Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group

Abstract

Recently we have reported that the ortho-hydroxy-protected aryl sulfate (OHPAS) system can be exploited as a new self-immolative group (SIG) for phenolic payloads. We extended the system to nonphenolic payloads by simply introducing a para-hydroxy benzyl (PHB) spacer. As an additional variation of the system, we explored a benzylsulfonate version of the OHPAS system and found that it has two distinct breakdown pathways, cyclization and 1,4-elimination, the latter of which implies that para-hydroxy-protected (PHP) benzylsulfonate (BS) can also be used as an alternative SIG. The PHP-BS system was found to be stable chemically and in mouse and human plasma, having payload release rates comparable to those of the original OHPAS conjugates.

Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay

“…Recently, the Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linker was developed as a new linker platform by IntoCell Inc. (Daejeon, Korea) and structurally designed with di-aryl sulfate, in which one aryl acting as a phenolic payload and the other acting as a self-immolative group (SIG) consisting a triggering phenol function at the ortho or para position. In the model study with tyrosine substrate of the previous reference, the OHPAS linker was stable in various species plasma and was able to release the payloads when triggered by beta-galactosidase, which is highly expressed in tumor cells [20][21][22].…”

Facile synthesis of sulfinate esters from aryl iodides via direct oxidation of thioesters

“…7,8 However, the direct oxidation of thioesters is challenging due to their reduced oxidizability and possible overoxidation to organosulfur( vi ) compounds. 8 b ,9,10 Since transformations of sulfinic acid esters allowed us to synthesize highly functionalized sulfoxides and sulfides in our recent studies (Fig. 1B), 11–13 we started to develop an efficient method to prepare sulfinic acid esters through the direct oxidation of thioesters.…”

“…4B, although oxidation mechanisms involving single-electron transfer cannot be excluded. 9 First, direct oxidation of thioester 4 with NBS would take place smoothly. Benzoylation of methanol with intermediate I to furnish methyl benzoate can lead to sulfenyl bromide II , which would undergo methanolysis to generate sulfenyl ester III .…”