Total synthesis of (+)-aspercyclide a and its analogues

Lead Research Organisation: Imperial College London
Department Name: Chemistry

Abstract

Allergic disorders such as hay fever and asthma currently afflict approximately one quater of the population of Europe and the USA. Current therapies only alleviate symptoms, they do prevent the conditions. The research proposed here is geared towards the development of an efficient chemical preparation of a natural substance, (+)-aspercyclide A, that is known to inhibit a key protein-protein recognition event involved in all allergic pathways and which could represent a crucial lead for the development of new preventative treatments for allergic disorders. The chemistry that is proposed to be developed will also allow structural analogues of the natural substance to be readily prepared such that, following biological screening, more potent substances can be identified.

Publications

10 25 50
publication icon
Spivey A (2009) A Method for Parallel Solid-Phase Synthesis of Iodinated Analogues of the CB 1 Receptor Inverse Agonist Rimonabant in Organic Letters

publication icon
Carr JL (2010) Total synthesis of (+/-)-aspercyclide A and its C19 methyl ether. in Chemical communications (Cambridge, England)

publication icon
Carr JL (2011) Synthesis of the C19 methyl ether of aspercyclide A via germyl-Stille macrocyclisation and ELISA evaluation of both enantiomers following optical resolution. in Organic & biomolecular chemistry

 
Description Allergic disorders such as hay fever and asthma currently afflict approximately one quater of the population of Europe and the USA. Current therapies only alleviate symptoms, they do not prevent the conditions. The research proposed here was geared towards the development of an efficient chemical preparation of a natural substance, (+)-aspercyclide A, that is known to inhibit a key protein-protein recognition event involved in all allergic pathways and which could represent a crucial lead for the development of new preventative treatments for allergic disorders. The total synthesis was completed via two racemic routes and the biological activities of the two enantiomers, which were separated by CSP-HPLC, were evaluated by ELISA and found to reside almost exclusively in the natural (+)-enantiomer. An enantioselective synthesis was also developed and this route used to prepare analogues whose activity is still being evaluated.
Exploitation Route The leads have potential for drug development in the anti-asthma arena. The research is ongoing with an EU Marie-Curie Grant. it is expected that more potent and potentially druggable analogues of this natural product will emerge.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology
URL http://www3.imperial.ac.uk/spiveygroup/research/signaltransduction
 
Description We understand that Novartis and UCB have used our synthesis route to aspercyclide A to make this for testing in their assays. There is great interest worldwide in finding small molecule inhibitors of the IgE-FceR1 PPI.
First Year Of Impact 2008
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Societal