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 1H 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 hetero-association. The magnitudes of parameters (equilibrium reaction constants, enthalpy (ΔH) and entropy (ΔS)) 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) l mol−1 and for hetero-association with CAF is 256 (±30) l 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.