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

• Published in: Bioconjugate chemistry 2020-05, Vol.31 (5), p.1392-1399
• Main Authors: Park, Suho, Kim, Sun Young, Cho, Jongun, Jung, Doohwan, Ha, Jihyeon, Seo, Donghoon, Lee, Jaeho, Lee, Sangkwang, Yun, Sanghyeon, Lee, Hyangsook, Park, Okku, Seo, Beomseok, Kim, Sena, Seol, Minah, Song, Jina, Park, Tae Kyo
• Format: Article
• Language: English
• Subjects: Animals; Aromatic compounds; Blood plasma; Breakdown; Cyclization; Drug Carriers - chemistry; Drug Liberation; Drug Stability; Humans; Mesylates - blood; Mesylates - chemistry; Mice; Payloads; Phenolic compounds; Phenols; Sulfates
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.0c00116

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.