ABSTRACT
The synthesis and in vivo anti-inflammatory activity of a series of pseudopterosin analogues are presented. Synthetic tricyclic catechol aglycons with different substitution patterns were monofucosylated or -xylosylated. Anti-inflammatory activity was conserved over a wide range of structural modifications. The most active synthetic compound 33 reduced phorbol myristate acetate (PMA)-induced inflammation in the mouse ear by 72% at 50 µg/ear. This corresponds to 80% of the activity of natural pseudopterosin A.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Diterpenes/chemistry , Galactosides/chemical synthesis , Glycosides/chemistry , Phenalenes/chemical synthesis , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Catechols/chemistry , Diterpenes/chemical synthesis , Diterpenes/therapeutic use , Galactosides/chemistry , Galactosides/therapeutic use , Glycosides/chemical synthesis , Glycosides/therapeutic use , Inflammation/chemically induced , Inflammation/drug therapy , Mice , Phenalenes/chemistry , Phenalenes/therapeutic use , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/toxicityABSTRACT
The free living ciliate Tetrahymena thermophila was chosen as a cellular model in order to investigate the mode of action of the anti-inflammatory marine natural product Pseudopterosin A (PsA). In this paper we present evidence that PsA inhibits phagosome formation (KD=10.5 microM) and triggers a discrete intracellular calcium release (depletion) from a site in T. thermophila cells (KD=6.4 microM). Pre-treatment with the Gi/o protein inhibitor, pertussis toxin (PTX), inhibits PsA activity of both responses providing pharmacological evidence that the site of action for PsA is at a PTX sensitive G protein or a G protein coupled receptor (GPCR). Addition of extracellular calcium induced a concentration dependent increase in the incidence of phagosome formation (KD=30.3 microM) and was blocked by PsA pre-treatment. This particular effect of PsA on extracellular calcium was not blocked by PTX pre-treatment.
