Abstract
The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5840-5844 |
| Number of pages | 5 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 24 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2014 |
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Keywords
- C,C-linked bisazoles
- Correctors
- Cystic fibrosis
- Transmembrane regulator
ASJC Scopus subject areas
- Biochemistry
- Clinical Biochemistry
- Molecular Biology
- Molecular Medicine
- Organic Chemistry
- Drug Discovery
- Pharmaceutical Science
Cite this
Δf508-CFTR correctors : Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles. / Ye, Long; Hu, Bao; El-Badri, Faris; Hudson, Brandi M.; Phuan, Puay Wah; Verkman, A. S.; Tantillo, Dean J.; Kurth, Mark J.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 24, 15.12.2014, p. 5840-5844.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Δf508-CFTR correctors
T2 - Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles
AU - Ye, Long
AU - Hu, Bao
AU - El-Badri, Faris
AU - Hudson, Brandi M.
AU - Phuan, Puay Wah
AU - Verkman, A. S.
AU - Tantillo, Dean J.
AU - Kurth, Mark J.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.
AB - The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.
KW - C,C-linked bisazoles
KW - Correctors
KW - Cystic fibrosis
KW - Transmembrane regulator
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UR - http://www.scopus.com/inward/citedby.url?scp=84912000365&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2014.09.067
DO - 10.1016/j.bmcl.2014.09.067
M3 - Article
C2 - 25452003
AN - SCOPUS:84912000365
VL - 24
SP - 5840
EP - 5844
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 24
ER -