Premium
Stereospecific effects of benzo[ d ]isothiazolyloxypropanolamine derivatives at β‐adrenoceptors: Synthesis, chiral resolution, and biological activity in vitro
Author(s) -
Comini Mara,
Pozzoli Cristina,
Incerti Matteo,
Rossi Daniela,
Collina Simona,
Azzolina Ornella,
Di Vittorio Elena,
Morini Giovanni,
Poli Enzo
Publication year - 2009
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20574
Subject(s) - chemistry , enantiomer , enantiopure drug , moiety , chiral column chromatography , stereochemistry , stereospecificity , carbamate , chirality (physics) , tris , high performance liquid chromatography , chiral derivatizing agent , enantioselective synthesis , chromatography , organic chemistry , biochemistry , catalysis , nambu–jona lasinio model , chiral symmetry breaking , physics , quantum mechanics , quark
We performed the asymmetric synthesis of four enantiopure benzo[ d ] isothiazo‐3‐or 5‐yloxypropanolamine derivatives, previously described as competitive antagonists at β‐adrenoceptors. The chemical characterization of each enantiomer was accomplished by 1 H NMR and HPLC/DAD/CD. The direct chromatographic separation of the enantiomers via chiral HPLC was investigated. The best resolutions were achieved using cellulose tris (3,5‐dimethylphenyl carbamate) (Chiralcel OD‐H) and amylose tris (3,5‐dimethylphenyl carbamate) (Chiralpak AD). The enantiomers obtained had enantiomeric purities suitable for biological assays. Tested in isolated rat cardiac and intestinal tissues to evaluate their effects at β 1 ‐ and β 3 ‐adrenoceptors, the ( S )‐enantiomers revealed a higher degree of antagonism than ( R )‐enantiomers at both subtypes, even though their activity was greater at the cardiac β 1 ‐subtype. The potent and cardiospecific antagonistic effect exerted by the compounds tested suggests that the benzisothiazole moiety could be an interesting scaffold for discovering new chiral β‐blocking drugs. Chirality, 2009. © 2008 Wiley‐Liss, Inc.