1H NMR structural and thermodynamical analysis of the hetero-association of daunomycin and novatrone in aqueous solution

The complexation of antitumour antibiotics novatrone (NOV) and daunomycin (DAU) in aqueous solution has been studied by one- and two-dimensional 1H-NMR spectroscopy (500 MHz) in order to elucidate the probable molecular mechanism of the action of aromatic antitumour drugs in combination chemotherapy. The equilibrium reaction constants, thermodynamical parameters (DH, DS) of hetero-association of NOV with DAU and the limiting values of proton chemical shifts of the molecules in the hetero-complexes have been determined from the experimental concentration and temperature dependences of proton chemical shifts of the aromatic molecules. The most favourable structure of the 1:1 NOV–DAU heteroassociation complex has been determined using both the molecular mechanics methods (X-PLOR software) and the limiting values of proton chemical shifts of the molecules. The obtained results have shown that intermolecular complexes between NOV and DAU molecules are mainly stabilized by stacking interactions of the aromatic chromophores. It is likely that there is an additional stabilization of the NOV–DAU hetero-complexes by intermolecular hydrogen bonds. It is concluded that aromatic molecules of antibiotics may form energetically stable hetero-association complexes in aqueous solution and hence effect their medical–biological (and probably toxic) activity. q 2004 Elsevier B.V. All rights reserved