Showalter H D, Fry D W, Leopold W R, Lown J W, Plambeck J A, Reszka K
Department of Chemistry, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105.
Anticancer Drug Des. 1986 Apr;1(2):73-85.
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.
对与米托蒽醌相关的蒽二酮进行发色团修饰，以期获得心脏毒性降低或无心脏毒性的药物，从而产生了一类新型的DNA结合剂——蒽吡唑类化合物。对一系列具有相同上下侧链但A环羟基化模式不同的化合物进行了选定的生物化学、电化学和肿瘤生物学研究。蒽吡唑类化合物与DNA紧密结合，是DNA合成的选择性强效抑制剂，并能导致DNA单链断裂。在大鼠肝微粒体系统中，它们诱导的超氧化物歧化酶敏感的氧消耗也比阿霉素少得多（20 - 200倍），这一特性可能表明心脏毒性降低。这一结果与它们的极谱性质相符，其中蒽吡唑类化合物相对于柔红霉素（E'1/2 = -0.625 V）和米托蒽醌（E'1/2 = -0.775 V）表现出对还原的更大抗性（E'1/2 = -0.983 - -1.085 V）。蒽吡唑类化合物在体内对多种小鼠肿瘤表现出高水平的活性，包括本研究中详细描述的P388白血病和乳腺腺癌16c细胞系。
