Phosphatidyl myo‐Inositol Mannosides Mimics Built on an Acyclic or Heterocyclic Core: Synthesis and Anti‐inflammatory Properties

Abstract

Phosphatidyl myo-inositol mannosides (PIMs) are constituents of the mycobacterial cell wall and possess immunomodulatory activities. Certain PIM derivatives have immunoprotective activity and are of interest as anti-inflammatory agents. In order to identify simplified analogues of PIMs that retain this interesting activity, we have prepared a series of new analogues based either on an acyclic or on a heterocyclic scaffold that replaces the inositol moiety, and evaluated these compounds for their inhibition of LPS-induced release of NO and pro-inflammatory cytokines by macrophages. It was found that the inositol moiety can be favourably replaced by an aza-cyclitol (trihydroxy-piperidine) or an oxa-cyclitol (trihydroxy-tetrahydropyran) unit, and that the configuration of the OH-carrying carbons does not play a significant role. The biological activity is reduced if the nitrogen atom is free in the aza-cyclitol unit.

Synthesis of Cardiotonic Steroids Oleandrigenin and Rhodexin B

“…Previously, our group encountered a related problem in the context of accomplishing a selective deprotection of the C19-position of cannogenol-α- l -rhamnoside, and the challenges associated with the selective deprotection of the C19-position in the presence of butenolide were solved by employing 2-methoxyacetate (MAc)-protecting group that is significantly more labile than benzoate under both acidic and basic conditions . Based on these considerations, the reaction of 7 and MAc-protected l -rhamnose trichloroacetimidate 25 was accomplished to provide α- l -rhamnoside 26 in an 87% yield as the only observable isomer. As before, minor amounts of the β14-hydroxide elimination accompanied the formation of 26 .…”

Biological activities of 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatives

“…59 and 60 are simplified analogues of the naturally occurring phosphatidyl myo ‐inositol mannosides (PIMs), that are constituents of the mycobacterial cell wall. PIMs display immunomodulatory activities and, in particular, are pro‐inflammatory (Table ) [37] . Front and Martin screened O ‐ and N ‐heterocyclic derivatives 59 and 60 in an anti‐inflammatory context: by inhibition of release of nitric oxide, and of pro‐inflammatory cytokines tumour necrosis factor (TNF) and interleukin‐12 subunit p40 (IL‐12p40) induced by lipopolysaccharide (LPS) in macrophages [37] .…”

“…PIMs display immunomodulatory activities and, in particular, are pro‐inflammatory (Table ) [37] . Front and Martin screened O ‐ and N ‐heterocyclic derivatives 59 and 60 in an anti‐inflammatory context: by inhibition of release of nitric oxide, and of pro‐inflammatory cytokines tumour necrosis factor (TNF) and interleukin‐12 subunit p40 (IL‐12p40) induced by lipopolysaccharide (LPS) in macrophages [37] . Both 59 and 60 retained anti‐inflammatory activity, although 60 was less active in inhibiting NO and TNF release.…”

Synthetic Routes to 3,4,5‐Trihydroxypiperidines via Stereoselective and Biocatalysed Protocols, and Strategies to N‐ and O‐Derivatisation

“…In terms of O ‐alkylation, fewer investigations are present in literature. Front and Martin alkylated hydroxyls OH‐3 and OH‐5 by in 76 by N ‐trifluoroacetylation, whereas others opted for bio ‐catalysis to affect OH‐4 ( meso ‐2 and 83 ) and OH‐3 ( meso ‐1 ) alkylations (Scheme ).…”

“…The synthesis of 80 and 81 , structural analogues of the naturally occurring phosphatidyl myo ‐inositol mannosides (PIMs) in which the core inositol structure was replaced by other cyclical scaffolds, including meso ‐1 , started from the symmetrical 3‐ O ‐benzyl‐iminoxylitol derivative 75 , which was obtained from diacetone‐ d ‐glucose according to the double reductive amination strategy. N ‐Debenzylation with Pearlman's catalyst followed by N ‐trifluoroacetylation with trifluoroacetic anhydride (TFAA) gave intermediate diol 76 .…”