Synthesis and biological evaluation of trehalose-based Bi-aryl derivatives as C-type lectin ligands

Omer K. Rasheed, Cassandra Buhl, Jay T. Evans, David Holley, Kendal T. Ryter

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The identification of Mincle as the C-type lectin receptor on innate immune cells responsible for binding TDM and the realization that this receptor could be key to productive vaccines for mycobacterial infection has raised interest in the development of synthetic Mincle ligands as novel adjuvants. We recently reported on the synthesis and evaluation of Brartemicin analog UM-1024 that demonstrated Mincle agonist activity, exhibiting potent Th1/Th17 adjuvant activity that was greater than that of trehalose dibehenate (TDB). Our pursuit to understand Mincle/ligand relationships and improve the pharmacologic properties of the ligands has expanded and continues to reveal new and exciting structure activity relationships. Herein we report the synthesis of novel bi-aryl trehalose derivatives in good to excellent yields. These compounds were evaluated for their ability to engage the human Mincle receptor and tested for the induction of cytokines from human peripheral blood mononuclear cells. A preliminary structure-activity relationship (SAR) of these novel bi-aryl derivatives revealed that bi-aryl trehalose ligand 3D showed relatively high potency in cytokine production in comparison to trehalose glycolipid adjuvant TDB and the natural ligand TDM and induced dose-dependent, Mincle selective stimulation in hMincle HEK reporter cells. Also, through computational studies, we provide an insight into the potential mode of binding of 6,6′-Biaryl trehalose compounds on human Mincle receptor.

Original languageEnglish
Article number133241
JournalTetrahedron
Volume132
DOIs
StatePublished - Feb 13 2023

Keywords

  • AJFPGZLPGGQLNH-YKDPPSDLSA-N
  • BJEIXGMLJLXZCU-LDTQUKOISA-N
  • Brartemicin: mincle: trehalose dimycolate: trehalose diester: C-Type lectin receptor
  • IAVQBWMHQPTHGI-YKDPPSDLSA-N
  • JLNUFTSWSLLWGJ-YKDPPSDLSA-N
  • LDRCSRJPTLLCEP-YKDPPSDLSA-N
  • LRQBJWSCDUTPAR-YKDPPSDLSA-N
  • MLWTUZXYRSPXCF-NBQCYIPYSA-N
  • POWAUXPGPOLVRV-ZGRFTMQBSA-N
  • RIFGJEOFHKIMAJ-YKDPPSDLSA-N
  • UACMUNZUTUPGPX-YKDPPSDLSA-N
  • XKILQAUOCPSSEE-YKDPPSDLSA-N
  • YAFROPMOCLCHLJ-YKDPPSDLSA-N
  • YIRDZNHDPUPWTN-LDTQUKOISA-N
  • YYJWAXZYSUGSTL-YKDPPSDLSA-N
  • ZSKNJADRPDJMHT-LDTQUKOISA-N
  • ZVHQICSIPIZVHB-LDTQUKOISA-N

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