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[摘要]：Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, Delta 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 Delta F508-CFTR targeting) and potentiator ("Po", normalizing Delta 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 double right arrow force-field lowest energy assessment double right arrow 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 pi-stacking conformations to elicit corrector and potentiator activities. |
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