Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids

Abstract

Over eight different families of natural products consisting of nearly 70 secondary metabolites that contain the bicyclo[2.2.2]diazaoctane ring system have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy.

Chemodiversity in the genus Aspergillus

“…Halotolerance or xerotolerance is also reflected in the halotolerant Polypaecilum pisci being transferred to Aspergillus pisci, and Basipetospora halophile = Oospora halophile = Scopulariopsis halophilica = Phialosimplex halophila (Pitt and Hocking 1985;Greiner et al 2014) being transferred to Aspergillus baarnensis and Phialosimplex salinarum obviously also to be transferred to Aspergillus . Subgenus Circumdati and and its sister subgenus Nidulantes are closely related, for example hülle cells, aflat o x i n s , k o j i c a c i d , i n d o l e d i t e r p e n e s , a n d bicyclo[2.2.2]diazaoctanes are found in both subgenera (Raper and Fennell 1965;Yaguchi et al 1994;Varga et al 2009;Finefield et al 2012;Cai et al 2013). Some known secondary metabolites, present in cladistically different sections of Aspergillus, are shown in Fig.…”

“…The bioactive bicyclo[2.2.2]diazaoctanes, such as aspergamides, stephacidins, aspergillimides and notoamides are produced by several species in closely related sections Circumdati, Nigri and Candidi (Finefield et al 2012;Cai et al 2013), but also by species in subgenus Nidulantes section Versicolores (Finefield et al 2012;Kato et al 2015). Some Aspergillus species produce both enantiomers of these bicyclo[2.2.2]diazaoctanes, and in some cases, the final biosynthetic product is only of one configuration (Kato et al 2015).…”

Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit. Heterointermediate reaction sequences toward the asperparalines and stephacidins

“…To date, nearly 70 secondary metabolites containing this central core structure have been isolated from various species of fungi, which is a testament to nature's ability to create diverse structures using a limited number of building blocks such as proline, tryptophan, and dimethylallyl pyrophosphate (DMAPP) [1]. The members of this superfamily of alkaloids include subfamilies like the brevianamides I, asperparalines II, paraherquamides III, having an attached five-membered ring, or the stephacidins IV, malbrancheamides V, or the recently isolated taichunamides VI [2] with an attached sixmembered ring to the common diazabicyclo[2.2.2]octane core (Figure 1).…”

EVOLUTION IN CHEMOTHERAPY OF HUMAN AND ANIMAL HELMINTHIASES (review)

“…Interaction of monepantel with nematode-specific nAChR Hco-MPTL-1 leads to dysfunction of this receptor which paralyzes helminth's muscles (84,85). Derquantel is semisynthetic derivative of paraherquamide A isolated from natural spiroindoles -products of Penicillium paraherquei (86,87). Derquantel inhibits nAChR (88), it has a broad spectrum of anthelmintic actions; the mixture derquantel-abamectin is often used in treatment and control of various nematodes in the gastrointestinal tract (even ones resistant to other drugs), which allows to expect finding anthelmintic properties in similar compounds.…”