Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity
Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity
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DOI：
10.1021/jm0108092
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发表时间：
2001-09-27
影响因子：
7.3
通讯作者：
Zunino, F
中科院分区：
文献类型：
--
作者：
Dallavalle, S;Ferrari, A;Zunino, F
为了合成潜在的通过抑制拓扑异构酶I(Topo I)发挥作用的抗癌药物，合成了一系列新的喜树碱(CPT)7位氧亚胺甲基衍生物。20S-CPT-7-醛或20S-CPT-7-酮与烷基、芳基、杂芳基、芳基和杂芳基O-取代羟胺的缩合反应。对37个化合物中的24个化合物在0.01-0.3微米的范围内对H460非小细胞肺癌细胞株进行了体外细胞毒活性测试。QSAR分析表明，亲脂性是与细胞毒性相关的主要参数。对DNA-Topo I-药物可裂解复合体的研究表明，细胞毒性和对Topo I的抑制大致平行。氯化钠介导的三元复合体被破坏后DNA裂解的持久性表明，对于最有效的化合物，例如15，其细胞毒性至少部分与复合体的稳定有关，这也得到了DNA-酶复合体在药物处理细胞中的持久性的支持。使用人肺癌异种移植模型，通过与拓扑替康的直接比较，评估了最有效的类似物(15)的体内抗肿瘤效果。在最佳剂量(2-3 mg/kg)范围内，15在抑制肿瘤生长和完全应答率方面的疗效有所改善。
In an attempt to synthesize potential anticancer agents acting by inhibition of topoisomerase I (Topo I) a new series of oxyiminomethyl derivatives in position 7 of camptothecin (CPT) was prepared. The synthesis relied on the condensation of 20S-CPT-7-aldehyde or 20S-CPT-7-ketones with alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl O-substituted hydroxylamines. The compounds were tested for their cytotoxic activity in vitro against H460 nonsmall lung carcinoma cell line, the activity being for 24 out of 37 compounds in the 0.01-0.3 muM range. A QSAR analysis indicated that lipophilicity is the main parameter correlated with cytotoxicity. Investigation of the DNA-Topo I-drug cleavable complex showed a rough parallelism between cytotoxicity and inhibition of Topo I. Persistence of the DNA cleavage after NaCl-mediated disruption of the ternary complex suggests that for the most potent compounds, e.g., 15, the cytotoxicity was at least in part related to stabilization of the complex, as also supported by the persistence of the DNA-enzyme complex in drug-treated cells. The in vivo antitumor efficacy of the most potent analogue (15) was evaluated in direct comparison with topotecan using human lung tumor xenograft models. In the range of optimal doses (2-3 mg/kg), the improved efficacy of 15 was documented in terms of inhibition of tumor growth and rate of complete response.