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Issue 1, 2005
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Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling

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Abstract

Conformations of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative were determined in various solvents. The experimental NMR data—coupling constants and NOE contacts—were compared with the results of molecular modelling—molecular mechanics calculations and molecular dynamics simulations. The conformational changes, on the right-hand side of the 14-membered ring, affected mostly the 3JH2,H3 values and NOE crosspeaks H3 or H4 to H11. Oleandomycin was found to be present predominantly in the C3–C5 folded-in conformations in DMSO-d6 solution, whereas in buffered D2O, acetone-d6 and CDCl3, there was a mixture of folded-in and folded-out conformational families. The predominant conformation of the 8-methylene-oleandomycin-9-oxime derivative in solution was a folded-out one although different amounts of folded-in conformation were also present depending on the solvent. Oleandrose and desosamine sugar moieties adopted the usual and expected chair conformation. The conformation around the glycosidic bonds, governing the relative orientation of sugars vs. the lactone ring, showed a certain flexibility within two conformationally close families. We believe that by combining the experimental NMR data and the molecular modelling techniques, as reported in this paper, we have made significant progress in understanding the conformational behaviour and properties of macrolides. Our belief is based on our own current studies on oleandomycins as well as on the previously reported results and best practices concerning other macrolides. A rational for macrolide conformational studies and advances in methodology has been suggested accordingly.

Graphical abstract: Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling

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Publication details

The article was received on 10 Aug 2004, accepted on 12 Oct 2004 and first published on 15 Nov 2004


Article type: Paper
DOI: 10.1039/B412294A
Org. Biomol. Chem., 2005,3, 39-47

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    Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling

    P. Novak, Z. B. Tomišić, P. Tepeš, G. Lazarevski, J. Plavec and G. Turkalj, Org. Biomol. Chem., 2005, 3, 39
    DOI: 10.1039/B412294A

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