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J. Biol. Chem., Vol. 276, Issue 23, 19723-19728, June 8, 2001
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From the The flavonoid genistein and the
benzo[c]quinolizinium MPB-07 have been shown to
activate the cystic fibrosis transmembrane conductance regulator
(CFTR), the protein that is defective in cystic fibrosis. Lead-based
combinatorial and parallel synthesis yielded 223 flavonoid,
quinolizinium, and related heterocyclic compounds. The compounds were
screened for their ability to activate CFTR at 50 µM
concentration by measurement of the kinetics of iodide influx in Fisher
rat thyroid cells expressing wild-type or G551D CFTR together with the
green fluorescent protein-based halide indicator YFP-H148Q. Duplicate
screenings revealed that 204 compounds did not significantly affect
CFTR function. Compounds of the 7,8-benzoflavone class, which are
structurally intermediate between flavones and
benzo[c]quinoliziniums, were effective CFTR activators
with the most potent being
2-(4-pyridinium)benzo[h]4H-chromen-4-one bisulfate
(UCCF-029). Compounds of the novel structural class of
fused pyrazolo heterocycles were also strong CFTR activators with the
most potent being
3-(3-butynyl)-5-methoxy-1-phenylpyrazole-4-carbaldehyde (UCCF-180). A CFTR inhibitor was also identified. The
active compounds did not induce iodide influx in null cells deficient
in CFTR. Short-circuit current measurements showed that the CFTR
activators identified by screening induced strong anion currents in the
transfected cell monolayers grown on porous supports. Compared with
genistein, the most active compounds had up to 10 times greater potency
in activating wild-type and/or G551D-CFTR. The activators had low cellular toxicity and did not elevate cellular cAMP
concentration or inhibit phosphatase activity, suggesting that
CFTR activation may involve a direct interaction. These results
establish an efficient screening procedure to identify CFTR activators
and inhibitors and have identified 7,8-benzoflavones and pyrazolo
derivatives as novel classes of CFTR activators.
Novel CFTR Chloride Channel Activators Identified by Screening of
Combinatorial Libraries Based on Flavone and Benzoquinolizinium Lead
Compounds*,
§,
Departments of Medicine and Physiology,
Cardiovascular Research Institute, University of California, San
Francisco, California, 94143-0521 and the ¶ Department of
Chemistry, University of California, Davis, California
95616-5295
*
This work was supported by a program grant from the Cystic
Fibrosis Foundation for CF drug discovery and National Institutes of
Health Grants DK43840, HL60288, HL59198, and DK35124.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains an appendix.
§
Present address: Instituto Gaslini, Genoa, Italy.
Cardiovascular Research Institute, 1246 Health Sciences E. Tower, University of California, San Francisco, CA 94143-0521. Tel.:
415-476-8530; Fax: 415-665-3847; E-mail: verkman@itsa.ucsf.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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