Hemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity

Molecular photoswitches transform light energy into reversible structural changes. Their combination with known pharmacophores often allows for photomodulation of the biological activity. The effort to apply such compounds in photopharmacology as light-activated pro-drugs is, however, hampered by serious activity reduction upon pharmacophore modifications, or limited biostability. Here we report that a potent antimitotic agent plinabulin and its derivatives demonstrate up to 56-fold reversible activity photomodulation. Alternatively, irreversible photoactivation with cyan light can enhance the cytotoxicity up to three orders of magnitude—all without compromising the original activity level, as the original pharmacophore structure is unchanged. This occurs due to the presence of a peptide-derived photoswitchable motif hemipiperazine inside the plinabulin scaffold. Furthermore, we systematically describe photochromism of these thermally stable and biocompatible hemipiperazines, as well as a photoswitchable fluorophore derived from plinabulin. The latter may further expand the applicability of hemipiperazine photochromism towards super-resolution microscopy.