METALK

Development of a novel tandem ring closing metathesis process as a general route to the first syntheses of various lycorine type alkaloids

Coordinatore	UNIVERSITE JOSEPH FOURIER GRENOBLE 1    more  Organization address address: "Avenue Centrale, Domaine Universitaire 621" city: GRENOBLE postcode: 38041 contact info Titolo: Mr. Nome: Yann Cognome: Le Roux Email: send email Telefono: +33 4 76 514488 Fax: +33 4 76 63 59 56
Nazionalità Coordinatore	France [FR]
Totale costo	193˙594 €
EC contributo	193˙594 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2011-IEF
Funding Scheme	MC-IEF
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-09-01   -   2014-08-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITE JOSEPH FOURIER GRENOBLE 1  Organization address address: "Avenue Centrale, Domaine Universitaire 621" city: GRENOBLE postcode: 38041 contact info Titolo: Mr. Nome: Yann Cognome: Le Roux Email: send email Telefono: +33 4 76 514488 Fax: +33 4 76 63 59 56	FR (GRENOBLE)	coordinator	193˙594.80

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 Obiettivo del progetto (Objective)

'Cancer is the leading cause of death worldwide and therefore a continued need exists for new drugs with new modes of action. To date, over 60% of drugs employed to target cancer are natural product derived or inspired and this places significant importance on research into the total synthesis of natural products. It also supports the need for the “next generation” of researchers to receive training in this area in order to enable the EU to remain globally competitive. The lycorine family of natural products have shown promise for the development of novel drugs; however a full study requires general access to these alkaloids. We propose a research project to develop methodology for the first syntheses of these complex natural products and novel derivatives, in order to enable future biological testing. For an efficient synthesis of these compounds, we envisage the development of a novel tandem RCM sequence, which can afford, in a single event, a decorated tetrahydroindole skeleton bearing an enol ether, which is crucial to the post-functionalisation of the bicycle. This methodology would allow a straightforward and selective synthesis of numerous lycorine alkaloids not synthesised to date. We also propose to explore the benefits of using Flow Chemistry, in particular to extend the methodology to more sensitive substrates. This is a rapidly expanding and exciting area of research, and dissemination of this knowledge within Europe in the near future is important. This proposal also offers the opportunity to establish future collaborations in this area, strengthening EU competitiveness. The applicant is an outstanding British female scientist and this fellowship would facilitate her pursuit of an independent academic career within the EU and her ability to become a future role model for women in science.'

Introduzione (Teaser)

Cancer treatment remains a significant medical challenge today and there is an urgent need for new drugs with novel modes of action. EU funding is enabling research in this area using synthetic lycorine-based products.

Descrizione progetto (Article)

Natural products based drugs are valuable source of drugs, and their structural diversity and mode of action helps to gain ground in the fight against various important diseases, including viral and bacterial infections as well as cancer. Lycorine type natural products are encountered in various forms of lilies that can be highly toxic if ingested in large quantities.

One of the known modes of actions of lycorine alkaloids is the inhibition of protein synthesis. However, exploration of the full repertoire of the biological activities of lycorine products is hampered by very low availability from naturals source of many alkaloids of this family and also due to the absence of efficient chemical synthesis.

The EU-funded METALK project proposed a novel methodology to enable an efficient chemical synthesis of these complex natural products and their derivatives for future biological testing. The synthetic approach should be flexible and versatile in order to obtain a variety of lycorine alkaloids, as well as analogues.

A particular imidate aldolization step has been explored and developed, using a Lewis acid to prevent the inherent reversibility of the reaction. This step generates a crucial precursor for the synthetic route toward lycorine alkaloids. Remarkably, this novel method also allowed accessing in enantiomerically pure form a neurotransmitter inhibitor in just four steps.

The METALK has enabled a crucial step toward the synthesis of a variety of lycorine alkaloids. It should now lead to the synthesis of many congeners and therefore to their comprehensive characterisation. It should be of particular interest to the pharmaceutical sector and facilitate the broad testing of lycorine products and analogues as drug candidates.