title: Investigation of N-hydroxythalidomide in vitro stability and comparison to other N-substituted derivatives.
abstract: The stability of N-substituted derivatives of thalidomide was studied and compared to that of thalidomide itself. Nitrogen atom included in glutarimide ring was successively substituted by a hydroxy group, a methyl acetate group, and an ethyl group. Lipophilicities of these compounds were determined using the method based on experimental determinations of partition coefficients developed by Hansch. Hydroxy group led to a decrease of lipophilicity. Substitution of the nitrogen atom by an ethyl group or a methyl acetate group allowed an increase of lipophilicity. Relative stabilities of each compound were determined under physiological conditions: pH (7.4) and temperature (37 degrees C) using high performance liquid chromatography procedure. The program Sigma Plot was used to fit experimental data in order to obtain the half-lifes of thalidomide and its analogs. In the case of substitution by an ethyl group, the increase of lipophilicity (Delta log P = 0.36) was in agreement with a higher stability in aqueous medium. In the case of methyl acetate group, hydrolysis of the cycle was chemically favoured despite a higher lipophilicity compared to those of thalidomide. In the case of N-hydroxy compound, the decrease in lipophilicity was not sufficient to affect the stability.
authors.affiliation: UMR 6014 CNRS, Université de Rouen, Equipe de chimie Pharmaceutique, Faculté de Médecine et de Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex 1, France.
authors.forename: François
authors.initials: F
authors.lastname: Estour
authors.forename: Vincent
authors.initials: V
authors.lastname: Ferranti
authors.forename: Christiane
authors.initials: C
authors.lastname: Chabenat
authors.forename: Emilie
authors.initials: E
authors.lastname: Toussaint
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Olivier
authors.initials: O
authors.lastname: Lafont
mesh_terms: D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013696:Temperature; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D008055:Lipids; D014867:Water; D013792:Thalidomide