Why natural antioxidants are readily recognized by biological systems? 3D architecture plays a role

[Display omitted] •More than 70 natural antioxidants were selected from the publications in the last five years.•The steric configurations of these antioxidants were analyzed at MM2 level.•The antioxidant-related bioactivities were summarized to correlate with their 3D architectures.•The conclusion obtained from the observation on the structures of natural antioxidants was confirmed by organic synthetic results. A great deal of investigations has convincingly outlined the correlation of pathogenesis of various fatal diseases with the damages caused by reactive oxygen species (ROS) in vivo. Not surprisingly, natural antioxidants play pivotal roles in the decreasing of these diseases by their hydrophilicity, permeability, multi-factored interactions with biological surroundings, while the antioxidative effects are dependent upon the bond energies, donors or acceptors of hydrogen bonds as well as other physical properties of the functional groups. However, in comparison with natural antioxidants the synthetic antioxidants sometimes exhibit potentially deleterious effects, viz., pro-oxidative properties, and it is thereby worth exploring the structures of natural antioxidants with the aim of achieving valuable information for the antioxidative structures. Here, more than 70 natural antioxidants are collected from recent publications, and their configurations are optimized at MM2 level for summarizing the common characteristics from their structures. It is found that all the natural phenols, flavonoids, anthraquinones, alkaloids, terpenoids, and steroids exert three-dimensional (3D) architectures rather than a merely planar conjugation system. Hence, this 3D conformation might be beneficial for the natural antioxidants being recognized by biological surroundings. This deduction has been demonstrated by some synthetic antioxidants, in which their structures have been conformed to be 3D architecture. The 3D architecture will become a direction for the designing of antioxidative structures, and the testing of antioxidative effect is encouraged to employ signaling pathways, protein targets, and cell lines rather than individual radical-scavenging evaluation.