Conformational change due to esterification of hydroxy groups in erythromycin A and its major metabolite: analysis of these derivatives with different biological properties using NMR and molecular dynamics (MD) data.
A conformational study is performed on the acylated erythromycin and erythralosamine derivatives from comparison between experimental results (NMR) and theoretical calculations by Molecular Dynamics (MD) in attempts to correlate their conformations with their abilities to generate cytochrome P450-nitroso metabolite complexes in vitro. As the 3'-dimethyl-amino function of the desosamine is metabolized and responsible for the interaction with cytochrome P450, its position, mobility and steric hindrance in the proximity of this functional group are related to its biological properties. The major conformations of the lactone ring were termed A (A1, A2, A3) and B (B1, B2), and this macrocycle flexibility induced five different orientations a, b, c, d and e for the desosamine sugar. Conformations A and B differ in many ways but the major change is the inward folding of the C(3) fragment in B. Conformer a exhibits an orientation of the desosamine nearly perpendicular to the macrocycle whereas the two units are in the same plane in conformations c and e. For conformation b, the cladinose unit lifts up above the macrocycle. Conformation d exhibits a turned-back cladinose. In the erythromycin derivatives esterification at the beta position to the N(CH3)2 group of the desosamine reduces the degree of freedom of the macrocyclic lactone ring which corresponds to conformation A only. The desosamine sugar was found to be perpendicular to the macrocycle (a conformer) and both sugar groups are parallel to reduce the steric energy. In the erythralosamine derivatives, the macrocycle is always present as conformation B with the two conformations b and c of the sugar rings. The steric parameters favour the b conformers in which the amino group is tilted up, while in 3,2'-dibenzoylated stacking aromatic attraction stabilizes the planar c conformer. Both isomers are thus shown to adopt well-defined conformations and to be well-adapted for a comparative structure-activity correlation studies. There is a significant relationship between the conformation b and the formation of cytochrome P450-nitroso metabolite complexes.
Ladam
P
P
Université René Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, C.N.R.S. U.R.A.
Gharbi-Benarous
J
J
Delaforge
M
M
van Calsteren
M R
MR
Jankowski
C K
CK
Girault
J P
JP
D000215:Acylation; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry; D003198:Computer Simulation; D004917:Erythromycin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D004951:Esterification; D017665:Hydroxyl Radical / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D012996:Solutions; D013329:Structure-Activity Relationship
D002241:Carbohydrates; D007783:Lactones; D012996:Solutions; D017665:Hydroxyl Radical; C045512:erythralosamine; D004917:Erythromycin