Population, acid-base, and redox properties of N-acetylcysteine conformers.
Rotamers of N-acetyl-L-cysteine (NAC, the most popular mucolytic drug) are characterized in terms of populations, site- and conformer-specific acid-base properties, reducing strength, and molecular pharmacology. A new, general relationship between the bulk- and rotamer-specific basicities is introduced. NAC at high pH predominantly exists in a trans thiolate-carboxylate rotameric form, whereas protonation promotes the occurrence of intramolecular hydrogen bond-forming isomers. Distribution curves of the rotamers are depicted as a function of pH. Rotamer-dependent thiolate basicities differ by up to 0.5 log k units. Carboxylate basicities show slight conformation-dependence only. The membrane-penetrating capabilities from various compartments of the body are assessed on the basis of the pH-dependent charge of the molecule. The thiol-disulfide half-cell potential is calculated, using the correlation between the thiolate basicity and oxidizability. The oxidation-reduction properties of NAC are compared to those of other biological thiols in their definite microscopic forms. The pharmacokinetic behavior is interpreted in terms of the physicochemical parameters, providing molecular/submolecular explanation for several therapeutic properties of NAC.
Noszál
B
B
Semmelweis University, Institute of Pharmaceutical Chemistry, Budapest, Hungary. nosbel@hogyes.sote.hu
Visky
D
D
Kraszni
M
M
D000111:Acetylcysteine / Q000737:chemistry* / Q000493:pharmacokinetics; D000136:Acid-Base Equilibrium; D004220:Disulfides / Q000737:chemistry; D016166:Free Radical Scavengers / Q000737:chemistry* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry
D004220:Disulfides; D016166:Free Radical Scavengers; D013438:Sulfhydryl Compounds; D000111:Acetylcysteine