Design, biochemical pharmacology, electrochemistry and tumour biology of anti-tumour anthrapyrazoles.
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.
D000818:Animals; D018943:Anthracyclines; D000880:Anthraquinones / Q000494:pharmacology / Q000633:toxicity; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004563:Electrochemistry; D005453:Fluorescence; D006321:Heart / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology / Q000633:toxicity; D012313:RNA / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
D018943:Anthracyclines; D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; D013481:Superoxides; D012313:RNA; D004247:DNA; C055925:anthrapyrazole