Focus feature - acyl glucuronide synthesis

Preclinical metabolite profiling of the macrolide Mcl-1 inhibitor AZD5991 in human hepatocytes by AstraZeneca revealed the presence of an abundant acyl glucuronide, for which larger amounts were required for further testing.

AZD5991 was screened against a panel of microbes at Hypha which revealed extensive metabolism via phase I and phase II pathways.  As observed in pre-clinical studies, a prominent glucuronide was formed by several microbes. The glucuronide produced was demonstrated by LC-MS/MS and NMR to match that observed from human hepatocyte incubations and excreta in rat bile at AstraZeneca. A 10L microbial biotransformation reaction yielded 109 mg of the purified acyl glucuronide of AZD5991.

A poster on this work undertaken by AstraZeneca and Hypha was presented at the recent Drug Discovery Chemistry meeting in San Diego.

We are frequently asked to make all types of glucuronides, using either late-stage synthesis or biotransformation methods. For acyl glucuronides, which may potentially be chemically reactive and therefore a safety risk, we support clients in need of pure metabolites as part of the safety and DDI assessments stipulated by regulatory bodies. We have designed our methods to minimise instability resulting from the formation of acyl migration isomers.

Hydroxylated metabolites of the FDA approved anti-fungal drug Rezafungin

A paper published by Cidara Therapeutics takes a look at the metabolism of the newly FDA approved drug rezafungin, in which Hypha are acknowledged for making all the metabolites of this echinocandin using one of our fungal strains, including their purification and characterisation by NMR spectroscopy.

The quaternary ammonium side chain in rezafungin prevents the spontaneous degradation to a ring-opened peptide observed in previously approved anti-fungals in this class. Metabolism is instead diverted to the end of the terphenyl pentyl side chain to form 3 hydroxylated metabolites. O-dealkylation also occurs to a lesser extent to a des-pentyl metabolite.  

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