Acyl Glucuronides:  Biological Activity, Chemical Reactivity, and Chemical Synthesis

Abstract

which after mutarotation at C(1) may transfer the acyl group back to the 1R-OH. This has been conclusively demonstrated by NMR spectroscopy. 14,30 Other rearranged forms of AGs are also known. When the Mitsunobu synthesis 32 (see Synthesis) is used, lactones of type 5 are byproducts, sometimes in appreciable yields. The mechanism of formation is not clear but presumably involves cyclization of the first-formed intermediate ester. If there were an in vivo route to such lactones via free carboxyl acyl glucuronides, they would doubtless be potent acylating agents, transferring in this case the sugar along with the acyl residue.Concerning 1β-AGs of benzoic acids, the chemical stability/ reactivity may be predicted with some confidence by a Hammett correlation, 33 as discussed in detail later (NMR section). Some preliminary studies have been carried out on the computational chemistry modeling of the relative stabilities of the isomers of the AGs of 2-, 3-, and 4-trifluoromethylbenzoic acids. 34 For nonarylcarboxylic acids, the structure-reactivity is more complex. Certainly branching at the R-carbon is a factor leading to increased stability; thus the AGs of gemfibrozil 6, 35 clofibric acid 7 36 and valproic acid 8, 37 all doubly R-substituted, display long half-lives (from about 6-70 h in pH 7.4 buffer 37 ).AGs derived from NSAIDs such as naproxen 9 and ibuprofen 10 generally have half-lives from 1 to 4 h under the same conditions. 38 In such compounds, an additional complication is the different rates of rearrangement of the (R)-and (S)-AG diastereoisomers. In the case of 2-phenylpropanoic acid itself 11, 38 this rate was found to be about twice as fast for the (2R)as for the (2S)-AG epimer, and this ratio is typical of the 2-aryl propanoate class. Scheme 2. Possible Fates of AGs Scheme 3. Reactivity of Acyl Glucuronides a a Clearly the rearrangement (pathway 2) requires migration of the acyl group at least as far as O(3).

In silico prediction of acyl glucuronide reactivity

“…Demonstrating the validity of this simplification for the purpose of ranking the reactivity of potential drug candidates removes the need for complex synthesis of the AG. The measured half lives for degradation of the AGs are in good agreement with previously reported values [22], once the half-life measured at 298 K is converted using the Arrhenius equation to a half-life predicted at 310 K (37°C). This conversion is based on an activation energy of 100,000 Jmol -1 , as reported [23] for the dominating acyl migration (noted previously).…”

Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

“…The corresponding aldehyde group can then condense with amino groups on the lysines or nucleic acids to form imines that undergo a rearrangement (amadori rearrangement) to yield the final adduct, a more stable 1-amino-1-deoxyketose structure, which retains both the sugar and the aglycone. Both these mechanisms have been discussed in several reviews over the years [31,32,[35][36][37][38][39][40][41][42][43]. Although no definitive relationship has been established, it is now accepted that covalent binding to amino acid residues of macromolecules and bases of nucleic acids often can result in hypersensitivity reactions, organ toxicities (hepatic or renal toxicities), mutagenesis, or carcinogenesis.…”

Assessment of reactive metabolites in drug-induced liver injury

“…Although metabolic activations are usually mediated by CYPs in the liver, phase II conjugation pathways, including glucuronidation, are also known to transform latent functional groups such as carboxylic acids into reactive intermediates (Spahn-Langguth and Benet, 1992;Stachulski et al, 2006). The formation of acyl glucuronides (AGs) has been implicated in hepatic injury via covalent binding to proteins, resulting in the withdrawal of drugs from the market.…”