Comparative phytochemistry of flavaglines (= rocaglamides), a group of highly bioactive flavolignans from Aglaia species (Meliaceae)

Abstract

Flavaglines are formed by cycloaddition of a flavonoid nucleus with a cinnamic acid moiety representing a typical chemical character of the genus Aglaia of the family Meliaceae. Based on biosynthetic considerations 148 derivatives are grouped together into three skeletal types representing 77 cyclopenta[b]benzofurans, 61 cyclopenta[bc]benzopyrans, and 10 benzo[b]oxepines. Apart from different hydroxy, methoxy, and methylenedioxy groups of the aromatic rings, important structural variation is created by different substitutions and stereochemistries of the central cyclopentane ring. Putrescine-derived bisamides constitute important building blocks occurring as cyclic 2-aminopyrrolidines or in an open-chained form, and are involved in the formation of pyrimidinone flavaglines. Regarding the central role of cinnamic acid in the formation of the basic skeleton, rocagloic acid represents a biosynthetic precursor from which aglafoline- and rocaglamide-type cyclopentabenzofurans can be derived, while those of the rocaglaol-type are the result of decarboxylation. Broad-based comparison revealed characteristic substitution trends which contribute as chemical markers to natural delimitation and grouping of taxonomically problematic Aglaia species. A wide variety of biological activities ranges from insecticidal, antifungal, antiprotozoal, and anti-inflammatory properties, especially to pronounced anticancer and antiviral activities. The high insecticidal activity of flavaglines is comparable with that of the well-known natural insecticide azadirachtin. Comparative feeding experiments informed about structure–activity relationships and exhibited different substitutions of the cyclopentane ring essential for insecticidal activity. Parallel studies on the antiproliferative activity of flavaglines in various tumor cell lines revealed similar structural prerequisites that let expect corresponding molecular mechanisms. An important structural modification with very high cytotoxic potency was found in the benzofuran silvestrol characterized by an unusual dioxanyloxy subunit. It possessed comparable cytotoxicity to that of the natural anticancer compounds paclitaxel (Taxol®) and camptothecin without effecting normal cells. The primary effect was the inhibition of protein synthesis by binding to the translation initiation factor eIF4A, an ATP-dependent DEAD-box RNA helicase. Flavaglines were also shown to bind to prohibitins (PHB) responsible for regulation of important signaling pathways, and to inhibit the transcriptional factor HSF1 deeply involved in metabolic programming, survival, and proliferation of cancer cells. Flavaglines were shown to be not only promising anticancer agents but gained now also high expectations as agents against emerging RNA viruses like SARS-CoV-2. Targeting the helicase eIF4A with flavaglines was recently described as pan-viral strategy for minimizing the impact of future RNA virus pandemics.

In silico study on the Hepatitis E virus RNA Helicase and its inhibition by silvestrol, rocaglamide and other flavagline compounds

“…This ancillary mechanism, which deserves www.nature.com/scientificreports/ further investigation with high priority, was found plausible also for other RCG/SLV-like compounds and may complement the already reported activity of this HEV impairing agents on host RNA Helicases. Furthermore, there are evidence reporting SLV as well-tolerated in animals 40 making it an interesting candidate as a feed additive. The described methodology, starting from the template selection moving to the actual modelling and testing, succeeded to build a reliable model able to qualitatively discriminate several ligands.…”

“…For the sake of identifying compounds with potential anti-viral properties, the model was targeted with natural bioactive compounds belonging to the cyclopenta[b]benzofuran/flavagline class to identify promising candidates to test in further dedicated investigations. This class of compounds has been described to have a broad spectrum of activity including insecticidal, antifungal, anti-inflammatory and anticancer activities to cite but a few 40 . However, the mechanisms of action underpinning those activities still need to be clarified, though RCG and other flavagline analogues proved to target prohibitins and to exert inhibitory activity towards RNA Helicases 27 .…”

Discovery of Anticancer Agents of Diverse Natural Origin

“…The structure and absolute configuration of this rare dioxanyl-ring-containing cyclopenta­[ b ]­benzofuran were reported initially in 2004 as a constituent of Aglaia foveolata (Meliaceae) from our work conducted at UIC, and then it was shown to be active in several cancer-related in vivo test systems at OSU . Recently, Greger has reviewed in detail the comparative phytochemistry of the rocaglate (flavagline) derivatives isolated from the genus Aglaia . Crucially, at McGill University in Montreal, silvestrol was determined to act mechanistically as a protein translation inhibitor by acting on eIF4A, which is an RNA helicase subunit of the eIF4F complex .…”

In silico, biochemical, and in vitro analysis of silvestrol binding to the DEAD box RNA helicase eIF4A reveals broad anti-pathogen potential of rocaglates across the eukaryotic tree of life

“…Over 200 natural and synthetic rocaglates have been described since rocaglamide A (RocA) was first isolated from Asian mahogany (Aglaia sp.) in 1982 [15][16][17][18]. Besides eIF4A, only two other molecular targets of rocaglates have been identified, albeit neither of them has been shown so far to be central to cell viability: the RNA helicase DEAD-box polypeptide 3 (DDX3), which facilitates translation of mRNAs with highly stable RNA secondary structures at the terminal part of the 5'UTR, and Prohibitins 1 and 2 (PHB1; PHB2), which as a complex contribute to the regulation of mitochondrial activity [19,20].…”