Abstract
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-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 ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-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 π-stacking conformations to elicit corrector and potentiator activities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1242-1251 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 55 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 9 2012 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in Δf508 cystic fibrosis transmembrane conductance regulator protein. / Knapp, John M.; Wood, Alex B.; Phuan, Puay Wah; Lodewyk, Michael W.; Tantillo, Dean J.; Verkman, A. S.; Kurth, Mark J.
In: Journal of Medicinal Chemistry, Vol. 55, No. 3, 09.02.2012, p. 1242-1251.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structure-activity relationships of cyanoquinolines with corrector-potentiator activity in Δf508 cystic fibrosis transmembrane conductance regulator protein
AU - Knapp, John M.
AU - Wood, Alex B.
AU - Phuan, Puay Wah
AU - Lodewyk, Michael W.
AU - Tantillo, Dean J.
AU - Verkman, A. S.
AU - Kurth, Mark J.
PY - 2012/2/9
Y1 - 2012/2/9
N2 - Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-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 ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-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 π-stacking conformations to elicit corrector and potentiator activities.
AB - Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The most common CF-causing mutation, ΔF508-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 ΔF508-CFTR targeting) and potentiator ("Po", normalizing ΔF508-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 π-stacking conformations to elicit corrector and potentiator activities.
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UR - http://www.scopus.com/inward/citedby.url?scp=84856850146&partnerID=8YFLogxK
U2 - 10.1021/jm201372q
DO - 10.1021/jm201372q
M3 - Article
C2 - 22214395
AN - SCOPUS:84856850146
VL - 55
SP - 1242
EP - 1251
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -