title: Carboxyl group catalysis of acyl transfer reactions in corticosteroid 17- and 21-monoesters.
abstract: Succinate esters, although frequently employed as water-soluble prodrugs of poorly soluble parent drugs, are not sufficiently stable to allow long-term storage in solution. Intramolecular catalysis of ester hydrolysis by the terminal succinate carboxyl group is a contributing factor to this instability. Methylprednisolone 21-succinate has recently been reported to undergo both hydrolysis and 21 in equilibrium 17 acyl migration in aqueous solutions. Intramolecular catalysis by the terminal carboxyl group is seen in both reactions, but the catalytic mechanisms are not well understood. While acyl migration can only be catalyzed via the carboxyl group acting as a general acid or general base, hydrolysis may undergo either nucleophilic or general acid-base catalysis. To gain further insight into the catalytic mechanism, hydrolysis of methylprednisolone 21-succinate was carried out in aniline buffers to trap any succinic anhydride (as the anilide) that would form if the catalysis were nucleophilic. The nucleophilic mechanism was shown to account for only 15-20% of the overall catalysis. Comparisons of the rates of the intramolecularly catalyzed reactions of methylprednisolone 21- and 17-succinate were made with the same reactions of methylprednisolone 21- and 17-acetate catalyzed intermolecularly by acetate ion. Interestingly, intramolecular catalysis appears to favor acyl migration over hydrolysis. Hence, the hydrolysis of methylprednisolone 21-succinate is faster in basic solutions (pH greater than 7.4), while acyl migration becomes the dominant reaction in the catalyzed region of the pH profile between pH 3.6 and 7.4. Arguments are presented to account for these differences in catalytic efficiency in terms of the transition-state structures for the two reactions.
mesh_terms: D000305:Adrenal Cortex Hormones / Q000032:analysis*; D002384:Catalysis; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008775:Methylprednisolone / Q000031:analogs & derivatives / Q000032:analysis; D000077555:Methylprednisolone Acetate; D008776:Methylprednisolone Hemisuccinate / Q000032:analysis; D014867:Water
chemical_list: D000305:Adrenal Cortex Hormones; D014867:Water; D000077555:Methylprednisolone Acetate; D008776:Methylprednisolone Hemisuccinate; C029110:methylprednisolone 17-hemisuccinate; D008775:Methylprednisolone