Naturally Occurring Diterpenoid Dimers: Source, Biosynthesis, Chemistry and Bioactivities

Abstract

Diterpenoid dimers are rare in nature and mainly found in higher plants including the families Acanthaceae, Annonaceae, Asteraceae, Calceolariaceae, Chrysobalanaceae, Cupressaceae, Euphorbiaceae, Fabaceae, Lamiaceae, Liliaceae, Meliaceae, Rhizophoraceae, Taxaceae, Velloziaceae, and Zingiberaceae. In addition, a few diterpenoid dimers have been also reported from fungi (Psathyrellaceae), liverworts (Scapaniaceae), and a gorgonian (Gorgoniidae). They feature a wide variety of structures due to different core skeletons, linkage patterns, substituents, and configurations. Accordingly, diterpenoid dimers exhibit a broad range of bioactivities, including cytotoxic, anti-inflammatory, antimicrobial, antimalarial, and antifouling properties, which have attracted more and more research interests in the past decades. This review with 176 metabolites from 109 references provides a comprehensive and up-to-date overview of the source, biosynthesis, structure, synthesis, and bioactivities of diterpenoid dimers.

An Overview of Biotransformation and Toxicity of Diterpenes

“…Diterpenes are, by definition, C 20 compounds based on four isoprene (C 5 H 8 ) units and can be found in plants, fungi, bacteria, and animals in both terrestrial and marine environments [ 1 , 2 , 3 , 4 , 5 ].…”

“…The chair-boat conformation leads to “syn” orientation of the hydride and methyl substituents across the C-9-C-10 bond, which can occur with the “normal” or “ent” absolute configuration [ 10 ]. The range of diterpenes is extended from labdane-related diterpenes, which are the most basic hydrocarbon backbones, by cyclisation reactions leading to the production of bicyclic, tricyclic, tetracyclic, pentacyclic, and macrocyclic types, as well as diterpene dimers [ 3 , 10 ]. The most common diterpene skeletal types are shown in Figure 2 .…”

“…Diterpenes from different sources have also been shown cytotoxicity against various cancer cell lines, nitric oxide inhibitory activity, plant-growth regulating properties, phytotoxic activity on root growth, as well as antiplasmodial, hypoglycemic, hypolipidemic, antimicrobial, antiviral, antifouling, larvicidal, algicidal, and insect antifeedant activities, among others [ 2 , 3 , 15 , 16 , 17 , 18 ].…”

Two novel diterpenoid heterodimers, Bisebracteolasins A and B, from Euphorbia ebracteolata Hayata, and the cancer chemotherapeutic potential of Bisebracteolasin A

“…To the best of our knowledge, compounds 1 and 2 are rare examples of diterpenoid heterodimers from the family Euphorbiaceae 36 . Plausible biosynthetic pathways to 1 and 2 are postulated (Fig.…”

Bioactive Natural Spirolactone-Type 6,7-seco-ent-Kaurane Diterpenoids and Synthetic Derivatives

“…Besides natural products, natural product-derived compounds are also important to cancer therapy [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. It is well known that diterpenoids are structurally diverse and widely distributed natural compounds, they have attracted interest from the scientific community because of their unique skeletons and therapeutic effects—antitumor [ 12 , 13 ], anti-inflammatory [ 14 ], antibacterial [ 15 , 16 ], and so on [ 17 , 18 , 19 , 20 , 21 ]—especially for anticancer agents, such as the most famous anticancer natural compound paclitaxel [ 22 , 23 , 24 , 25 ].…”