A comparative NMR study between the macrolide antibiotic roxithromycin and erythromycin A with different biological properties.
1H nuclear Overhauser enhancement studies and 1H NMR 3J analysis establish the similarity between the major solution-state conformation of roxithromycin (1) and the erythromycin (2). A major difference between the structure of antibiotics 1 and 2 is the replacement of the 9-keto group in 2 by a 9-[O-(2,5-dioxahexyl)oxime] group. The NOE studies show that this oxime chain is oriented above the macrocyclic lactone ring and that the oxygen atoms of this chain are engaged in tight hydrogen bonding with a water molecule and with the 6- and 11-hydroxyl groups of the macrocycle. It results in a globular form of the whole roxithromycin molecule. These data explain also a relative hydrophobicity of this antibiotic. Erythromycin A (2), which presents a less rigid macrocycle with two free hydroxyl groups (6-OH and 11-OH), forms a dimer detected by FAB mass spectroscopy. 1H and 13C NMR relaxation measurements (T1) for both antibiotics show that interresidue hydrogen bonds in roxithromycin reduce the rotational freedom of the macrocyclic lactone ring and consequently the motions of desosamine and cladinose sugars. In another way, an ionization of the amino function occurs in the various media according to the nature of the antibiotic. This would allow the reactivity modification of the desosamine unit. In the biological study, the modifications of the 455-nm metabolite-cytochrome P-450 complex formation are observed.
Gharbi-Benarous
J
J
Université René Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS URA 400, Paris, France.
Delaforge
M
M
Jankowski
C K
CK
Girault
J P
JP
D003460:Crystallization; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004917:Erythromycin / Q000737:chemistry*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D015575:Roxithromycin / Q000737:chemistry*; D013696:Temperature
D046911:Macromolecular Substances; D015575:Roxithromycin; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System