6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships.
6- and 7-substituted 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones: synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships.
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6-和7-取代的2-[2-(二甲氨基)乙基]-1,2-二氢-3H-二苯并[de,h]异喹啉-1,3-二酮：合成、亲核置换、抗肿瘤活性和定量
DOI：
10.1021/jm950742g
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Remers,WA
中科院分区：
文献类型：
--
作者：
Sami,SM;Dorr,RT;Solyom,AM;Alberts,DS;Iyengar,BS;Remers,WA
合成了新的2-[2‘-(二甲氨基)乙基]-~3H-联苯并[de，h]异喹啉-1，3-二酮。亲核芳香族取代反应是合成中的关键反应。在包括人类黑色素瘤和卵巢癌以及小鼠敏感和多药耐药L1210白血病在内的一组肿瘤细胞中，有10种新化合物比未被取代的化合物氮硫化物更有效。在细胞培养中，它们的心脏毒性也较小。其中四个化合物与MDR白血病没有交叉耐药性，其中一个化合物6-乙氧基偶氮硫化物对实体瘤细胞的作用几乎与白血病细胞一样强。这些化合物对人乳腺、结肠癌和肺癌细胞也有很好的效力，包括对阿霉素和米托蒽醌耐药的细胞系。与氮化物相比，新类似物在体内的优势较小，但6-乙氧基氮化物对小鼠L1210白血病和皮下B16黑色素瘤的疗效更好。尽管未发现细胞内抗肿瘤活性与取代基的物理化学性质的相关性，但6-取代氮杂环胺类化合物的实体瘤细胞和敏感的、耐多药的L1210白血病细胞以及7-取代氮杂氮杂环类化合物的实体瘤细胞的Δ-TM与其抗肿瘤活性有统计学意义的相关性。
New 2-[2‘-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were lessinvivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (ΔTm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.