Synthesis and antiproliferative evaluation of L-amino acid-6-gliotoxin ester trifluoroacetates

This study aimed to develop gliotoxin derivatives with high yield and low toxicity through fermentation optimisation and structural modification. First, the culture conditions were optimised, resulting in a yield of 208 mg L^-1. Subsequently, 17 new salt-type derivatives were synthesised by introducing amino acid esters at the 6-position. These compounds retained the essential disulphide pharmacophore while exhibiting significantly reduced toxicity towards normal GES-1 cells. Representative compounds 3b and 3e exhibited good inhibitory activity against breast cancer MCF-7 and oesophageal cancer ECa-109 cells. This work provides a comprehensive example, from fermentation to structural optimisation, for developing antitumor lead compounds based on fungal toxins.