Synthesis, Chiral Separation, Absolute Configuration Assignment, and Biological Activity of Enantiomers of Retro-1 as Potent Inhibitors of Shiga Toxin

The Shiga toxin (Stx) family is composed of related protein toxins produced by the bacteria Shigella dysenteriae and certain pathogenic strains of E. coli. No effective therapies for Stx intoxication have been developed yet. However, inhibitors that act on the intracellular trafficking of these toxins may provide new options for the development of therapeutic strategies. This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of Retro‐1, a compound active against Stx and other such protein toxins. Retro‐1 works by inhibiting retrograde transport of these toxins inside cells. In vitro experiments proved that the configuration of the stereocenter at position 5 is not crucial for the activity of this compound. X‐ray diffraction data revealed (S)‐Retro‐1 to be slightly more active than (R)‐Retro‐1. Stopping traffic: We report the synthesis of Retro‐1 and the separation of its enantiomers. Our data demonstrate that the stereochemistry is not crucial for this compound′s activity, as both enantiomers are active at protecting cells against Shiga toxin. Nevertheless, the absolute stereochemistry of the eutomer was assigned by X‐ray diffraction data; (S)‐Retro‐1 is slightly more active than the R isomer.