Use of triethylene glycol to mimic oligosaccharides: Design and synthesis of a ligand based on chromomycin A 3

Abstract

Chromomycin A 3 (CRA 3) is an antitumor antibiotic that binds to DNA. It contains an acac-like metal binding site and forms a 2:1 complex with Mg 2+. Interestingly, acac ligands similar to CRA 3 form 1:1 complexes with Mg 2+. We have previously shown that the unusual stability of the 2:1 CRA 3-Mg 2+ complex is related to a favorable intermolecular interaction between the CDE trisaccharide of one CRA 3 molecule and the chromophore of the other. We have used this knowledge to design and synthesize a very simple molecule in which a triethylene glycol chain mimics the CDE trisaccharide of CRA 3. This minimalist ligand behaves like CRA 3 with respect to dimer formation. This result sheds light on how the CRA 3 sugars function to stabilize the dimer. At the same time, the work provides a starting point for investigating the relationship between dimer formation and DNA binding. Starting from these relatively simple metal complexes, it should be possible to develop a better understanding of the structural requirements for DNA binding by CRA 3 and related molecules.