New inhibitors of the complement system inspired in K76-COOH. A SAR study of filifolinol derivatives through modifications of the C3' position

LARGHI ENRIQUE L; OPERTO, MARIA A.; TORRES, MIGUEL R.; KAUFMAN, TEODORO S.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Elsevier

Año: 2009 vol. 19 p. 6172 - 6175

0960-894X

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 classical complement pathway inhibitory activity was determined aiming to probe the importance of structural characteristics of the alicyclic part of K76-COOH. The results suggest that the diol moiety of the natural product may not be relevant for its activity, but useful for improving compound solubility. The presence and stereochemistry of O- and N-  functionalities on C3’ may be relevant for biological activity of the filifolinol derivatives. The IC50 values of the most potent compounds were comparable or surpassed the activity of K76-COOH.