Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

Abstract

Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

“…Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].…”

“…Moreover, because gliotoxin can be considered as the prototype ETP, studies on gliotoxin can be instrumental in revealing the biosynthetic mechanisms of related ETPs which are biosynthesized by a range of fungi [12]. Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].…”

“…Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].In addition to studying how gliotoxin contributes to organismal virulence, it has also been deployed to explore and reveal novel biochemistry within both fungal and animal cells [15,16]. Thus, we contend that it is the ability of gliotoxin to interfere with so many cellular processes that makes it such a useful tool to access the many important, although occluded, systems interactions within fungi.…”

Enantioselective Synthesis of (−)-Acetylapoaranotin

“…1 Although they are biosynthetically 2 related to diketopiperazines (DKPs)—a widespread and structurally diverse family of natural products produced by plants, bacteria, and fungi 3 —ETPs are exclusively isolated from fungal species. In many cases, they are hypothesized to serve as virulence or defense factors and exhibit various antimicrobial, antiviral, and anticancer activities.…”

Interplay between Gliotoxin Resistance, Secretion, and the Methyl/Methionine Cycle in Aspergillus fumigatus

“…This finding suggests that the ⌬gliG strain retains the ability to maintain cellular SAM levels consistent with those in the wild type upon exogenous gliotoxin exposure, unlike other gli mutants, and consequently is resistant to the growth-inhibitory effects. GliG mediates the conjugation of glutathione (GSH) to a gliotoxin biosynthetic intermediate during synthesis (4,18,44,45). This reaction is effectively inhibited in the ⌬gliG strain; thus, it is possible that in the ⌬gliG strain, surplus GSH can be converted to Hcy and, consequently, SAM through the transsulfuration process, accounting for the maintenance of cellular SAM levels upon the addition of exogenous gliotoxin.…”