Self-association of the antitumour agent novatrone (mitoxantrone) and its hetero-association with caffeine

The self-association of the antitumour drug, novatrone, NOV (mitoxantrone) and its hetero-association with caffeine (CAF) have been investigated by 1D and 2D 500 MHz H-1 NMR spectroscopy. Two-dimensional homonuclear correlation NMR spectroscopy (2D TOCSY and 2D ROESY) has been used for complete assignment of proton signals and for a qualitative analysis of the mutual arrangements of the aromatic drug molecules in the aggregates. The structural and thermodynamical parameters of molecular self- and hetero-association of the aromatic compounds have been determined from measurements of the NMR chemical shifts of the drug protons as a function of concentration and temperature. The self-association of NOV has been analysed using both the indefinite cooperative and non-cooperative models, and the hetero-association of NOV and CAF has been analysed in terms of a statistical-thermodynamical model, in which molecules form indefinite aggregates for both self- and heteroassociation. The magnitudes of parameters (equilibrium reaction constants, enthalpy (DeltaH) and entropy (DeltaS)) have been calculated for self-association of NOV and its complexation with CAF; at 318 K the equilibrium constant for self-association of NOV is 12400 (+/-4000) 1 mol(-1) and for hetero-association with CAF is 256 (+/-30) 1 mol(-1), The most favourable structures of the NOV dimer and the 1 : 1 NOV-CAF hetero-association complexes have been determined from the calculated limiting values of the induced chemical shifts of the drug protons.