Synthesis and Comparison of the Antiinflammatory Activity of Manoalide and Cacospongionolide B Analogues

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• 作者：Margherita De Rosa ; Silvana Giordano ; Arrigo Scettri ; Guido Sodano ; Annunziata Soriente ; Pablo Garcí ; a Pastor ; Maria J. Alcaraz ; and Miguel Payá
• 刊名：Journal of Medicinal Chemistry
• 出版年：1998
• 出版时间：August 13, 1998
• 年：1998
• 卷：41
• 期：17
• 页码：3232 - 3238
• 全文大小：102K
• 年卷期：v.41,no.17(August 13, 1998)
• ISSN：1520-4804

文摘

We have synthesized analogues of two naturally occurring antiinflammatory marine compounds,manoalide and cacospongionolide B, containing a pyranofuranone moiety which is consideredthe pharmacophoric group. The two compounds, and hence their analogues, differ in thepresence or absence in the dihydropyran ring of an hemiacetal function which was consideredessential to irreversibly inactivate phospholipase A₂ (PLA₂). The two series of compounds weretested for their inhibitory effects on secretory PLA₂ belonging to the groups I, II, and III, andthe activities were found to be similar in both series, irrespective of the presence or absence ofthe additional hemiacetal function. In addition, the PLA₂ inhibitory activity increases withthe increasing hydrophobic character of the side chain linked to the pyranofuranone moiety.The most active compounds, FCA and FMA, carry a farnesyl residue linked to the pyranofuranone substructure. The most potent PLA₂ inhibitor, FMA, was tested in the mousecarrageenan paw edema at the oral dose of 10 mg/kg and showed an activity similar to thereference antiinflammatory drug, indomethacin.