Chemical activation of piperidine by formaldehyde and formation of lysine-specific Maillard reaction products

Piperidine is considered as a lysine-specific Maillard reaction product that can be formed from free lysine through decarboxylation and deamination reactions or through cyclization of pent-4-en-1-amine, the counterpart of acrylamide from lysine. Due to the importance and reactivity of piperidine its further interaction products in glucose/lysine model system was investigated. A useful strategy based on Py-GC/MS analysis was developed using an isotope labelling technique to identify reaction products incorporating piperidine moieties. Products simultaneously possessing five lysine carbon atoms (C2′–C6′) and the Nε-amino group from lysine in addition to glucose carbon atoms were targeted using specifically labelled precursors such as [15Nα]Lysine·2HCl, [15Nε]Lysine·2HCl, [U-13C6]Lysine·2HCl, [13C-6]Lysine·2HCl and [U-13C6]Glucose. Detailed labelling studies using specifically 13C-enriched sugars have shown that the piperidine can form reactive 1-methylidenepiperidinium ion with formaldehyde, which is able to undergo further aldol addition reactions to form compounds, such as 3-(piperidin-1-yl)propanal and 3-(pyridin-1(4H)-yl)propanal. Furthermore, these studies have also demonstrated that oxidation of piperidine into di- and tetrahydropyridine derivatives can generate reactive eneamine moieties capable of nucleophilic attack at carbonyl groups and formation of pyridine derivatives.