Final Activity Report Summary - BIOMEDCHEM (Training for new approaches in anti-parasite and anti-tumour drug discovery)
The objective of the project was to provide postgraduate students a multi-disciplinary qualification for future career in medicinal chemistry through research training, focussed on two of the most important human health world problems, namely cancer and parasite diseases, such as malaria, leishmaniasis and Chagas disease. The training consisted in acquiring techniques of lead discovery, rational drug design, organic synthesis, bioassays and cell biology, establishing a single training site, i.e. the Faculty of Pharmacy, Universite Paris-sud, France, with three academic partners, and one small and medium enterprise (SME) that was involved in bio-informatics.
Most of the drugs currently in use for malaria were designed decades ago and exhibit decreasing efficacy due to the increasing resistance of parasites. The anti-leishmania therapy is also becoming an important stake, even at the European level, with the emergence of canine leishmaniasis in south Europe. The problem is different for cancer, because of the intense interest of pharmaceutical companies worldwide for fighting this disease. However, despite some obtained success, cancer remains one of the most important causes of death in the world. In order to improve the efficiency of treatment, decrease the adverse effects of chemotherapies and overpass the important drug-resistance phenomena, alternative strategies and drugs have to be found. New natural products and new biochemical targets are two promising and valuable tools for the accomplishment of this aim.
Fourteen fellows, corresponding to 203 months, were hired on the project, four of them having prepared a PhD on the site. The core of research was devoted to the search of new hits through natural product chemistry, i.e. extraction, structure determination and synthesis, and through mechanism-based drug design, including in silico approaches. Numerous aspects of organic synthesis, such as asymmetric synthesis, organometallic chemistry and fluorine chemistry, were then essential to improve, from an initial 'hit', the biological activity and the physico-chemical properties for better pharmacological profile, to decrease toxicity and to provide innovative tools for better knowledge of mechanisms of action.
Additional training activities on other facets in the drug development or on fundamental knowledge were also available, through the Doctoral School, in other laboratories of the campus, through the collaboration with SMEs and through national and international collaborations. Most of the projects initially proposed had been achieved by the time of the project completion. More specifically, the project resulted in:
1. the discovery of new leads and new targets through a total phytochemical study of a rutaceae. A library of new derivatives of one major component, canthin-6-one, was synthesised and evaluated. Canthin-6-one derivatives, known for their anti Chagas and anti-tuberculosis activities, unexpectedly also exhibited activity against neuroglioma cancer stem cells. This part of the project went beyond our objectives and was anticipated to offer new research axes in the future.
2. the set up of a new screening method based on binding with heme, using mass spectrometry, in order to identify new anti-malaria agents.
3. the improvement of activity and pharmacological profile of molecules chosen for their anti-tumour activity. Two approaches were investigated. One concerned the design of fluorinated analogues of natural styryllactones, avoiding thus the generation of toxic metabolites. The second strategy concerned the inhibition of the protein Hsp90, a recently exploited anticancer drug target. We identified a novobiocin analogue, with IC50 equalling 1 microM. An unprecedented result was its co-crystallisation with hsp90 at the c-terminal part.
4. improved knowledge of resistance of leishmania donovani to amphotericin b. Through the application of a proteomic approach, 10 proteins were detected with a level of expression that was different in treated and non treated parasites.
Regarding chemical synthesis, efforts were devoted to new methodologies in order to minimise the number of steps and waste. These methodologies included multicomponent reactions, new reaction media, in particular fluorinated alcohols, and recovery of catalysts. During this effort it was clear that all medicinal chemists would have to take care of environmental requirements.
Most of the drugs currently in use for malaria were designed decades ago and exhibit decreasing efficacy due to the increasing resistance of parasites. The anti-leishmania therapy is also becoming an important stake, even at the European level, with the emergence of canine leishmaniasis in south Europe. The problem is different for cancer, because of the intense interest of pharmaceutical companies worldwide for fighting this disease. However, despite some obtained success, cancer remains one of the most important causes of death in the world. In order to improve the efficiency of treatment, decrease the adverse effects of chemotherapies and overpass the important drug-resistance phenomena, alternative strategies and drugs have to be found. New natural products and new biochemical targets are two promising and valuable tools for the accomplishment of this aim.
Fourteen fellows, corresponding to 203 months, were hired on the project, four of them having prepared a PhD on the site. The core of research was devoted to the search of new hits through natural product chemistry, i.e. extraction, structure determination and synthesis, and through mechanism-based drug design, including in silico approaches. Numerous aspects of organic synthesis, such as asymmetric synthesis, organometallic chemistry and fluorine chemistry, were then essential to improve, from an initial 'hit', the biological activity and the physico-chemical properties for better pharmacological profile, to decrease toxicity and to provide innovative tools for better knowledge of mechanisms of action.
Additional training activities on other facets in the drug development or on fundamental knowledge were also available, through the Doctoral School, in other laboratories of the campus, through the collaboration with SMEs and through national and international collaborations. Most of the projects initially proposed had been achieved by the time of the project completion. More specifically, the project resulted in:
1. the discovery of new leads and new targets through a total phytochemical study of a rutaceae. A library of new derivatives of one major component, canthin-6-one, was synthesised and evaluated. Canthin-6-one derivatives, known for their anti Chagas and anti-tuberculosis activities, unexpectedly also exhibited activity against neuroglioma cancer stem cells. This part of the project went beyond our objectives and was anticipated to offer new research axes in the future.
2. the set up of a new screening method based on binding with heme, using mass spectrometry, in order to identify new anti-malaria agents.
3. the improvement of activity and pharmacological profile of molecules chosen for their anti-tumour activity. Two approaches were investigated. One concerned the design of fluorinated analogues of natural styryllactones, avoiding thus the generation of toxic metabolites. The second strategy concerned the inhibition of the protein Hsp90, a recently exploited anticancer drug target. We identified a novobiocin analogue, with IC50 equalling 1 microM. An unprecedented result was its co-crystallisation with hsp90 at the c-terminal part.
4. improved knowledge of resistance of leishmania donovani to amphotericin b. Through the application of a proteomic approach, 10 proteins were detected with a level of expression that was different in treated and non treated parasites.
Regarding chemical synthesis, efforts were devoted to new methodologies in order to minimise the number of steps and waste. These methodologies included multicomponent reactions, new reaction media, in particular fluorinated alcohols, and recovery of catalysts. During this effort it was clear that all medicinal chemists would have to take care of environmental requirements.