SYNTHESIS AND COMPARISON OF THE ANTIINFLAMMATORY ACTIVITY OF MANOALIDE AND CACOSPONGIONOLIDE-B ANALOGS

We have synthesized analogues of two naturally occurring antiinflammat ory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. Th e two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was c onsidered essential to irreversibly inactivate phospholipase A(2) (PLA (2)). The two series of compounds were tested for their inhibitory eff ects on secretory PLA(2) belonging to the groups I, II, and III, and t he activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In add ition, the PLA(2) inhibitory activity increases with the increasing hy drophobic character of the side chain linked to the pyranofuranone moi ety. The most active compounds, FCA and FMA, carry a farnesyl residue linked to the pyranofuranone substructure. The most potent PLA(2) inhi bitor, FMA, was tested in the mouse carrageenan paw edema at the oral dose of 10 mg/kg and showed an activity similar to the reference antii nflammatory drug, indomethacin.