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ANR funded project

Blanc - SIMI 7 - Chimie moléculaire, organique, de coordination, catalyse et chimie biologique (Blanc SIMI 7)
Edition 2012


Multi-click


Click strategies for multifunctional anti-Alzheimer agents

Click strategies for multifunctional anti-Alzheimer agents
The aim of this project is to synthesize multi-target directed ligands (MTDLs) aimed at the treatment of Alzheimer disease (AD) through the assembly of high-affinity precursors via click chemistry.

Evaluation of new «click« reactions adaptable to kinetic TGS and exploitation of these reactions to produce molecules in order to develop a new treatment toward Alzheimer’s disease.
Alzheimer’s disease, which is the most common cause of senile dementia, is a major public health issue. In this context, the objective of this project is to evaluate new «click« reactions adaptable to kinetic target guided synthesis (TGS), and our ultimate goal is to exploit these reactions to produce molecules that will aid fighting Alzheimer's disease.

Development of new click reactions and application of the discovery of new treatment towards Alzheimer’s disease
Alzheimer Disease is a multifaceted illness requiring the combination of synergetic treatment strategies. We have thus chosen to use new click reactions to prepare new multi-target directed ligands (MTDLs) that will act simultaneously on the different players in AD pathology and, thereby, will allow a more efficient treatment of AD

Results

The first multi-target compounds show an inhibitory activity towards acetylcholinesterase, beta-secretase and the aggregation of A? peptide, involved the neurodegenerative cascade.

Outlook

This project will allow to give new alternatives for potential treatments of Alzheimer’s disease and to give new tools to biologists in order to understand the complex mechanism of the neurodegenerative cascade leading to the development of Alzheimer’s disease.

Scientific outputs and patents

None after 30 months, since we are awaiting for the biological results of the synthezized compounds. The organic chemistry part has given two international publications.

Partners

UMR 6014 CNRS Chimie organique Biiorganique Réactivité Analyse

UMR 5075 CNRS - CEA Institut de biologie structurale

UMR 6507 CNRS Laboratoire de Chimie Moléculaire et Thioorganique

ANR grant: 408 000 euros
Beginning and duration: novembre 2012 - 48 mois

Submission abstract

The objective of this project is to evaluate new "click" reactions adaptable to kinetic target guided synthesis (TGS), such as described by K. B. Sharpless et al. ten years ago. In situ click chemistry has indeed proven to be a new and elegant paradigm for drug discovery. Based on our successful experience on the use of Huisgen cycloaddition on human acetycholinesterase (AChE), which allowed us to estimate scopes and limitations of this reaction, four new reactions will be targeted, namely the “Aubé”, “Pictet-Spengler” and “carbonyle-ène” reactions, as well as the “Kondrat' Eva's“ cycloaddition for which we already have obtained encouraging preliminary results.
Our ultimate goal is to exploit these reactions to produce molecules that will aid fighting Alzheimer's disease (AD). AD is a neurodegenerative process occurring in the central nervous system (CNS). It is the most common cause of dementia in elderly. It is clinically characterized by a loss of memory and cognition, associated to a deterioration of the basal-forebrain cholinergic-neurons network and a consequent lack of acetylcholine (ACh) around brain cells. While the process leading to the development of AD is complex and multifactorial, and the etiology of AD is not completely known, it is nowadays clear that AD is a multifaceted illness requiring the combination of synergetic treatment strategies. Although several research strategies have been envisaged in the last decades, these molecules only alleviate the symptoms of the illness, and do not cure it. The current view of AD physiopathology is indeed that its onset and progression are the result of a complex network of genetic predispositions, enzymatic activities, receptors expression, protein interactions, alteration of metal concentrations, cell cycle survival disruption, ion homeostasis dysregulation, protein misfolding, etc. The “multifactorial hypothesis” led to the proposal that the multi-target-directed ligands strategy is needed to treat the disease more efficiently. The first objective in this project will, therefore, be to use the classical Huisgen reaction as well as the above-mentioned, newly-developed click reactions, so as to prepare new multi-target directed ligands (MTDLs) that will act simultaneously on the different players in AD pathology and, thereby, allow a more efficient treatment of the disease. The envisaged MTDLs should combine at least two functionalities, among which acetylcholinesterase (AChE) inhibition, an action against Abeta aggregation, anti-oxidative properties, BACE-1 inhibition, GSK-3 beta inhibition or alpha 7 nAChR activation. The second objective of the project is to use the more complex in situ click chemistry approach for the discovery of potent MTDLs. It is using this methodology, also coined kinetic target guided synthesis (TGS), that Sharpless et al. indeed obtained the most potent AChE inhibitors with a femtomolar inhibitory activity. As for our first objective, we will expand the toolkit of click-reactions beyond the classical Huisgen reaction, so as to produce a wider diversity of possible ligands. Additionally, and based on our already-existing know-how, we will expand the in situ click chemistry to another enzyme involved in AD, viz. BACE-1, which is one of the two enzymes involved in the proteolytic release of the amyloid-beta peptide.

 

ANR Programme: Blanc - SIMI 7 - Chimie moléculaire, organique, de coordination, catalyse et chimie biologique (Blanc SIMI 7) 2012

Project ID: ANR-12-BS07-0008

Project coordinator:
Monsieur Pierre-yves Renard (Chimie organique Biiorganique Réactivité Analyse)
pierre-yves.renard@nulluniv-rouen.fr

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.