Conformation and atropisomeric properties of indometacin derivatives

Abstract

The stereochemistry around the N-benzoylated indole moiety of indometacin was studied by restricting the rotation about the N-C7′ and/or C7′-C1′ bond. In the 2′,6′-disubstituted ones, an atropisomeric property was found and the atropoisomers were separated and isolated as stable forms. Their biological abilities to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were examined. Only the aR-isomer showed specific inhibition of COX-1, and COX-2 was not inhibited by either atropisomer. Conformational analysis in NMR studies and X-ray crystallography, and CD spectra in combination with calculations were utilized to elucidate the bioactive conformations. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.