Showalter H D, Johnson J L, Hoftiezer J M, Turner W R, Werbel L M, Leopold W R, Shillis J L, Jackson R C, Elslager E F
J Med Chem. 1987 Jan;30(1):121-31. doi: 10.1021/jm00384a021.
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. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.
对与米托蒽醌相关的蒽二酮进行发色团修饰，以期获得心脏毒性减弱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。它们的合成是通过一个两步缩合序列进行的，起始原料为所需的1,4 - 或1,5 - 二氯 - 9,10 - 蒽二酮前体。与单烷基肼反应得到氯代蒽吡唑中间体，该中间体随后与伯胺或仲胺缩合，得到目标“双臂”蒽吡唑类化合物。A环7,10 - 二羟基蒽吡唑类化合物可通过胺与中间体5 - 氯 - 7,10 - 二羟基蒽吡唑缩合得到，或者由中间体5 - 氯 - 7,10 - 双(苄氧基)蒽吡唑经苄基保护基团氢解得到目标化合物。在体外对小鼠L1210白血病（IC50 = 10(-7)-10(-8) M）以及在体内对多种结构变体的P388白血病均显示出强效的体外活性。一般来说，对P388细胞系的活性在N - 2和C - 5位具有碱性侧链、侧链近端和远端氮原子之间有两到三个碳间隔以及A环羟基化时达到最大。除了对P388细胞系具有治愈活性外，活性更强的化合物在体内对小鼠B - 16黑色素瘤也具有治愈活性。基于其卓越的体内抗癌活性，本研究报道的A环二羟基化合物71和74已被选作开展临床试验的研发对象。
