Exploration of glycyrrhizin derivatives exploiting bioconversion by endophyte inside licorice root.

Abstract

Almost all plants are not axenically and have commensal “endophyte” in their body. We yielded slightly modified 2 derivatives of glycyrrhizin from licorice endophyte. Glycyrrhizin has been known to inhibit high-mobility group box (HMGB)1, a proinflammatory cytokine-like protein, by direct interaction. Here we investigated the effect of the glycyrrhizin derivatives on HMGB1 with primary-cultured macrophage. Both derivatives were hydroxylated at the C-15 position and one was further ketonated at the C-3 position. These derivatives had lower toxicity than glycyrrhetinic acid; however, lost the ability to inhibit HMGB1. This was probably due to increased polarity at the C-15 position. Accordingly, taking advantage of ketone at the C-3 position, we synthesized a methyl ester at the C-30 position. This compound suppressed the interleukin-1b mRNA expression more strongly than glycyrrhizin in macrophages challenged by HMGB1, and showed neuroprotection based on edema relief in an in vivo murine intracerebral hemorrhage (ICH) model. These results show that this glycyrrhizin derivative is a promising compound for the ICH therapy.