Advancements in the singlemer separation of polymethoxyflavones in citrus peels

Polymethoxyflavones (PMFs) including 5,6,7,4′-tetramethoxyflavone (TMF), tangeretin, sinensetin, nobiletin, and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), possess multiple significant health-promoting activities. They have drawn increasing attention in recent years. However, the supply of pure singlemers of these PMFs, even the major content of tangeretin, nobiletin, HMF and TMF has been a limiting factor for their in vivo study and human testing, due to the difficulties in large scale preparation. Due to the close structural and configurational similarities of these PMFs in plants such as citrus peels, the purification to obtain single PMFs for in-depth efficacy evaluation has been an enormous challenge, preventing further large scale and broad study for their potential excellent biological properties. In this review, we summarized the up to date reported purification methods chiefly from citrus peel extract using various chromatography techniques to obtain singlemers of these PMFs. These methods including normal phase and reversed phase liquid chromatography, macroporous gel separation, counter current chromatography, and supercritical fluid chromatography as well as the combination of those isolation techniques. The aim of this review is to provide key references to establish an efficient and scalable separation method in acquiring single polymethoxyflavone isomers which will enable further investigations on the health-promoting and medicinal properties of these PMFs and associated mechanisms.