Anthracycline mechanisms in analogue selection

Several simple test methods that revealed alterations in mechanisms of action proved to be useful in the selection of three new anthracycline analogues that are currently in preclinical development. 5-Iminodaunorubicin is a quinone-modified analogue, and the resultant suppression of quinone redox cycling appears to correlate with diminished cardiotoxicity rather than with any effect on antitumour activity. N,N-Dibenzyldaunorubicin is an inactive prodrug requiring metabolic activation, a process that appears to give some selectivity of action leading to improved activity. The cyanomorpholino derivative of doxorubicin shows an intense potency against tumours that is not encountered in other closely-related analogues, indicating a highly specific mode of action as yet unidentified. Results with these examples suggest that simple tests related to mechanisms of action may be more useful for analogue selection than extended tests to define antitumour activity.