ABSTRACT
A series of carboxylic acids carrying various functionalization on C-7 of their common 3H-spiro[benzofuran-2,1'-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural Complement inhibitor K-76 COOH. In order to probe the relevance of the C-7 functionalization on their bioactivity, the ability of the analogs to inhibit Complement activation through the classical pathway was determined. The observed results suggest that functionalization of C-7 can modulate the inhibitory activity of the tested compounds. The 7-trifluoromethyl derivative was the compound with the lowest IC(50) value among the tested analogs (IC(50) = 100 µM), being more potent than K-76 COOH (IC(50) = 570 µM).
Subject(s)
Benzofurans/chemical synthesis , Benzofurans/pharmacology , Complement System Proteins/metabolism , Sesquiterpenes/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Benzofurans/chemistry , Chemistry Techniques, Synthetic , Humans , Spiro Compounds/chemistryABSTRACT
A new series of tricyclic carboxylic acids with a 3H-spiro[benzofuran-2,10-cyclohexane] skeleton were synthesized from filifolinol, as analogs of the natural complement inhibitor K76-COOH. Their complement inhibitory activity was determined aiming to probe the importance of structural characteristics of the alicyclic part of K76-COOH. The presence and stereochemistry of O- and N-functionalities on C3' of the filifolinol derivatives are relevant for biological activity. The IC50 values of the most potent compounds were comparable or surpassed the activity of K76-COOH. The results also suggest that the diol moiety of the natural product may be useful for improving compound solubility.
Subject(s)
Complement Inactivating Agents/chemistry , Complement System Proteins/chemistry , Sesquiterpenes/chemistry , Complement Inactivating Agents/chemical synthesis , Complement Inactivating Agents/pharmacology , Complement System Proteins/metabolism , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Structure-Activity RelationshipABSTRACT
Six 3H-spiro[benzofuran-2,1'-cyclohexane] derivatives were synthesized from naturally occurring filifolinol, and their classical complement pathway inhibitory activity was determined. IC(50) values of the most potent compounds were comparable to the activity of the natural complement inhibitor K76-COOH and some synthetic tricyclic analogs of it.
