Synthetic Diastereomers of the Fungal Cycloheptapeptide Paraisariamide A Retain Ternatin-Like Biological Activity.

Paraisariamides (Psds) are a family of fungal N-methylated cyclic heptapeptides with structural similarity to the translation eukaryotic elongation factor 1A inhibitor ternatin. Initial characterization of the eight known Psds A-H revealed a complex biological activity profile; Psd A and Psds E-H showed differential cytotoxicity to HCT116 colon cancer cells, whereas Psds B-D were inactive. Here, we report that Psd A is a weak inhibitor of total protein synthesis and that three synthetic diastereomers of Psd A retain comparable pharmacological activity. Psd A and all structural variants decreased the level of expression of extracellular Gaussia luciferase in a phenotypic assay that senses endoplasmic reticulum stress in living cells. Inhibition of cellular secretion was fully reversible; however, the three Psd A diastereomers were all eventually cytotoxic to HCT116 colon cancer cells. The stereochemistry of Psd A, a weak cytotoxin relative to Psds E-H, is anticipated to inform future structure-activity relationship studies of these ternatin-like molecules.