Synthesis and evaluation of a netropsin–proximicin-hybrid library for DNA binding and cytotoxicity

The proximicins A–C ( 1– 3) are novel naturally occurring γ-peptides with a hitherto unknown 2,4-disubstituted furan amino acid as a core structure. They show a moderate cytotoxic activity and induce upregulation of cell cycle regulating proteins (p53 and p21) and lead to cell cycle arrest in G0/G1-phase. Hybrid molecules combining structural motifs of the proximicins and of netropsin ( 4), a structurally related natural product, seem to have similar effects. Herein we describe the synthesis of a netropsin–proximicin-hybrid library and its evaluation regarding cytotoxicity and minor groove binding activity.