Intracellular Oxidation of Dipeptides. Base-Promoted Elimination from N-Halodipeptides to 2-[N-Alkyl-N-(2-N-alkylimino-2-alkylethanoyl)amino]-2,2-dialkylethanoic Acids

Abstract

One of the possible ways of intracellular oxidation of peptides is via the formation of the corresponding (N-X)-dipeptides, that then undergo base-promoted elimination to yield intermediate 2-[N-alkyl-N-(2-N-alkylimino-2-alkylethanoyl)amino]-2,2-dialkylethanoic acids, which subsequently hydrolyze. Such an elimination process is general-base catalyzed, with Brønsted beta values ranging from 0.26 to 0.31, which suggests an essentially constant degree of proton transfer at the TS. For (N-X)-dipeptides, the ratio k(N-Br)/k(N-Cl) ranges from 2.5 to 15, suggesting a structural dependence of the degree of N-X bond breaking at the TS. The values of beta and k(N-Br)/k(N-Cl) support a concerted asynchronous A(xh)D(H)D(N) mechanism, its TS changing from reactant-like to slightly nitrenium-like depending on the structure of the starting dipeptide. As a consequence of the antiperiplanarity requirements of the reaction, the steric interaction between the leaving group and the substituent on the C bearing the H to be eliminated controls the reaction rate. Such steric interaction is rather important, as indicated by the steric crossed-interaction coefficient (p(ssy') = 0.33). Semiempirical calculations show that bulky substituents in the vicinity of the reaction center imply additional energy requirements for the system to achieve the antiperiplanarity needed at the TS for the reaction to proceed. From the observations reported it follows that (N-X)-dipeptides lose their oxidizing power more readily than analogous (N-X)-amino acids or (N-X)-amines, opening a possible pathway to lessen intracellular halogen-based oxidative stress.

Myeloperoxidase-catalyzed chlorination: The quest for the active species

“…(N-Cl)-Pro-GlyGly shows an UV band with maximum at k = 259 nm. The decomposition of the chlorinated compound must be described as an elimination reaction [26] yielding chloride ion and a Schiff base, which in turn rapidly hydrolyzes in solvent water to the parent amine and carbonyl compounds [32]. This process presents a prominent band at k = 238 nm, which could be affected by the solvent cutoff, corresponding to the decomposition product, and an isosbestic point at k = 270.6 nm.…”

“…This is in contrast to (N-halo)-dipeptides with Gly as the N-terminal residue or with a tertiary amide, i.e. substituted peptidic nitrogen, that cause acceleration of their decomposition [26]. Table 1 Proposed mechanism of MPO-catalyzed chlorination of amino compounds…”