Interdependent chemical-electrochemical steps in retrometabolism-based drug and safer chemical design.

An extension of the retrometabolic based drug (chemical) design concept, specifically the soft drug approach, to the family of nitrone compounds is presented. Nitrones oppose oxidative challenges by virtue of their ability to very rapidly trap free radical species that are more stable and biochemically less harmful than the original molecular fragments. Moreover, the spin adducts may undergo further transformations including reaction with a second radical and decomposition (hydrolysis) to hydroxylamines and carbonyl compounds. Nitrones and their spin adducts may generate nitric oxide in vivo, which, like nitrones themselves, exerts a number of diverse activities in phylogenetically distant species as well as opposing effects in related biological systems. It was described as a major messenger in the cardiovascular, immune, and nervous systems, in which it plays regulatory, signaling, cytoprotective, and cytotoxic effects. Nitrones play an important role in the synthesis of drugs belonging to chemically and pharmacologically very different classes. A combined chemical-electrochemical synthesis of nitrones has been elaborated. These compounds may be obtained from aldehydes or ketones and N-substituted hydroxylamines. These reactions were performed directly, in situ in the electrochemical cell, where phenylhydroxylamine obtained by electroreduction of nitrobenzene derivatives reacts with the carbonyl compound introduced in the cell. The kinetic and thermodynamic parameters of the processes were determined by analyzing the adequate polarographic curves. Differences between purely chemical and mixed chemical-electrochemical methods are discussed. Analysis of the experimental data permits optimization of the investigated process from a preparative point of view. Effects of structural factors were systematically evaluated. The proposed method may be useful for combinatorial chemistry as well.