Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in ?F508 cystic fibrosis transmembrane conductance regulator protein.

ABSTRACT: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ?F508-CFTR, produces CFTR loss-of-function by impairing its cellular targeting to the plasma membrane and its chloride channel gating. We recently identified cyanoquinolines with both corrector ("Co", normalizing ?F508-CFTR targeting) and potentiator ("Po", normalizing ?F508-CFTR channel gating) activities. Here, we synthesized and characterized 24 targeted cyanoquinoline analogues to elucidate the conformational requirements for corrector and potentiator activities. Compounds with potentiator-only, corrector-only, and dual potentiator-corrector activities were found. Molecular modeling studies (conformational search ? force-field lowest energy assessment ? geometry optimization) suggest that (1) a flexible tether and (2) a relatively short bridge between the cyanoquinoline and arylamide moieties are important cyanoquinoline-based CoPo features. Further, these CoPo's may adopt two distinct ?-stacking conformations to elicit corrector and potentiator activities.

SUBMITTER: Knapp JM 

PROVIDER: S-EPMC3277286 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature