The European Lead Factory (ELF; www.europeanleadfactory.eu) is an EU-led initiative (part of the Innovative Medicines Initiative), involving pharmaceutical companies, academic organisations, SMEs and public bodies who are collaborating on drug discovery. Part of the initiative involves generating a Public Compound Collection that can be used for screening. Initially, 300,000 unique and novel compounds have been supplied by pharmaceutical companies in the consortium. This will be supplemented by a further 200,000 compounds, from libraries that will be synthesised as part of this project, based on proposals from the European public domain. The combined public-private library is known as the Joint European Compound Collection (JECC).
The new compounds will be based on Library Design Proposals (LDPs) that are approved by the consortium’s Library Selection Committee. This committee comprises eight respected synthetic and medicinal chemists with complementary backgrounds, all bound by confidentiality. LDPs are now actively welcomed from external academics and SMEs, and may be submitted through the European Lead Factory website. Successful proposals will be rewarded with a fixed payment, following the production of at least 50 compounds based on the LDP. This payment is assigned by the Library Selection Committee, and is based on the scientific and technical maturity of the LDP. Academic groups and SMEs may submit proposals for high-throughput screening assays.
This poster describes two case studies where natural product-inspired libraries have been designed and synthesised as part of the European Lead Factory project. Both libraries utilise cycloaddition chemistry as the key scaffold forming reaction and were designed to give a large number of compounds with properties suitable for lead discovery.
The first library employed a one-pot, multicomponent reaction, involving a triple Diels-Alder cascade sequence, which rapidly constructed a highly 3-dimensional tetracyclic scaffold from relatively simple starting materials. These scaffolds were then further diversified using a range of N-capping groups to deliver a diverse compound library.
The second library was designed around an intramolecular [3+2] azomethine ylide cycloaddition of O-allyl salicaldehydes to give a natural product-like tricyclic scaffold. Diversification was introduced through the use of alternative salicaldehyde starting materials and manipulation of the cycloaddition products through N-capping and amide formation.
