Synthesis and Structure−Activity Relationships of Carboxyflavones as Structurally Rigid CysLT₁ (LTD₄) Receptor Antagonists

Abstract

The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT1 affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT1 affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT1 receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT1 receptor antagonists known to date, and they are useful in the development of a CysLT1 antagonist model, which is discussed in the companion paper.

2-(3-Morpholinopropyl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one monohydrate

“…For the properties and biological activity of quinoline derivatives, see: Vaitilingam et al (2004); Lee et al (2004); Zwaagstra et al (1998); Roma et al (2000); Ferrarini et al (2000). For the preparation of quinoline derivatives, see: Zhou et al (2010); Yang et al (2008).…”

Structural Manipulation of Eicosanoid Receptors and Cellular Signaling

“…4) for the leukotriene agonists/antagonists, namely, (1) a lipophilic anchor (side chain), (2) a central flat unit (triene), (3) an ionic pocket (peptide and/or carboxylic acid group), and (4) a hydrophilic site (acidic group). Since this description, other workers have further refined this conceptual model to a three-dimensional one [44,45,46,47]. Interestingly, the three-dimensional models have suggested that all CysLT 1 antagonists may not bind to the same site or in the same manner as the endogenous ligand.…”

Cyclization of 2′-hydroxychalcones to flavones using ammonium iodide as an iodine source: An eco-friendly approach

“…19 The main known synthetic methods for obtaining flavones are oxidative cyclization of 2′-hydroxychalcones, 20 the cyclodehydration of 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione 21 and via an intermolecular Wittig reaction. 22 Reagents that have been used for the oxidation of 2′-hydroxychalcones and flavanones to obtain flavones are SeO 2 -pentan-1-ol, 20 Pd-C/vacuum, 22 I 2 -DMSO, 23 SeO 2 -DMSO, 24 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-dioxane, 25 NaIO 4 --DMSO, 26 nickel peroxide-dioxane, 27 H 2 O 2 -NaOH, 28 Dowex H + -2-propanol, 23a,29 SeO 2 -dioxane, 30 SeO 2 -3-methyl-1-butanol (isoamyl alcohol), 31 Br 2 --NaOH, 32 Tl(NO 3 ) 3 ·3H 2 O 33 and I 2 -triethylene glycol. 34 Most of these methods are of limited use as they suffer from low yields and often afford a mixture of products containing flavones, flavanones and aurones.…”