Health associated matters like asthma are exceedingly widespread in the UK, influencing over 5 million people. These disorders are mostly imposed by the release of substances from immune cells when immunoglobin E binds to its receptor FcɛRI. In alignment to avert the issue of these mediators, an antibody, which acts to impede the protein-protein interaction (PPI) between IgE and FcɛRI, would verify successful.
An antibody, commonly known as anti-IgE, approved by the European Commission in 2005, has verified to take on this function and thus is helpful in the therapy of numerous allergies. Despite the acceptance, costly manufacture and repetitive injection have emphasised some handicaps of the antibody, proposing a similar antagonist would be more effective.
Aspercyclide A-C, isolated by Singh following ELISA-guided fractionation of Aspergillus, have similar structural properties, as shown in figure 1. Aspercyclide A, with R group CHO, has shown to be the most productive molecule to diminish agonist-mediated responses, with an IC50 of 200µM. Irrespective of their structural similarities, deviating approaches were needed to successfully synthesise aspercyclides A-C. Aspercyclide C, described by furstner and Muller in 2005, utilised ring closing metathesis (RCM) to form the cyclic macromolecule, accomplishing an E:Z ratio of 5:1. However, synthesis of the more sterically hindered aspercyclide A and B, R groups CHO and CH2OH respectively, required a Nozaki-Hiyama-Kishi (NHK) reaction to effect formation of the cyclic macromolecule.
This report explores the formulation of aspercyclide A (1) and makes relative links to its C19 methyl ether (15a), focusing on how both molecules can proceed to inhibit the IgE- FcɛRI PPI.
Considerably distinct to the synthesis described by Furstner, two synthetic sequences were examined utilising both methyl and PMB as R groups, applying in this case, a Heck-Mizoroki reaction to aid ring closing. Both reactions were initiated with a Boeckman modified Takai-Utimoto acrolein acetal-hexanal condensation, producing antidiols 5a and 5b shown in figure 2 with 56% and 64% yields respectively.
Reaction steps b and c made use of two different reagents in order to achieve products 7a and 7b. The synthesis of 7a used the the organolithium reagent n-BuLi to aid in the metalation of alcohol 5a 5a, and further required the supplement of benzoyl chloride 6 to achieve the final product with a 66% yield. The alternative route to afford 7b utilised NaH as a strong base, proving more effective with a yield of 85%. This was pursued by the acetonide protected bromobenzoquinol 8 leading to displacement of the bromine atom to accomplish the biaryl ethers 9a and 9b with yields 70% and 54% respectively.
An interesting observation was discovered, after analysis of a variety of reaction conditions, highlighting that 9a formed dibenzofuran 13a rather than the required macrocycle 12a. Ligand 11 shown in figure 2 was discovered to be appropriate in conversion of 13a to 12a with incorporation of AgI to supress the direct arylation. Under these new conditions, the ratio of 13a:12a was changed from 4:1 to 1:5.
Exchange of the halogen in macrocycle 9a from bromine to iodine produced 10a, which after the Heck-Mizoroki ring concluding reaction proved more successful in isolation of macrocycle 12a, with an improved 13a : 12a ratio of 1:10, with 12a giving a yield of 52%. Diols 14a and 15a were then synthetically produced easily via “acid catalysed acetal deprotection” of 12a and 12b.
The reagent MnO2 is selective for the oxidation of benzylic alcohols to the required aldehyde and therefore was appropriate in the oxidation of 14b to the desired product. This was pursued by removal of the PMB group to obtain aspercyclide A with a 72% yield. Alternatively, oxidation of alcohol 14a, again using MnO2, produced the product 15a where R=Me.
ELISA studies confirmed that both aspercyclide A and its C19 methyl ether 15a displayed similar activity when acting to inhibit IgE- FcɛRI protein-protein interactions PPI, (portraying an IC) with an IC50 of .......
This new synthetic finding has not only assisted in the prevention of health concerning matters like asthma, but has furthermore become a point of interest for future study concerning relationships between the structure and activity of a molecule.