Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban

Abstract

Centella asiatica accumulates large quantities of pentacyclic triterpenoid saponins, collectively known as centelloids. These terpenoids include asiaticoside, centelloside, madecassoside, brahmoside, brahminoside, thankuniside, sceffoleoside, centellose, asiatic-, brahmic-, centellic- and madecassic acids. The triterpene saponins are common secondary plant metabolites and are synthesized via the isoprenoid pathway to produce a hydrophobic triterpenoid structure (aglycone) containing a hydrophilic sugar chain (glycone). The biological activity of saponins has been attributed to these characteristics. In planta, the Centella triterpenoids can be regarded as phytoanticipins due to their antimicrobial activities and protective role against attempted pathogen infections. Preparations of C. asiatica are used in traditional and alternative medicine due to the wide spectrum of pharmacological activities associated with these secondary metabolites. Here, the biosynthesis of the centelloid triterpenoids is reviewed; the range of metabolites found in C. asiatica, together with their known biological activities and the chemotype variation in the production of these metabolites due to growth conditions are summarized. These plant-derived pharmacologically active compounds have complex structures, making chemical synthesis an economically uncompetitive option. Production of secondary metabolites by cultured cells provides a particularly important benefit to manipulate and improve the production of desired compounds; thus biotechnological approaches to increase the concentrations of the metabolites are discussed.

Figure 1

Aglycone skeletons of pentacyclic (A) steroidal spirostane, (B) steroidal furostane and (C) triterpenoid saponins. The R-group is a sugar moity [16]. Tetracyclic terpenes such as lanosterol, sitosterol and cycloartenol can also be derived from oxidosqualene through a different pathway utilizing cycloartenol synthase (CAS₁) [19].

Figure 2

A simplified scheme of triterpenoid biosynthesis in Centella. Farnesyl diphosphate synthase (FPS) isomerizes isopentyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) to farnesyl diphosphate (FPP), which squalene synthase (SQS) converts to squalene. Squalene epoxidase (SQE) oxidises squalene to 2,3-oxidosqualene. Oxidosqualene cyclase (OSC) enzymes cyclize 2,3-oxidosqualene through cationic intermediates (e.g. dammarenyl cation) to one or more cyclic triterpene skeletons. Other enzymes involved include α/β-amyrin synthases (α/β-AS) which can also form the lupenyl cation but further ring expansion and rearrangements are required before the deprotonation to α/β-amyrin, the precursors of the sapogenins, to generate the products listed in Table 1. Adapted from [19,20].

Figure 3

The model triterpenoid compound from C. asiatica. These triterpenes can occur in the ursane (R₆, R₇ = methyl) or oleanane (R₇, R₈ = methyl) types with double bonds occurring at C₁₂-C₁₃, C₁₃-C₁₈ or C₂₀-C_21.