Triostin A derived hybrid for simultaneous DNA binding and metal coordination

Abstract

The natural product triostin A is known as an antibiotic based on specific DNA recognition. Structurally, a bicyclic depsipeptide backbone provides a well-defined scaffold preorganizing the recognition motifs for bisintercalation. Replacing the intercalating quinoxaline moieties of triostin A by nucleobases results in a potential major groove binder. The functionalization of this DNA binding triostin A analog with a metal binding ligand system is reported, thereby generating a hybrid molecule with DNA binding and metal coordinating capability. Transition metal ions can be placed in close proximity to dsDNA by means of non-covalent interactions. The synthesis of the nucleobase-modified triostin A analog is described containing a propargylglycine for later attachment of the ligand by click-chemistry. As ligand, two [1,4,7]triazacyclononane rings were bridged by a phenol. Formation of the proposed binuclear zinc complex was confirmed for the ligand and the triostin A analog/ligand construct by high-resolution mass spectrometry. The complex as well as the respective hybrid led to stabilization of dsDNA, thus implying that metal complexation and DNA binding are independent processes.

Fig. 1

Structures of triostin A (1), TANDEM (2), aza-TANDEM (3), and hybrid of the nucleobase substituted aza-TANDEM 4 with a ligand capable of forming binuclear transition metal complexes

Scheme 1

Ligation of the aza-TANDEM scaffold 5 with ligand 6 by means of copper-mediated [3 + 2] cycloaddition

Scheme 2

Synthesis of the propargylglycine-functionalized aza-TANDEM analog 5

Scheme 3

Synthesis of the metal chelating building block 6 and unprotected ligand 16

Fig. 2

High-resolution MS of complex 19 (left) in comparison with the respective isotopic distribution obtained by calculation (right)

Fig. 3

UV-melting curves of DNA 20 with the hybrid molecule 4 and the respective binuclear zinc complex 19 (2 μM DNA 20, 2 mM HEPES, pH 7.0, 10 mM NaCl)