Structure–Activity Relationships of Photoswitchable Diarylethene-Based β‑Hairpin Peptides as Membranolytic Antimicrobial and Anticancer Agents

Five series (28 structures)
of photoswitchable β-hairpin
peptides were synthesized based on the cyclic scaffold of the natural
antibiotic gramicidin S. Cell-type selectivity was compared for all
activated (diarylethene “ring-open”) and deactivated
(“ring-closed”) forms in terms of antibacterial activity
(MIC against Escherichia coli and Bacillus subtilis), anticancer activity (IC50 against HeLa cell line), and hemolytic cytotoxicity (HC50 against human erythrocytes). Correlations between the conformational
plasticity of the peptides, their hydrophobicity, and their bioactivity
were also analyzed. Considerable improvements in selectivity were
achieved compared to the reference compound. We found a dissociation
of the anticancer activity from hemolysis. Phototherapeutic indices
(PTI), HC50(closed)/MIC­(open) and HC50(closed)/IC50(open), were introduced for the peptides as safety criteria.
The highest PTI for HeLa-selective toxicity were observed among analogues
containing hydroxyleucine on the hydrophobic face. For one compound,
high PTIs were demonstrated across a range of different cancer cell
lines, including a doxorubicin-resistant one.