Formation of Bridged Disulfide in Epidithiodioxopiperazines.

Abstract

Epidithiodioxopiperazine (ETP) alkaloids, featuring a 2,5-diketopiperazine core and transannular disulfide bridge, exhibit a broad spectrum of biological activities. However, the structural complexity has prevented efficient chemical synthesis and further clinical research. In the past few decades, many achievements have been made in the biosynthesis of ETPs. Here, we discuss the biosynthetic progress and summarize them as two comprehensible metabolic principles for better understanding the complex pathways of α, α'- and α, β'-disulfide bridged ETPs. Specifically, we systematically outline the catalytic machineries to install α, α'- and α, β'-disulfide by flavin-containing oxygenases. This concept would contribute to the medical and industrial applications of ETPs.