2: Status of the research of the field

The field of discovery and synthesis of biological active natural products represents a dynamic and largely growing research area. Over the last two decades many complex molecules have been synthesised using elegant and novel synthetic methods based on catalysis, asymmetric reactions, and bio-mediated reactions. By the use of new strategies to discover natural products of interest, many molecules with novel structural features have been isolated and their structures have been elucidated. Besides plants and animals more recently secondary metabolites of bacteria, fungi, and marine origin have been intensively studied. This led to very interesting and novel structures with outstanding biological properties that require further development of strategies for total synthesis and new methodology to synthesise these molecules. Especially for the use in drug discovery in pharmaceutical industry flexible entries to biologically active molecules need to be developed. A major advantage will be the target-orientated search of new low molecular weight natural products, because the understanding of the biological mechanism of action will provide a useful tool to generate analogues.

In addition, structure-activity-relationships (SAR) play a very important role to discover new drugs and this requires flexible approaches in synthesis to make these molecules in mg scale. In addition, computer modelling and receptor studies will be of importance.

There is still a demand in Europe to strengthen discovery and total synthesis of natural products. Most of the funding is located in the development of new synthetic methods lacking to tackle complex natural product synthesis. Target-orientated discovery of new compounds combined with efforts in total synthesis will be an ideal platform to educate students for future positions in academia and industry.

A3: Relationship with other European Programmes

Several conference series, both on European, and world-wide international scale, with visible European participation have been set up to encourage scientific exchange in the field of natural product synthesis and discovery of new molecules (e. g. IUPAC conferences on natural products).

B. OBJECTIVES OF THE ACTION AND SCIENTIFIC CONTENT

B1: Main objective

The main objective of the action is the target-orientated discovery of new natural products with an important biological profile based on new and unusual sources, e.g. secondary metabolites of bacteria or marine organisms (only 4% of known bacteria have been analysed) combined with efforts to synthesise these molecules by the use of novel strategies and methods. The development of new strategies to synthesise complex natural products will be the second main objective. As a result of that, a broad screening of analogues will be possible. Structure activity data will then be used to further refine the pharmacophore model, enabling the rational design and synthesis of more focused active compounds. Special emphasis is placed on MDR cells, because a major problem in cancer therapy based on cytotoxic agents is the resistance development via an over expression of ? phospho-glucoprotein or a mutation of tubulin. New compounds that would overcome this problem would be of enormous importance.

In summary, new strategies for the synthesis of complex natural products and the biological function of these molecules is the main objective for the proposed new action.

Therefore, this COST action will bundle research directions all over Europe and will generate new joint research projects on the target-orientated discovery of new leads based on unusual sources, e.g. non-studied bacteria or rare marine organisms. In addition, promotion of research projects with complementary expertise (isolation and structure elucidation versus total synthesis of natural products).

For this reason, the action on "Natural Products as a Source for Discovery, Synthesis, and Application of New Pharmaceuticals" will bring together experts from academic laboratories specialised in isolation and structural elucidation of natural products, strategy of total synthesis, as well as scientists engaged in the development of new synthetic methods. In addition, groups from industry will gain expertise in biological testing and scale-up of relevant synthetic problems to approach the synthesis of complex molecules in chemical development.

Activities in European laboratories have to be coordinated via a future COST Action in order to strengthen this competitive field versus the US.

This action will provide substantial improvement on the discovery of new leads and of the understanding of synthesising complex natural products as potentially new pharmaceuticals. This could lead to immediate use in pharmaceutical industry.

B2: Sub-Topics

(a) Isolation of natural products

Isolation of new structures (e.g. secondary metabolites like macrolides, alkaloids, terpenes) represents a fundamental research topic. Only a few research teams focusing on isolation techniques are active in Europe. A major aim of this action will be to emphasise new research directions in this very important area. Especially actinomyceten and soil fungi based on European sources will be of interest. Ethnopharmacologically plants applied for the treatment of specified diseases will be studied. Invertebrates from the Mediterranean Sea (e.g. sponges, molluses, tunicates, bryozoans) could offer an enormous basis of compounds. Finally, rare bacteria, e.g. the gliding myxobacteria provided already a great variety of new structures (ratjadones, sorangicins, soraphenes, epothilones). The epothilone case (discovered at the Gesellschaft f_r Biotechnologische Forschung, Braunschweig, Germany) could be a story of success, because epothilone B and some analogues are currently in clinical trials. These new compounds are superior over taxol in in vivo studies.

