Leopold W R, Nelson J M, Plowman J, Jackson R C
Cancer Res. 1985 Nov;45(11 Pt 1):5532-9.
A series of 5-[(aminoalkyl)amino]-substituted anthra[1,9-cd] pyrazol-6(2H)ones (anthrapyrazoles) were synthesized. These compounds, which differ from the anthracenediones in that an additional pyrazole ring has been fused to the anthracene system in place of one carbonyl group, were evaluated in vivo for their anticancer activity in eight different mouse tumor systems. Compounds were selected for testing primarily on the basis of their high levels of activity P388 leukemia and occasionally for structural considerations. Sixty-seven % of the 21 analogues studied were curative in the National Cancer Institute P388 screen. Many of the compounds tested were highly active against each of the tumors of the National Cancer Institute panel. Thus 82, 73, 45, and 80% of the compounds tested were curative for L1210 leukemia, B16 melanoma, M5076 sarcoma, and the MX-1 mammary xenograft, respectively. Several of the compounds studied were curative against every tumor of the above panel. Because of the high activity of the anthrapyrazole series as a class in the National Cancer Institute tumor panel, additional testing was necessary to allow selection of clinical candidates. Twenty-one anthrapyrazoles were tested against mammary adenocarcinoma 16C, colon adenocarcinoma 11a, and the Ridgway osteogenic sarcoma. Four compounds, PD 113,309 (Cl-937), PD 113,785 (Cl-941), PD 111,815 (Cl-942), and PD 115,593, were judged superior to the rest on the basis of the expanded panel testing. The preclinical data to date suggest that these anthrapyrazoles are similar to doxorubicin in both degree and spectrum of activity. Each of these anthrapyrazoles were significantly more active than were the other synthetic intercalating agents, the anthracenediones mitoxantrone and ametantrone, against the tumors of the expanded panel. On the basis of their high level of broad spectrum activity in preclinical systems, ease of formulation, possible lack of cross-resistance with doxorubicin, and potential lack of cardiotoxicity, Cl-937, Cl-941, and Cl-942 have been selected for further preclinical evaluation and possible clinical development.
合成了一系列5-[(氨基烷基)氨基]取代的蒽[1,9-cd]吡唑-6(2H)酮（蒽吡唑）。这些化合物与蒽二酮不同，因为在蒽体系中额外的吡唑环取代了一个羰基，在八种不同的小鼠肿瘤模型中对其体内抗癌活性进行了评估。选择化合物进行测试主要基于它们在P388白血病中的高活性水平，偶尔也考虑结构因素。在国家癌症研究所的P388筛选中，所研究的21种类似物中有67%具有治愈性。许多测试的化合物对国家癌症研究所小组的每种肿瘤都具有高活性。因此，所测试的化合物中分别有82%、73%、45%和80%对L1210白血病、B16黑色素瘤、M5076肉瘤和MX-1乳腺异种移植瘤具有治愈性。所研究的几种化合物对上述小组的每种肿瘤都具有治愈性。由于蒽吡唑系列作为一个类别在国家癌症研究所肿瘤小组中具有高活性，因此需要进行额外的测试以选择临床候选药物。对21种蒽吡唑针对乳腺腺癌16C、结肠腺癌11a和里奇韦骨肉瘤进行了测试。根据扩展小组测试，四种化合物，PD 113,309（Cl-937）、PD 113,785（Cl-941）、PD 111,815（Cl-942）和PD 115,593被判定优于其他化合物。迄今为止的临床前数据表明，这些蒽吡唑在活性程度和活性谱方面与阿霉素相似。这些蒽吡唑中的每一种对扩展小组的肿瘤的活性都明显高于其他合成嵌入剂、蒽二酮米托蒽醌和氨甲蒽醌。基于它们在临床前系统中的高广谱活性水平、易于制剂化、可能与阿霉素缺乏交叉耐药性以及潜在的无心脏毒性，Cl-937、Cl-941和Cl-942已被选择进行进一步的临床前评估和可能的临床开发。
