Isomeric C12-alkamides from purple coneflower (Echinacea purpurea) exhibit characteristics of a PPARγ partial agonist

Type 2 diabetes is a metabolic disorder that is characterized by hyperglycemia in the context of insulin resistance and relative lack of insulin. Type 2 diabetes is often treated by insulin sensitizing drugs such as thiazolidinediones (TZDs). The primary target for the TZDs is the peroxisome proliferator-activated receptor (PPAR) γ. However, critical side effects of TZDs can occur, as they are full PPARγ agonists. Partial PPARγ agonists are associated with fewer side effects but still may maintain the effect on insulin resistance. A dichloromethane extract of Echinacea purpurea roots increasing glucose uptake (GU) and activating PPARγ was subjected to bioassay-guided chromatographic fractionation. Basal and insulin-dependent GU in 3T3-L1 adipocytes and PPARγ transactivation assay were used to assess the bioactivity of extract, fractions and isolated metabolites. Two novel isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic acid 2-methylbutylamides together with two known C₁₂-alkamides and a-linolenic acid were isolated from active fractions. The compounds were found to activate PPARγ but only the isomeric alkamides were able to increase basal and insulin-dependent GU in adipocytes in a dose dependent manner. Docking studies were performed to determine possible binding modes of the novel isomeric C₁₂-alkamides within the PPARγ ligand binding domain. The weak activation of PPARγ as well as the results of docking mode of the novel isomeric C12-alkamides suggests that these compounds exhibit characteristics of a PPARγ partial agonist indicating that they may represent a chemical scaffold for the development of novel compounds with insulin sensitizing potential.

Keywords: Echinacea purpurea, PPARγ, diabetes, glucose uptake, in silico