Design, Synthesis, and Conformation–Activity Study of Unnatural Bridged Bicyclic Depsipeptides as Highly Potent Hypoxia Inducible Factor‑1 Inhibitors and Antitumor Agents

By carrying out structural modifications
based on the bicyclic
peptide structure of echinomycin, we successfully synthesized various
powerful antitumor derivatives. The ring conformation in the obtained
compounds was restricted by cross-linking with an unnatural bond.
The prepared derivatives were demonstrated to strongly suppress the
hypoxia inducible factor (HIF)-1 transcriptional activation and hypoxia
induction of HIF-1 protein expression. Particularly, alkene-bridged
derivative 12 exhibited remarkably potent cytotoxicity
(IC50 = 0.22 nM on the MCF-7 cell line) and HIF-1 inhibition
(IC50 = 0.09 nM), which considerably exceeded those of
echinomycin. Conformational analyses and molecular modeling studies
revealed that the biological activities were enhanced following restriction
of the conformation by cross-linking through a metabolically stable
and rigid bridge bond. In addition, we proposed a new globular conformation
stabilized by intramolecular π stacking that can contribute
to the biological effects of bicyclic depsipeptides. The developments
presented in the current study serve as a useful guide to expand the
chemical space of peptides in drug discovery.