Hemipiperazines – novel peptide-derived thermostable molecular photoswitches

• Applicant: Privatdozent Dr. Zbigniev Pianowski
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation ; Biological and Biomimetic Chemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522704814

Molecular photoswitches are molecules that reversibly change their geometry, polarity and other molecular properties upon irradiation. This effect can be explored for changing biological activity of adjacent pharmacophores. Most common switches are based on the azobenzene, spiropyran, diarylethene, or indigoid scaffold. Upon investigation of plinabulin – a semisynthetic low-nM anticancer drug candidate derived from 2,5-diketopiperazine (DKP) scaffold – we have discovered an interesting photochromic behavior in aqueous solutions. The stable Z-configured plinabulin and its derivatives can photoisomerize to the less stable E isomers upon irradiation with blue, violet or UV light. The E-forms are relatively long-living (t1/2 of several months) and exhibit 2 to 4 orders of magnitude lower cytotoxicity than the stable Z isomers. The Z/E-isomerization is caused by previously unreported photoswitching mechanism on the arylidene-diketopiperazine (“hemipiperazine, HPI”) fragment of plinabulin. Additional structural modification of plinabulin resulted in a photoswitchable fluorophore. In this project, we want to investigate photophysical properties and photochromism of the newly discovered hemipiperazine photoswitch with variable heterocyclic substituents. These results will help us to design heterocyclic plinabulin analogues with improved photophysical properties – for future use in photopharmacology directed to human cancer therapies, and as entirely photoreversible inhibitors of microtubule dynamics for basic research. In parallel, we will investigate photophysical properties and photochromism of newly discovered plinabulin-derived photoswitchable fluorophores, their behavior in aqueous solutions and localization inside living cells, as well as their potential for superresolution microscopy of biological systems. Finally, we want to synthesize a panel of antimicrobial agents containing the HPI chromophore, and investigate photomodulation of their antibiotic activity against non-pathogenic bacteria. In synergy with the ongoing project PI 1124/6-3, we will use photoswitchable hydrogels developed there together with plinabulin derivatives to construct a two-step system for concomitant release and activation of the anticancer agent with high spatiotemporal precision. The overall goal of this project is to demonstrate the scope and limitations of applying the new photochromic HPI motif to modulate biological activity, and to open up a realistic perspective for implementation of these principles into human anticancer and antimicrobial therapies.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Ute Schepers