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

Susanne Kirchner, Anna-Lena Leistner, Peter Gödtel, Angelika Seliwjorstow, Sven Weber, Johannes Karcher, Martin Nieger and Zbigniew Pianowski ()
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Susanne Kirchner: Institute of Organic Chemistry, Karlsruhe Institute of Technology
Anna-Lena Leistner: Institute of Organic Chemistry, Karlsruhe Institute of Technology
Peter Gödtel: Institute of Organic Chemistry, Karlsruhe Institute of Technology
Angelika Seliwjorstow: Institute of Organic Chemistry, Karlsruhe Institute of Technology
Sven Weber: Institute of Organic Chemistry, Karlsruhe Institute of Technology
Johannes Karcher: Institute of Organic Chemistry, Karlsruhe Institute of Technology
Martin Nieger: University of Helsinki
Zbigniew Pianowski: Institute of Organic Chemistry, Karlsruhe Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33750-7

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