Glycation is a natural process in which sugars in the bloodstream attach to various nucleophilic molecules which are present in the body. Amadori compounds are formed in this reaction, which may then further react and become advanced glycation end-products (AGEs). These can have deleterious effects on health. This process can be halted by scavenging carbonyl and radical species, and chelating metal ions, such as Cu(II) and Fe(III). Several molecules have been tested as potential glycation inhibitors, such as pyridoxamine (PM) and aminoguanidine (AG). It is expected that these molecules will hinder the formation of AGEs if they coordinate to copper and iron more strongly than Amadori compounds. In a set of investigations, we decided to explore the stability of the complexes PM and AG form with the aforementioned metal ions, as well as complexes with ascorbic acid (ASC) and a model Amadori compound (AMD). In all cases we employed the M05(SMD)/6-311+G(d,p) level of theory. Acid-base properties and physiological pH were always considered. We found that PM forms the most stable compounds with both metal ions, followed by AMD, and then AG and ASC. This agrees with experimental research, as only PM can prevent the formation of AGEs. Moreover, the Fe(III) complexes proved to be much more stable than the Cu(II) complexes when PM was the ligand, but the contrary was true when considering AG.

Furthermore, we also explored the secondary antioxidant activity of both AG and PM, considering the most stable complexes with Cu(II) and Fe(III). A compound is said to present this activity if it can coordinate to Cu(II) or Fe(III) and slow down the rate constant of the first step of the Haber-Weiss cycle. In this reaction, any of these two metal ions reacts with either the superoxide radical anion or the ascorbate anion. We found that the most stable complexes of AG with Cu(II) and Fe(III) can slow down the first step of the Haber-Weiss cycle when the reductant is ascorbate. In the case of the superoxide anion, AG did reduce the rate constant when considering Cu(II), albeit to a much lesser degree. However, this is not the case with Fe(III). On the other hand, PM did present strong antioxidant activity, even when the reducing agent was the superoxide radical anion. Once again, this is in agreement with experimental data, as both AG and PM can prevent the oxidation of ascorbic acid in the presence of Cu(II) and Fe(III). Thus, at physiological conditions, PM will preferentially form complexes with Fe(III), and AG with Cu(II). When PM is present at sufficiently high concentrations, the most stable complexes will be formed, and this molecule will show its secondary antioxidant activity. This collection of work sets the way for future studies with potentially new drugs to inhibit glycation. [1-3]

[1] G. García-Díez, R. Ramis, N. Mora-Diez, ACS Omega, 2020, 5, 14502-14512.

[2] G. García-Díez, N. Mora-Diez, Antioxidants, 2020, 9, 756.

[3] G. García-Díez, R. Monreal-Corona, N. Mora-Diez, Antioxidants, 2021, 10, 208.