(b) Discovery of new leads

A very important step will be the discovery of a new lead structure based on natural products. Again, the epothilones, secondary metabolites from myxobacteria, are one of the most important leads in cancer therapy today. Special attention will be focused on test systems provided by industry. High throughput screening and target-orientated assays will provide quick access to interesting structures.

(c) Structure determination

Structure elucidation of new complex molecules requires considerable knowledge on new analytical techniques, like HPLC, GC, MS, and NMR. Especially, high field NMR combined with novel pulse sequences will be of great importance and allow several groups to benefit from exchanging data and samples. In addition, solid phase NMR will be important to study interactions of small molecules with proteins (rational design of drugs), which finally could lead to a receptor model.

(d) New Strategies for total synthesis of biologically active natural products

This sub-topic represents an extremely important aspect in the new action. The development of new strategies for total synthesis combines in ideal form different areas in organic synthesis. Research collaboration will create a flexible access to interesting and novel routes to synthesise new molecules. Stereochemistry (dia- and enantioselective reagents) will be a major aspect and will train students to get a more detailed insight of this important issue. Furthermore, domino reactions play an important role in the synthesis of complex natural products, because in a sequence of events several strategic bonds can be formed stereoselectively in one-pot.

(e) Novel synthetic methods and new reagents

The basis of all synthetic strategies will be the availability of new synthetic methods. Therefore, a key feature in this action will be to study new reactions that can be used for the synthesis of complex molecules. The COST actions D 24 (Sustainable Chemical Processes: Stereoselective Transition Metal-Catalysed Reactions) and D 25 (Applied Biocatalysis: Stereoselective and Environmentally Friendly Reactions Catalysed by Enzymes) will be ideal to supplement the "know how" to synthesise complex molecules. Especially, molecules with different functional groups and various protecting groups are good testing grounds for such studies. Reagents based on catalysis with transition metals and/or enzymes (e.g. metathesis, aldolases) will be of great importance. Finally, aldol reactions and related processes are very useful methods to approach complex molecules. The detailed study of the stereochemical outcome of these reactions will even generate knowledge to understand the biosynthesis of several metabolites, e.g. macrolides.

(f) Drugs from natural products

Semi-synthesis plays an important role in drug development (taxol, epothilones). Quite often, a fine-tuning of complex natural products is required to improve the biological profile. Novel synthetic methods combined with elegant strategies have to be used to generate analogues with a better "therapeutic window". These achievements will be of considerable interest for the pharmaceutical industry.

(g) Total synthesis in chemical development

Scale-up of chemical reactions is always critical and creates major problems. At least for cost reasons several major changes have to be made starting from a synthesis based on a research laboratory. In addition to economical facts, the ecological point of view will be of importance (e.g. use of halogen free solvents, reagents).

This COST action complements the COST actions D12 ("Organic Transformations: Selective processes and Asymmetric Catalysis"), D25 ("Sustainable Chemical Processes: Stereoselective Transition Metal-Catalysed Reactions") and D13 ("New Molecules for Human Health Care"). The former action is focussed on transformations of organic molecules, critical to the synthesis of important targets that is part of the proposed new action. The latter action is primarily concerned with understanding the relationships between the molecular structure and the biological activity of organic compounds including natural products, but not with their discovery and synthesis.

C. ORGANISATION, 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 co-ordination at the European level.

C2:Responsibilities

The Management Committee has responsibilities for:

(1)Drawing up the inventory during the first year, organisation of workshops and start of the activity; existing contacts will be used which should greatly facilitate this task;
(2)Co-ordination of the joint activities with other COST Actions; joint meetings are likely to result from this activity;
(3)Explore the possibilities for wider participation and exchange of information with EU-specific programmes, ESF, etc;
(4)Planning the intermediate report, the final report and the concluding symposium.

