δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors

Abstract

δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydro-thiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 value for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.

Atmospheric Oxygen Mediated Radical Hydrothiolation of Alkenes

“…Recognizing that by incorporation of a thioester, we are introducing a thiol in protected form, we were able to transform A13 to 5‐mercaptopentanoic acid ( F1 ) by subjecting the product of the hydrothiolation reaction to an acidic workup and affording the free thiol in 92 % yield (Scheme 4 A). This thiol can then easily be converted to a δ‐thiolactone by Steglich thiolactonization, delivering a class of compound important in numerous fields [17, 18, 69–75] . In addition to this, we also attempted the hydrothiolation of an alkyne (thiol‐yne reaction) [76, 77] .…”

5‐exo versus 6‐endo Thiyl‐Radical Cyclizations in Organic Synthesis

“…Thiolactones are endocyclic sulfur‐containing analogues of lactones and represent a fascinating class of heterocyclic compounds. Less abundant than lactones, this family of compounds has been identified as having potential impact in numerous fields, including chemical biology, medicinal chemistry, drug discovery, and materials science . Interest in these compounds stems from the unique reactivity bestowed upon them by the incorporation of the sulfur atom, allowing them to undergo chemical, and biochemical reactions not available to lactones.…”

“…Less abundant than lactones, this family of compounds has been identified as having potential impact in numerous fields, including chemical biology, medicinal chemistry, drug discovery, and materials science. [64][65][66][67][68][69] Interest in these compounds stems from the unique reactivity bestowed upon them by the incorporation of the sulfur atom, allowing them to undergo chemical, and biochemical reactions not available to lactones. Thiolactones have proven highly valuable in synthesis and biology.…”

Radical-Mediated Reactions of α-Bromo Aluminium Thioacetals, α-Bromothioesters, and Xanthates for Thiolactone Synthesis

“…We set out to investigate if the α-bromo aluminium acetal methodology developed for lactone synthesis could be applied to allylic α-bromo aluminium thioacetals, in an attempt to synthesise thiolactols suitable for conversion into thiolactones. Thiolactones have emerged as fascinating targets for organic synthesis with intense interest from numerous fields of chemical research, particularly polymer science and medicinal chemistry [ 13 , 14 , 15 ]. Their synthesis through radical-mediated C–C bond forming reactions has not previously been reported.…”