Design and synthesis of pironetin analogues with simplified structure and study of their interactions with microtubules

The preparation of a series of pironetin analogues with simplified structure is described. Their cytotoxic activity and their interactions with tubulin have been investigated. It has been found that, while less active than the parent molecule, the pironetin analogues still share the mechanism of action of the latter and compete for the same binding site to α-tubulin. Variations in the configurations of their stereocenters do not translate into relevant differences between biological activities.

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► Pironetin analogues having a simplified structure are less cytotoxic than the parent compound but are still able to block the cell cycle in the G2/M phase.
► Pironetin analogues having a simplified structure still retain the ability of the parent compound to bind to the same alfa-tubulin site.
► Pironetin analogues having a simplified structure inhibit in vitro tubulin assembly.
► Pironetin analogues having a simplified structure disrupt cellular microtubule cytoskeleton.