Modelling the dependence on medium, ionic strength and temperature of N-acetyl-L-cysteine acid-base properties, and its interactions with Na+, Mg2+, Ca2+ and Zn2+

Abstract

N-acetyl-L-cysteine (NAC) is the acetylated precursor of L-cysteine, and it is strictly related to glutathione activity. NAC is used in medicine since more than 30 years, primarily as a mucolytic, though its properties are exploited in the treatment of many diseases, such as acute poisoning by acetaminophen (restoring protective levels of glutathione), HIV, contrast-induced nephropathy, type-2 DM (diabetes mellitus), and it also looks promising in the treatment of several psychiatric disorders [1]. This resulted in a huge number of scientific contributions published during the years on NAC (searching in some scientific databases, more than 10000 papers appear). As expected, most of them are focused on the biological and therapeutic activity of NAC, while relatively few data are reported on the solution chemistry of this molecule, despite the thorough knowledge of its acid-base and coordination behaviour are of fundamental importance for the understanding of its properties in aqueous solution, as biological fluids are. Moreover, the relatively few thermodynamic data available (necessary to assess the speciation of this ligand in the system under study) are reported in single, specific conditions, while it is well known that the most of biological fluids (and natural waters) are, from a chemico-physical perspective, multielectrolyte aqueous solutions of very variable composition, ionic strength, and temperature [2]. Therefore, in this contribution we report the results of an investigation on the modelling of the acid-base properties of NAC in different ionic media (sodium and tetramethylammonium chlorides and tetraethylammonium iodide) at different ionic strengths (0 < I / mol dm-3 ≤ 3.0) and temperatures (283.15 ≤ T / K ≤ 318.15). Due to their importance from a biological perspective, we also report the results on the binding ability of NAC towards Na+, Mg2+, Ca2+ and Zn2+ in NaClaq at T = 298.15 K and different ionic strengths (0 < I / mol dm-3 ≤ 2.0). Surprisingly, despite the importance of these cations and their involvement in many biological mechanisms strictly connected with NAC activity, to our knowledge almost no data (only some for Zn2+) are present in literature on these interactions. The dependence on medium, ionic strength and temperature of the protonation and complex formation constants obtained has been modelled by classical approaches, such as the Extended Debye-Hückel (EDH), Specific ion Interaction Theory (SIT), Pitzer, and by the van’t Hoff equation.