Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

Abstract

The guaianolide group of sesquiterpene lactones contains a large number of compounds with biological activity. One of these guaianolides, thapsigargin from the genus Thapsia (Apiaceae), has been a subject of particular interest in recent years because of its ability to induce apoptosis, as the active part of a pro-drug, has produced promising results for the targeted treatment of prostate cancer. In this review, recent advances in understanding the biosynthetic pathway of sesquiterpenes in plants is described with a special emphasis on guaianolides, and a hypothetical pathway for the biosynthesis of thapsigargin is presented. Eighty-seven guaianolides from Apiaceae are presented. These compounds provide clues to possible enzymatic mechanisms generating the guaianolides in Apiaceae. Some of these 87 compounds have proven or might prove interesting with regards to their biological activity.

Transcriptome Analysis of Thapsia laciniata Rouy Provides Insights into Terpenoid Biosynthesis and Diversity in Apiaceae

“…The relatively large number of terpene synthases found in T. laciniata roots is in contrast to T. garganica roots, where only two sesquiterpene synthases were found in the transcriptome in a recent study [14]. This is in agreement with the larger chemical diversity of complex terpenoids found in the roots of T. laciniata , which is in accordance with several studies on the chemistry of Thapsia plants [5,6]. The sesquiterpene synthases described here are currently undergoing biochemical characterization.…”

“…The most characteristic constituents of Apiaceae are coumarins and sesquiterpene lactones [2–5], and also irregular terpenoids based on the thapsane carbon skeleton [6]. Several of the irregular terpenoids that have been found in Apiaceae have a structure that cannot be formed from the usual acyclic substrate molecules geranyl diphosphate (GPP, precursors to monoterpenoids), farnesyl diphosphate (FPP, precursors to sesquiterpenoids) and geranylgeranyl diphosphate (GGPP, precursors to diterpenoids) that are biosynthesized through head-tail fusion of IPP units, but are formed from tail-tail or head-head fused IPP units.…”

“…In addition to this class of irregular terpenoids, Thapsia laciniata also contains regular sesquiterpenoids, such a guaienes, germacrenes, cadinenes, humulenes and hydroxylated derivatives thereof, such as oxy-caryophyllenes, and guaianolides (Figure 1B) [1,4,5]. The latter group includes thapsigargin, a major component and bioactive constituent of some Thapsia species.…”

Conditions for a Rh(I)-catalyzed [2+2+1] cycloaddition reaction with methyl substituted allenes and alkynes

“…1,2 Despite their potential value as medicinal agents only one guaianolide, arglabin ( 1 , Figure 1), has been approved as a drug, marketed for lung, liver, and ovarian cancer treatment, 3 and another, thapsigargin ( 2 ), is being developed as a prodrug for prostate cancer. 4 This dearth of medicinally relevant guaianolides is largely due to the presence of one or more α, β-unsaturated carbonyl groups in the substructures of these natural products.…”

“…1 For example, guaianolides commonly have reactive functional groups that require incorporation at a late-stage in the synthetic sequence or alternatively incorporation of the groups at an early-stage, necessitating a series of protecting group manipulations. 6 The former approach limits the number of synthetic strategies available for compound preparation, while the latter approach is not step economical.…”