Synthesis of Bioactive Nobiletin Metabolites

Abstract

Increasing attention has been given to nobiletin (1) due to its diverse biological properties including anticancer, anti-inflammatory, and neurotrophic activities. Recent studies of the metabolites of 1 have revealed that 3 and 4 possess in some cases more potent biological activities than nobiletin. Although a significant amount of 1 can be obtained from sweet orange peels, its chemical conversion into 2–4 is of great difficulty. Herein we have reported a concise synthesis of nobiletin metabolites, in which the key intermediate of flavone A-ring was obtained through 7 steps from methyl 3,4,5-trimethoxybenzoate in 49% overall yield. Preliminary assay of the metabolites thus synthesized reveals that 3 inhibits expression of matrix metalloproteinase-9 in human lens epithelial cells much stronger than 1, whereas 2 and 4 possess comparable activity to that of 1.