A Computational Investigation of the Uncatalysed and Water-Catalysed Acyl Rearrangements in Ingenol Esters

Asja A. Kroeger, Amir Karton

Research output: Contribution to journalArticle

3 Citations (Scopus)
130 Downloads (Pure)

Abstract

Ingenol esters have been identified as potent anticancer and HIV latency reversing agents. Ingenol-3-angelate was recently approved as a topical treatment for precancerous actinic keratosis skin lesions. It was found, however, that ingenol esters can undergo a series of acyl rearrangements, which may affect their biological potency and the shelf-life of drug formulations. We use double-hybrid density functional theory to explore the mechanisms for the uncatalysed and water-catalysed acyl migrations in a model ingenol ester. The uncatalysed reaction may proceed either via a concerted mechanism or via a stepwise mechanism that involves a chiral orthoester intermediate. We find that the stepwise pathway is kinetically preferred by a significant amount of ΔΔH 298 ≤ 44.5 kJ mol-1. The uncatalysed 3-O-acyl to 5-O-acyl and 5-O-acyl to 20-O-acyl stepwise rearrangements involve cyclisation and ring-opening steps, both concomitant with a proton transfer. We find that the ring-opening step is the rate-determining step for both rearrangements, with reaction barrier heights of ΔH 298 ≤ 251.6 and 177.1 kJ mol-1 respectively. The proton transfers in the cyclisation and ring-opening steps may be catalysed by a water molecule. The water catalyst reduces the reaction barrier heights of these steps by over 90 kJ mol-1.

Original languageEnglish
Pages (from-to)212-221
Number of pages10
JournalAustralian Journal of Chemistry
Volume71
Issue number4
DOIs
Publication statusPublished - 1 Jan 2018

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