In this work the reductive cleavage of several anthracyclines and their analogues, substituted 9,10-anthraquinones, will be examined with a view to establishing the mode of action of these antitumor agents. At present, there is uncertainty regarding the precise mechanism whereby anthroacyclines function as antitumor agents. The overall objectives of this study are two-fold. First, efforts will be directed towards identifying the intermediate that actually undergoes cleavage in aqueous media. Both the hydroquinone and semiquinone derived from anthracyclines have been postulated in the literature. Preliminary work in this laboratory has shown that hydroquinones of several analogues cleave slowly in comparison to their conjugate bases. Second, rate constants for reductive cleavage of anthracyclines and their analogues in both protoic and aprotic media will be measured using electrochemical techniques and UV/visible spectroscopy. It is anticipated that this project will provide a better understanding of reductive cleavage processes and thereby provide a basis for the synthesis of anthracyclines and related compounds that function as superior drugs.
