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

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 ∆∆H ‡ 298 = 35.3 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 ringopening step is the rate-determining step (RDS) for both rearrangements, with reaction barrier heights of ∆H ‡ 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 .

A Density Functional Theory (DFT) Study of the Acyl Migration Occurring during Lipase-Catalyzed Transesterifications

“…The participation of one water molecule led to the formation of a six-membered ring in the TSs of both steps, which are more energetically stable. Therefore, the water molecule, as both a base and a weak acid during AM, activated nucleophiles and electrophiles by hydrogen bonding, thus facilitating AM [32]. While the role of the water molecule dramatically lowered the activation energy barriers of AM, it was still so high that it was difficult for AM to occur under this simulated circumstance (298.15 K).…”

A computational foray into the mechanism and catalysis of the adduct formation reaction of guanine with crotonaldehyde

“…Water is a well-known proton-transfer catalyst [45][46][47][48][49][50][51][52][53][54] and abundant in the biological system. It can be envisaged that participation of an explicit water molecule in all steps of both pathways may facilitate the proton transfers, thereby lowering energy barriers toward the transformations.…”

Mechanistic insights into the water-catalysed ring-opening reaction of vitamin E by means of double-hybrid density functional theory

“…The participation of catalytic water molecules in reactions involving proton transfers is well documented and can significantly reduce activation barriers by reducing strain energies involved in the TSs. 40,41,42,43,44,45,46 Here, we examine the catalytic effect of one and two explicit water molecules on the rearrangement reaction of α-tocopherone to ATQ. The reaction profile for the H2O-catalysed reaction is shown in Figure 4 (red line).…”