H-1-NMR INVESTIGATION OF SELF-ASSOCIATION OF AROMATIC DRUG MOLECULES IN AQUEOUS-SOLUTION - STRUCTURAL AND THERMODYNAMICAL ANALYSIS

Self-association of aromatic drug molecules, proflavine (PF), Acridine Orange (AO), ethidium bromide (EB) and actinomycin D (ActD), in aqueo us salt solution has been studied by one- and two-dimensional 500 MHz H-1 NMR spectroscopy. 2D-COSY and 2D-NOESY measurements were used for complete assignment of proton signals of EB and ActD in solution and f or a qualitative determination of their self-association, i.e. the mut ual arrangement of the drug molecules in the complexes. Concentration and temperature dependences of proton chemical shifts of the drugs hav e been measured. Experimental results have been analysed using indefin ite non-cooperative and cooperative models of molecular self-associati on, enabling the determination of equilibrium reaction constants, para meters of cooperativity, the thermodynamical parameters (enthalpy and entropy) of the self-association reactions and the limiting values of drug proton chemical shifts in the complexes. The most favourable dime r structures of PF, AO, EB and ActD have been constructed using calcul ated values of induced chemical shifts of drug protons in conjunction with intermolecular NOEs. The results show that the drug chromophores have an antiparallel orientation in all the dimers studied.