Project 7: Viriditoxin Derivatives

Viriditoxin (VDT) is a classic fungal secondary metabolite of a C-6/C-6’ linked dimeric naphthopyranone. It exhibits intriguing biological activities, initially identified as a potent antibacterial agent through its inhibition of the bacterial protein FtsZ. Subsequently, VDT was explored as a moderate tubulin inhibitor in various solid tumor cell lines.

Notably, recent research has uncovered VDT’s therapeutic potential in leukemia and lymphoma cells in contrast to solid tumor cells, but only low cytotoxic effects in human hematopoietic stem cells and peripheral blood lymphocytes. The mechanism of VDT to directly activate the mitochondrial apoptosis pathway represents a promising therapeutic approach for the treatment of therapy-resistant leukemia and lymphoma.

Our ongoing research not only focuses on elucidating the molecular mechanism of VDT but also involves the isolation and characterization of novel VDT derivatives from endophytic fungi. The absolute configurations of all isolated derivatives are determined and correlated with their bioactivity to gain deeper insights into their structure–activity relationship (SAR). Additionally, to generate novel VDT analogs, OSMAC (One Strain, Many Compounds) and precursor feeding approaches are employed to activate silent biosynthetic gene clusters and enhance the chemical diversity of secondary metabolites.