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 journalArticlepeer-review

59 Scopus citations


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

Bibliographical note

Funding Information:
This work was supported by a drug discovery grant from the Cystic Fibrosis Foundation. We thank Mr. Sung Hee Hwang for assistance with compound preparations. A.A.S. is supported by the National Defense Science and Engineering Graduate Fellowship.

ASJC Scopus subject areas

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


Dive into the research topics of 'Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: Towards a pharmacophore model for the nucleotide-binding domain'. Together they form a unique fingerprint.

Cite this