Antitumor activity, X-ray crystal structure, and DNA binding properties of thiocoraline A, a natural bisintercalating thiodepsipeptide

Abstract

The marine natural product thiocoraline A displayed approximately equal cytotoxic activity at nanomolar concentrations in a panel of 12 human cancer cell lines. X-ray diffraction analyses of orthorhombic crystals of this DNA-binding drug revealed arrays of docked pairs of staple-shaped molecules in which one pendent hydroxyquinoline chromophore from each cysteine-rich molecule appears intercalated between the two chromophores of a facing molecule. This arrangement is in contrast to the proposed mode of binding to DNA that shows the two drug chromophores clamping two stacked base pairs, in agreement with the nearest-neighbor exclusion principle. Proof of DNA sequence recognition was obtained from both classical DNase I footprinting experiments and determination of the melting temperatures of several custom-designed fluorescently labeled oligonucleotides. A rationale for the DNA-binding behavior was gained when models of thiocoraline clamping a central step embedded in several octanucleotides were built and studied by means of unrestrained molecular dynamics simulations in aqueous solution.