Capsaicin, a Powerful •OH-Inactivating Ligand

Abstract

Oxidative conditions are frequently enhanced by the presence of redox metal ions. In this study, the role of capsaicin (8-methyl-N-vanillyl-6-nonenamide, CAP) in copper-induced oxidative stress was investigated using density functional theory simulations. It was found that CAP has the capability to chelate Cu(II), leading to complexes that are harder to reduce than free Cu(II). CAP fully turns off the Cu(II) reduction by Asc^-, and slows down the reduction in this cation by O₂^•-. Therefore, CAP is proposed as an ^•OH-inactivating ligand by impeding the reduction in metal ions (OIL-1), hindering the production of ^•OH via Fenton-like reactions, at physiological pH. CAP is also predicted to be an excellent antioxidant as a scavenger of ^•OH, yielded through Fenton-like reactions (OIL-2). The reactions between CAP-Cu(II) chelates and ^•OH were estimated to be diffusion-limited. Thus, these chelates are capable of deactivating this dangerous radical immediately after being formed by Fenton-like reactions.

Keywords: Cu-complexes; DFT; capsaicin; fenton reaction; molecular dynamics; natural antioxidant; oxidative stress.

Figure 1

Chemical structure of capsaicinoids, bioactive compounds present in Capsicum annum varieties.

Figure 2

Capsaicin (CAP). Structure and chelation sites numbering.

Figure 3

Gaussian distribution of O1a-C16 distance (left side), and Ramachandran-like plot (right side) of ω and τ dihedral angles calculated along the MDs.

Figure 4

Molecular electrostatic potential (a) and the non-covalent interaction (NCI) plot (b) for both the extended and close conformations.

Scheme 1

Mechanisms explored to analyze the OIL-2 activity of CAP.

Figure 5

Scan coordinates of the HAT and RAF reactions between CAP-Cu(II) and ^•OH.

Figure 6

Transition state (IIB-O1a-O2a_n8) (left) and intermediate (IIB-O1a-O2a_n8_I) (right) of the reaction between CAP-Cu(II) and the OH free radical.

Figure 7

Reaction profile for the HAT reaction CAP-Cu(II) + OH, pathway n8. Isolated reactants: IR, intermediate: I, transition state: TS, products: P.