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Speciation 98: Abstracts
Dóra Visky, Márta Kraszni, Béla Noszál
Semmelweis University, Institute of Pharmaceutical
Chemistry, H-1092 Budapest, Hõgyes E. u. 9, Hungary
e-mail: nosbel@hogyes.sote.hu
Hydrolysis is the most important biotransformation pathway for ester group-containing bio- and drug molecules.
The hydrolytic reaction usually results in loss of biological effect. On the other hand, hydrolysis, in many cases produces the active substance. Thus, characterisation of ester-hydrolysis is equally important to understand drug metabolism and to design prodrugs.
The kinetics and equilibrium of hydrolysis are generally known to be dependent on extramolecular factors, such as temperature, pH and solvent. There are, however, hardly any data on the effects of the intramolecular environment, including the protonation and conformation stage of neighbouring moieties.
In order to specifically characterise these effects, we introduced the microscopic rate constant of hydrolysis, which defines the above parameters for coexisting, unseparable microspecies in different protonation states of the side-chain.
Experimentally, the progress of hydrolysis was followed by high performance capillary electrophoresis, the proton-binding equilibria was quantified by pH-potentiometry.
Our key-molecule, histidine-ethyl ester exists in solution in four protonated forms, depending on the protonation state of imidazole and amino sites. Accordingly, we determined the four microscopic equilibrium constants of proton binding and the four microscopic rate constants of OH--catalysed hydrolysis. Of the microscopic rate constants, the highest and lowest ones belong to the doubly cationic and neutral species, respectively, and an amino-protonation accelerates the hydrolysis more than an imidazole protonation. A microscopies distribution diagram was formed and improved, and the resulting diagram shows the pH-dependent hydrolysis-driving capacity of the microspecies.
