Structure-Antioxidant Activity Study of Caffeoyl Dipeptides and Synthesis and Bioactive Compounds as Antioxidant and Tyrosinase Inhibitor

Abstract

Various bioactive compounds were modified by peptide conjugation for enhancing their biological activity. In the first part, caffeoyl dipeptide derivatives were prepared to give sufficient stability and synergistically enhanced antioxidant activity. When carnosine (β-alanine-histidine) was conjugated to caffeic acid (CA), they showed good antioxidant activity in both hydrophilic and hydrophobic assay system. In addition, we found that caffeoyl proline-histidine (CA-Pro-His) showed the excellent antioxidant activity amongst a small library of caffeoyl histidine-containing dipeptides (CA-His-Xaa, CA-Xaa-His) and caffeoyl proline dipeptides (CA-Pro-Xaa). NMR study confirmed that CA-Pro-His mostly existed as s-cis conformation. We assumed that proline afforded a structural benefit, and thus, histidine imidazole might stabilize semi-quinone radicals of CA after hydrogen atom abstraction. In addition, CA-Pro-His revealed no cytotoxicity and showed antioxidant activity in cell systems. In the second part, we designed and synthesized bioactive compounds having both antioxidant and tyrosinase inhibition activity. Expecting a synergistic effect, we synthesized a conjugated form of caffeoyl amino acidyl hydroxamic acid (CA-Xaa-NHOH). They acted as both a good antioxidant and tyrosinase inhibitor, in particular, when CA was conjugated with proline or amino acids having aromatic ring like phenylalanine. Various hydroxycinnamic acid derivatives were further conjugated with phenylalanyl hydroxamic acid and prolyl hydroxamic acid (HCA-Phe-NHOH, HCA-Pro-NHOH). When their biological activities were evaluated, CA-Pro-NHOH turned out to be the best antioxidant molecule in both hydrophilic and hydrophobic environments, and also a good tyrosinase inhibitor. In addition, CA-Pro-NHOH showed mild anti-melanogenesis activity in Mel-Ab cells without cytotoxicity. From these studies, we found that amino acid or peptide conjugated antioxidants and tyrosinase inhibitors could be a good starting point for further refinement as well as potentially useful bioactive compounds in the fields of medicine, agriculture, and cosmetic industry.