- Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: Towards a pharmacophore model for the nucleotide-binding domain
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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.
- 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,Kurth, Mark J.,Nantz, Michael H.
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p. 4113 - 4120
(2007/10/03)
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- Reactivity of 2'-Hydroxy-3',4'-benzochalkone Dibromides
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Bromination of 2'-hydroxy-4-methoxy-3',4'-benzochalkone (Ia) with 2 mol of bromine in acetic acid gives 5'-bromo-2'-hydroxy-4-methoxy-3',4'-benzochalkone α,β-dibromide (IIa) which on treatment with hot aq. ethanolic alkali or pyridine does not give the ex
- Paranjape, M. V.,Wadokar, K. N.
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p. 808 - 809
(2007/10/02)
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