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

Bioconjug Chem. 2020 May 20;31(5):1392-1399. doi: 10.1021/acs.bioconjchem.0c00116. Epub 2020 Apr 2.

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.

MeSH terms

  • Animals
  • Cyclization
  • Drug Carriers / chemistry*
  • Drug Liberation
  • Drug Stability
  • Humans
  • Mesylates / blood
  • Mesylates / chemistry*
  • Mice
  • Prohibitins

Substances

  • Drug Carriers
  • Mesylates
  • PHB protein, human
  • Prohibitins
  • phenylmethanesulfonic acid