O

Elinafide

Ditercalinium

Echinomycin is an antitumor antibiotic isolated from S. echinatus, which consists of two quinoxaline chromophores attached to a cyclic octadepsipeptide ring, with a thioacetal cross-bridge. Because of its potent antitumor activity, this compound has been advanced to several Phase II clinical studies,34,35 although it was eventually withdrawn from further clinical trials because it showed a high toxicity without any marked therapeutic benefit. More recently, echinomycin has been characterized as a very potent inhibitor of the binding of HIF-1 (hypoxia-inducible factor 1) to DNA. This is an interesting feature because HIF-1 is a transcription

FIGURE 7.6 Schematic interaction between a bis-intercalator and DNA.
FIGURE 7.7 Schematic interaction between echinomycin and DNA.

factor that controls genes involved in processes important for tumor progression and metastasis, including angiogenesis, migration, and invasion.36

Several studies have proved that both echinomycin quinoxaline rings bis-intercalate into DNA, with CG selectivity, while the inner part of the depsipeptide establishes hydrogen bonds with the DNA bases of the minor groove region of the two base pairs comprised between the chromophores (Fig. 7.7).37 A calorimet-ric study has proved that the binding reaction is entropically driven, showing that the complex is predominantly stabilized by hydrophobic interactions, although direct molecular recognition between echinomycin and DNA, mediated by hydrogen bonding and van der Waals contacts, also plays an important role in stabilizing the complex.38

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