Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: Towards a pharmacophore model for the nucleotide-binding domain

Mark F. Springsteel, Luis J V Galietta, Tonghui Ma, Kolbot By, Gideon O. Berger, Hong Yang, Christopher W. Dicus, Wonken Choung, Chao Quan, Anang A. Shelat, R. Kiplin Guy, A. S. Verkman, Mark J. Kurth, Michael H. Nantz

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Our previous screen of flavones and related heterocycles for the ability to activate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel indicated that UCCF-029, a 7,8-benzoflavone, was a potent activator. In the present study, we describe the synthesis and evaluation, using cell-based assays, of a series of benzoflavone analogues to examine structure-activity relationships and to identify compounds having greater potency for activation of both wild type CFTR and a mutant CFTR (G551D-CFTR) that causes cystic fibrosis in some human subjects. Using UCCF-029 as a structural guide, a panel of 77 flavonoid analogues was prepared. Analysis of the panel in FRT cells indicated that benzannulation of the flavone A-ring at the 7,8-position greatly improved compound activity and potency for several flavonoids. Incorporation of a B-ring pyridyl nitrogen either at the 3- or 4-position also elevated CFTR activity, but the influence of this structural modification was not as uniform as the influence of benzannulation. The most potent new analogue, UCCF-339, activated wild-type CFTR with a Kd of 1.7 μM, which is more active than the previous most potent flavonoid activator of CFTR, apigenin. Several compounds in the benzoflavone panel also activated G551D-CFTR, but none were as active as apigenin. Pharmacophore modeling suggests a common binding mode for the flavones and other known CFTR activators at one of the nucleotide-binding sites, allowing for the rational development of more potent flavone analogues.

Original languageEnglish (US)
Pages (from-to)4113-4120
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number18
DOIs
StatePublished - Sep 1 2003

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Benzoflavones
Cystic Fibrosis Transmembrane Conductance Regulator
Nucleotides
flavone
Flavonoids
Flavones
Apigenin
Chloride Channels
Structure-Activity Relationship
Cystic Fibrosis
Assays
Nitrogen
Chemical activation
Binding Sites

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator : Towards a pharmacophore model for the nucleotide-binding domain. / Springsteel, Mark F.; Galietta, Luis J V; Ma, Tonghui; By, Kolbot; Berger, Gideon O.; Yang, Hong; Dicus, Christopher W.; Choung, Wonken; Quan, Chao; Shelat, Anang A.; Guy, R. Kiplin; Verkman, A. S.; Kurth, Mark J.; Nantz, Michael H.

In: Bioorganic and Medicinal Chemistry, Vol. 11, No. 18, 01.09.2003, p. 4113-4120.

Research output: Contribution to journalArticle

Springsteel, MF, Galietta, LJV, Ma, T, By, K, Berger, GO, Yang, H, Dicus, CW, Choung, W, Quan, C, Shelat, AA, Guy, RK, Verkman, AS, Kurth, MJ & Nantz, MH 2003, 'Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: Towards a pharmacophore model for the nucleotide-binding domain', Bioorganic and Medicinal Chemistry, vol. 11, no. 18, pp. 4113-4120. https://doi.org/10.1016/S0968-0896(03)00435-8
Springsteel, Mark F. ; Galietta, Luis J V ; Ma, Tonghui ; By, Kolbot ; Berger, Gideon O. ; Yang, Hong ; Dicus, Christopher W. ; Choung, Wonken ; Quan, Chao ; Shelat, Anang A. ; Guy, R. Kiplin ; Verkman, A. S. ; Kurth, Mark J. ; Nantz, Michael H. / Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator : Towards a pharmacophore model for the nucleotide-binding domain. In: Bioorganic and Medicinal Chemistry. 2003 ; Vol. 11, No. 18. pp. 4113-4120.
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AU - By, Kolbot

AU - Berger, Gideon O.

AU - Yang, Hong

AU - Dicus, Christopher W.

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AU - Quan, Chao

AU - Shelat, Anang A.

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AU - Verkman, A. S.

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