QSAR of acridines, III. Structure-activity relationship for antitumour imidazoacridinones and intercorrelations between in vivo and in vitro tests.

A study on quantitative relationships between the biological activity and physicochemical properties of antitumour 5-alkylaminoimidazoacridinone derivatives was carried out. The activity was based on the results of several in vitro tests as well as experimental antileukaemic therapy. The capacity factor, log k', determined by the reverse-phase HPLC method, was a measure of lipophilic properties. UV and NMR spectra of the compounds were employed to describe electronic parameters. Values of steric descriptors were calculated as topological indexes. Results obtained by means of principal component analysis (PCA) allow us to group biological tests into two subsets: the lipophilicity-dependent and lipophilicity-independent test groups. The highest intercorrelation, R = 0.92, was shown between the optimal dose, pOD, determined in leukaemia P388-bearing mice and cytotoxicity expressed as pEC50 in leukaemia cells. The equation describing this relationship could be applied to predict the therapeutic doses of imidazoacridinone derivatives which would be effective in experimental antileukaemic therapy. The quantitative structure-activity relationship (QSAR) study showed that lipophilic properties significantly influence cytotoxicity, pEC50, and antileukaemic potency, pOD, only in the case of 8-hydroxy analogues of imidazoacridinones, whereas the activity of the remaining derivatives is very low and does not depend on lipophilicity. Electronic resonance properties seem to influence this specific impact of lipophilicity on the biological activity of 8-hydroxy derivatives. Hence, it may be possible to improve the antitumour activity of 8-hydroxyimidazoacridinones by obtaining more hydrophilic derivatives, up to the optimal value of the lipophilic parameter.