Progress reports will also be provided by each respective participant in 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 working group coordinator. These will describe the results of research obtained through concerted action. The Management Committee will prepare a milestone report after 2 years of joint activities. The report will be presented to the COST Technical Committee for Chemistry for their review and to the COST Senior Officials Committee for information. 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 review 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. It will be accessible to other scientists.

D. TIMETABLE

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 to allow further planning.
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 two years for review by the COST Technical Committee for Chemistry and for information to 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 organisation of a symposium for all the participants and co-workers. The final report will be submitted to the COST Technical Committee for Chemistry for scientific assessment and after to the COST Senior Officials Committee.

In summary the total timetable can be represented as follows:

-Start 1st year
-Formation of projects 1st and 2nd year
-Workshop of group leaders end of 1st year and each year later on
-Overview available; start meetings; continue meetings on subtopics end of 2nd year
-Start exploration of wider participation 3rd and 4th year
-Intermediate Progress Report available for the Chemistry Technical Committee and the CSO end of 2nd year
-Start evaluation of results continuously each year after 1st year at the yearly workshop
-Concluding Symposium end of 5th year

E. DURATION OF THE ACTION

The Action will last for five years

Five years are required because of the complexity of the research focus, especially the very complex molecules (discovery, total synthesis and applications in pharmaceutical industry). In addition, complex methodology in organic synthesis is needed to solve the problems within the working groups. Finally for biological testing, special assays need to be provided by the industry to gain into the biological activities of molecules.

F. ECONOMIC DIMENSION OF THE ACTION

It is to be expected that many teams in the working groups in the COST D12 Action and groups in the COST Actions D24 and D25 will transfer the knowledge into this COST Action, following some regrouping and extension by additional laboratories. It is estimated that a total of 50 laboratories will eventually be involved in the Action.

Based on experience in the COST D12 programme, it is estimated that the economic dimension of the Action (initial estimate of total costs = personnel + operational + running) will be 100 million Euro.

F1.Personnel costs

The total human efforts in the Action "Natural Products as a Source for Discovery, Synthesis, and Application of New Pharmaceuticals" as described in this document, amounts to 800 man-years (160 researchers during 5 years), being equivalent to 80 million Euro.
Estimates of personnel costs (research and administration) will depend on the rates applicable to various EU countries. Based on the expected number of participating countries of 28, a total estimate 80 million Euro is expected.

F2. Operational and running costs

The estimate of the total operational and running costs including costs of instruments and materials is 20 million Euro.

The estimate of the total economic dimension of the action is therefore 100 million Euro.

G. DISSEMINATION OF SCIENTIFIC RESULTS

All publications arising from research carried out under COST Action D28 will credit COST support and the Management Committee will encourage and promote all co-authored papers. Results of research carried out by the working groups under COST Action D28 will be submitted to international scientific journals and reviews.

Joint meetings among different working groups in COST Action D28 and with working groups from other COST Actions, particularly with those of COST Actions D12, D24 and D25 will be organised in such a way as to best promote interdisciplinary communication. Also the COST Chemistry web site (http://www.unil.ch/cost/chem) will be exploited for the dissemination.

The Management Committee (MC), in conjunction with the working groups (WG) of the Action, will meet every year with the main aim of presenting results to the MC as a whole and, where possible, the MC will invite potential users and interested parties to this meeting.

The Management Committee will, during the first year of the Action, also set up a work-plan for interdisciplinary events for the dissemination of results of the Action COST D28.

Programma(i)

IC-COST - European cooperation in the field of scientific and technical research (COST), 1971-

Argomento(i)

13 - Chemistry

Invito a presentare proposte

Data not available

Meccanismo di finanziamento

Data not available

Coordinatore

N/A

Contributo UE

Nessun dato

Indirizzo

Costo totale