Gliotoxin: nature's way of making the epidithio bridge.

Alkaloids containing a central bicyclo[n.2.2]piperazinedione (diketopiperazine, DKP, n 2) ring system, bridged at positions 3 and 6, constitute an ever-growing class of secondary metabolites. DKPs 1, biosynthesized from amino acids either by nonribosomal peptide synthases (NRPS) or by tRNA-dependent enzymes called cyclodipeptide synthases (CDPS), are the central precursors, from which diverse alkaloids with different bridge types and sizes arise through further enzymatic transformations (Figure 1). Such alkaloids include the prenylated indole alkaloids such as brevianamide A (2) and the unusual antibiotic bicyclomycin (3). Oxidative modifications of 1 also provide structurally diverse natural sulfur compounds named epipolythiodioxopiperazines (ETPs), such as gliotoxin (4) or other higher order ETP alkaloids, such as 5 or 6. Gliotoxin (4), isolated in 1943, was the first member of the ETP class and bridged DKP alkaloids in general. Its structure remained incorrectly assigned until 1958, when Woodward and co-workers suggested the correct, but unprecedented at that time, structure incorporating a disulfide bridge. The wide range of biological properties, such as antiviral, antibacterial, and immunosuppressive activities, are all presumed to be a direct consequence of the reactivity of the epidithio bridge (Scheme 1), which is capable of generat-