Mannose derivatives of ferrocene-containing desmuramyl peptides: Synthesis, characterization and in vitro...

Muramyl dipeptide is a bona fide nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) agonist with well-established adjuvant properties. Replacement of its N-acetylmuramyl moiety and installation of lipophilic aromatic fragments have been utilized to afford desmuramyl peptides with improved pharmacological properties. Herein, we have constructed mannosylated desmuramyl peptides conjugated with ferrocene via amide or ester bonds incorporating linkers of different lengths. Their immunomodulatory effects were assessed in THP-1-derived macrophages, wherein the best performing derivatives, the ester 9a and amide 10a, significantly increased the levels of pro-inflammatory cytokine TNF-α. These findings show that 9a and 10a exert modest pro-inflammatory effects on TNF-α secretion in vitro, while overall exhibiting limited immunological activity.