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 correlati on NMR spectroscopy (2D TOCSY and 2D ROESY) has been used for complete assi gnment of proton signals and for a qualitative analysis of the mutual arran gements of the aromatic drug molecules in the aggregates. The structural an d thermodynamical parameters of molecular self- and hetero-association of t he aromatic compounds have been determined from measurements of the NMR che mical shifts of the drug protons as a function of concentration and tempera ture. The self-association of NOV has been analysed using both the indefini te cooperative and non-cooperative models, and the hetero-association of NO V and CAF has been analysed in terms of a statistical-thermodynamical model , in which molecules form indefinite aggregates for both self- and heteroas sociation. The magnitudes of parameters (equilibrium reaction constants, en thalpy (DeltaH) and entropy (DeltaS)) have been calculated for self-associa tion of NOV and its complexation with CAF; at 318 K the equilibrium constan t for self-association of NOV is 12400 (+/-4000) 1 mol(-1) and for hetero-a ssociation with CAF is 256 (+/-30) 1 mol(-1), The most favourable structure s 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.