title: Enantioresolution, stereochemical characterization and biological activity of a chiral large-conductance calcium-activated potassium channel opener.
abstract: A number of large-conductance calcium-activated potassium (BK) channel openers based on the 2-aryl-1,4-benzothiazine scaffold were previously synthesized, and 2-(5-bromo-2-methoxyphenyl)-6-trifluoromethyl-2H-1,4-benzothiazin-3(4H)-one (1) was identified as the most active compound. Since a stereoselective activation of BK channels was demonstrated for arylindolone derivatives, the effect of the absolute configuration at the C-2 position on the vasorelaxing potency of 2-aryl-1,4-benzothiazines is investigated in this article. Compound 1 was initially evaluated as a racemate: subsequently, the "racemic approach" was used to isolate its enantiomers. The excellent enantioresolution obtained using the Sepapak-4 column (CSP 4, cellulose tris(4-chloro-3-metylphenylcarbamate); RS=8.36; α=2.03) allowed to collect highly pure enantiomeric fractions, with enantiomeric excess (e.e.) values higher than 97% and 98% for the first- and second-eluted enantiomer, respectively. Electronic circular dichroism (ECD) studies on the two isolated enantiomers, combined with time-dependent density functional theory (TD-DFT) calculations allowed to characterize the configuration of the enantiomers and determine a (R), (S) elution order. Results from biological assays indicated that the racemate and the isolated enantiomers are endowed with comparable vasorelaxing potency.
authors: Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy.
authors: Roccaldo
authors: R
authors: Sardella
authors: Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy.
authors: Andrea
authors: A
authors: Carotti
authors: Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy.
authors: Giuseppe
authors: G
authors: Manfroni
authors: Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
authors: Daniele
authors: D
authors: Tedesco
authors: Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors: Alma
authors: A
authors: Martelli
authors: Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
authors: Carlo
authors: C
authors: Bertucci
authors: Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy.
authors: Violetta
authors: V
authors: Cecchetti
authors: Department of Pharmaceutical Sciences, University of Perugia, via Fabretti 48, 06123 Perugia, Italy. Electronic address: benedetto.natalini@unipg.it.
authors: Benedetto
authors: B
authors: Natalini
mesh_terms: D002942:Circular Dichroism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels
keywords: Absolute configuration; BK channel opener; Electronic circular dichroism; Polysaccharide-based stationary phases; Preparative enantioresolution; Vasorelaxing potency