Living beings have evolved over the past two billon years through adaptation, to an increasing atmospheric oxygen concentration, by both taking advantage of oxygen activating function and developing a complex control network. In these regards, potentially damaging species (reactive oxygen, nitrogen and chlorine species) arise as by-products of metabolism and also work as physiological mediators and signalling molecules. Oxidative stress may be an important factor in numerous pathological conditions, i.e. infection if micronutrients are deficient. Levels of these species are controlled by the antioxidant defence system, which is composed by antioxidants and pro-antioxidants. Several components of this system are micronutrients (e.g. vitamins C and E), are dependent upon dietary micronutrients (e.g. CuZn and Mn superoxide dismutase) or are produced by specific endogenous pathways. The antioxidant defences act, to control levels of these species, as a coordinated system where deficiencies in one component may affect the efficiency of the others. In this network some of the components act as direct antioxidants whereas others act indirectly (proantioxidants) either by modulation of direct agents or by regulation of the biosynthesis of antioxidant proteins. Thus, entities usually not considered as antioxidants, also act efficiently counteracting damaging effects of oxidative species. In this contest, the design of new molecules that take into account synergistic interactions among different antioxidants, could be useful both to address mechanistic studies and to develop possible therapeutic agents. In this review the principal categories of antioxidants and pro-antioxidants that goes from vitamins through phyto-derivatives to minerals, are critically reviewed, with particular emphasis on structure-function considerations, together with the perspective opened, in the design of possible therapeutic agents, by the antioxidants interplay.
antioxidants, pro-antioxidants, structure-function relationships, drug design
Department of Pharmaceutical Science, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy.