Structural diversity, biological activities and biosynthetic pathways of [2 + 2] and [4 + 2] amide alkaloid dimers from Piperaceae: An updated review

The Piperaceae family is distributed widely in tropical and subtropical areas. It encompasses around 5 genera and over 3000 species. They are distinguished by the substantial chemical diversity and potential medicinal applications. Amide alkaloids, as the main secondary metabolites in the Piperaceae family, exhibit various biological activities, and the discovery of [2 + 2] and [4 + 2] amide alkaloid dimers has led to a surge in phytochemical research on Piperaceae plants. Although the identification of these dimers has been gradually increasing in recent years, there remains a lack of comprehensive and systematic evaluations of these compounds. This review aims to summarize the latest advancements in the research on natural amide alkaloid dimers, focusing on their structural diversity, biological activities and biosynthetic pathways, and the enzymatic advances of [2 + 2] and [4 + 2] cyclase enzymes. Until October 2024, research has documented 99 amide alkaloid dimers, including 37 dimers possessing [2 + 2] cyclobutanes skeletons and 62 [4 + 2] cyclohexene skeletons derived from the Piperaceae family. These compounds demonstrate a range of in vitro biological activities including anti-inflammatory, anticancer, acetylcholinesterase inhibitory, anti-platelet aggregation, hepatoprotective, antimalarial, antitubercular, anti-diabetic and notable interactions with CYP3A4 and CYP2D6 enzymes. A systematic review of these [2 + 2] and [4 + 2] amide alkaloid dimers in Piperaceae family can provide a critical scientific foundation and theoretical support for the discovery and development of novel pharmaceutical agents.