Design, biochemical pharmacology, electrochemistry and tumour biology of anti-tumour anthrapyrazoles.

Abstract

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Selected biochemistry, electrochemistry and tumour biology were carried out for a series of compounds possessing the same upper and lower side chains but with varying A-ring hydroxylation patterns. The anthrapyrazoles bind strongly to DNA, are selective and potent inhibitors of DNA synthesis and cause the formation of single-strand breaks in DNA. They also induced far less (20-200-fold) superoxide dismutase-sensitive oxygen consumption than doxorubicin in the rat liver microsomal system, a property that may be indicative of reduced cardiotoxicity. This result is in accord with their polarographic properties in which the anthrapyrazoles show a much greater resistance to reduction (E'1/2 = -0.983- -1.085 V) relative to daunorubicin (E'1/2 = -0.625 V) and mitoxantrone (E'1/2 = -0.775 V). The anthrapyrazoles demonstrate high levels of activity against a broad range of murine tumours in vivo including the P388 leukaemia and mammary adenocarcinoma 16c lines detailed in this study.