New inhibitors of the complement system inspired in K76-COOH. A SAR study of filifolinol derivatives through modifications of the C3' position.
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.
Instituto de Química Rosario (IQUIR, CONICET-UNR), Suipacha 531, S2002LRK Rosario, Argentina. larghi@iquir-conicet.gov.ar
Enrique L
EL
Larghi
María A
MA
Operto
Rene
R
Torres
Teodoro S
TS
Kaufman
D051056:Complement Inactivating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003165:Complement System Proteins / Q000737:chemistry* / Q000378:metabolism; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D051056:Complement Inactivating Agents; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid; D003165:Complement System Proteins