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

• Published in: Journal of medicinal chemistry Vol. 41; no. 17; pp. 3232 - 3238
• Main Authors: De Rosa, Margherita, Giordano, Silvana, Scettri, Arrigo, Sodano, Guido, Soriente, Annunziata, Pastor, Pablo García, Alcaraz, Maria J, Payá, Miguel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.08.1998; Amer Chemical Soc
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemical synthesis; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Bee Venoms; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan; Cell Line; Chemistry, Medicinal; Cytosol - enzymology; Drug Design; Edema - chemically induced; Edema - drug therapy; Elapid Venoms; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Female; Humans; Kinetics; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Structure; Pancreas - enzymology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Phospholipases A2; Pyrans - pharmacology; Science & Technology; Structure-Activity Relationship; Swine; Synovial Membrane - enzymology; Terpenes - chemical synthesis; Terpenes - chemistry; Terpenes - pharmacology; INACTIVATION; ETHERS; INHIBITION; LUFFARIELLOLIDE; BEE VENOM PHOSPHOLIPASE-A2; MODEL; SESTERTERPENE; CELL-LINE; Furan derivatives; Esterases; Structure activity relation; Chemical synthesis; Edema; Enzyme; Aliphatic compound; Rodentia; Antiinflammatory agent; Pyran derivatives; Oral administration; Enzyme inhibitor; Lactone; Hemiacetal; In vitro; Phospholipase A; Carboxylic ester hydrolases; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Polyenic compound; Animal; Hydrolases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980027h

We have synthesized analogues of two naturally occurring antiinflammatory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. The two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was considered essential to irreversibly inactivate phospholipase A2 (PLA2). The two series of compounds were tested for their inhibitory effects on secretory PLA2 belonging to the groups I, II, and III, and the activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In addition, the PLA2 inhibitory activity increases with the 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 mouse carrageenan paw edema at the oral dose of 10 mg/kg and showed an activity similar to the reference antiinflammatory drug, indomethacin.