TSASPERA · Total Synthesis of (+)-Aspercyclide A and Analogues

Total synthesis of (+)-aspercyclide A and analogues

Human allergic disorders ranging from hay fever (allergic rhinitis), eczema (atopic dermatitis) and food allergies through to the potentially life threatening asthma and anaphylactic shock are increasing worldwide. Epidemiological studies indicate that allergic manifestations afflict more than a quarter of the population in industrialised countries, and a dramatic increase has been reported during the last three decades. Allergies including asthma afflict 40 % of the United Kingdom (UK) population and bronchial asthma currently affects 5.2 million. The yearly cost to the UK National Health System in primary care alone exceeds EUR 1 200 million, and the loss of 18 million working days costs further EUR 1 400 million. The quality of life for many sufferers is severely impaired. Currently available medications for the management of allergy and asthma are generally unsatisfactory and often associated with debilitating side effects. Allergic disorders are caused by inflammatory mediators (e.g. leukotrienes) released by mast cells and basofils. Allergen specific soluble immunoglobulin E (IgE) proteins bind to high-affinity membrane receptors (Fc epsilon RI) on these cells and cross-linking of these complexes by multivalent allergens activates inflammatory mediator release. Small molecules that bind to Fc epsilon RI and block binding of IgE should therefore be efficacious in treating allergic disorders. Proof of the principle that IgE is a valid target for therapy has been forcefully provided by the 2005 European Union (EU) approval of the humanised monoclonal anti-IgE antibody Xolair (omalizumab, from Novartis / Genentech) for severe asthma and allergic rhinitis. However, XolairTM costs EUR 12 000 / patient / year in the UK, requires subcutaneous injection every two to four weeks, and has a dosing regime that is unsuitable for heavier individuals. Clearly, a more convenient therapeutic agent with an equivalent therapeutic profile would represent a massive step-forward in the fight against asthma and other IgE-based allergic manifestations. Aspercyclide A, a macrocycle isolated from the Tanzanian soil bacterium Aspergillus sp., displays moderate antagonistic activity against the human IgE - Fc epsilon RI Protein-protein interaction (PPI), and thus constitutes a promising strategy for the treatment of asthma and allergies. In order to establish structure-activity relationships (SAR), a range of analogues of aspercyclide A C19 methyl ether was prepared. Biological evaluation of these analogues is currently ongoing. Furthermore, the (+)- and (-)-enantiomers of a racemic mixture of synthetic aspercyclide A were separated and studies on these demonstrate that only the (+)-enantiomer (same configuration as natural aspercyclide A shows significant antagonist activity against the human IgE-Fc epsilon RI PPI; the unnatural (-)-enantiomer is at least 10-fold less active, which suggests a specific mode of action. Parallel to this work, an enantio and diastereoselective synthesis of (+)-aspercyclide A was developed. This offered access to optically pure (+)-aspercyclide A and analogues. A significant concern about the utility of (+)-aspercyclide A as a lead for further development towards a therapeutic agent for asthma and allergy is the presence of the ring-A aldehyde moiety. Aldehydes can potentially react with protein lysine side chains to form Schiff bases leading to unselective irreversible toxicity. To discount this mode of reactivity as being responsible for the activity of (+)-aspercyclide A, two analogues which do not contain an aldehyde group were designed and prepared via the developed enantioselective route. Biological evaluation of these is currently ongoing. In summary, an enantio and diastereoselective synthesis of (+)-aspercyclide A has been developed. Analogues have been prepared via this route, as well as a racemic route in order to enable biological studies into the mechanism of action and to establish a SAR. Furthermore, two analogues were prepared for the purpose of discounting a concern that the activity of aspercyclide A is caused by the reaction of the aldehyde moiety with protein lysine side chains to form Schiff bases, which would result in unselective irreversible toxicity. Biological studies are currently ongoing and the results will be disclosed in due course.

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