Isolation, synthesis, mechanism of action, and pharmacological activities of bisabolangelone and related bisabolenoids

Abstract

The bisabolene-type sesquiterpene bisabolangelone (BBG) can be found in several Angelica species, notably in the seeds of A. silvestris L. from which it was first isolated. BBG can be extracted from those plants or obtained by total synthesis from the monoterpenoid pulegone. Efficient procedures have been proposed to synthesize BBG and derivatives. The present review discusses the origin, bio- and chemical syntheses, and pharmacological properties of BBG. Three main activities have been reported, corresponding to three study periods. Initially, BBG was investigated as an insecticide active against Dermatophagoides (house dust mites) and a few other pest species. Later, the compound revealed marked hypopigmenting and anti-melanogenic activities of potential interest to treat hyperpigmented skin lesions. BBG was shown to competitively inhibit cAMP binding to the regulatory subunit of protein kinase A, to alter the functioning of transcription factors CREB and SOX9 implicated in melanogenesis. More recently, BBG was found to inhibit gastric H⁺/K⁺-ATPase, presumably via a direct binding to a site on the luminal surface of the proton pump. This mechanism of action, coupled with the antioxidant and anti-inflammatory effects, stimulated the design of more stable anti-ulcer BBG analogues with a reinforced H⁺/K⁺-ATPase inhibitory activity, such as oxime and hydrazone carboxamide derivatives. The better knowledge of the bioactivities and the mechanism of action of BBG should encourage studies of natural products with a similar scaffold, such as paniculides A-D, liginvolones A-D, osterivolones A-D, ashitabaol A and other bisabolenoids. Altogether, the review provides a complete survey of the chemistry and pharmacology of bisabolangelone to shed light on its potential therapeutic interest.