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首页> 外文期刊>Bioorganic and Medicinal Chemistry >3-Aminomethyl derivatives of 4,11-dihydroxynaphtho(2,3-f)indole-5,10-dione for circumvention of anticancer drug resistance.
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3-Aminomethyl derivatives of 4,11-dihydroxynaphtho(2,3-f)indole-5,10-dione for circumvention of anticancer drug resistance.

机译：4,11-二羟基萘并（2,3-f）吲哚-5,10-二酮的3-氨基甲基衍生物，用于规避抗癌药耐药性。

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摘要

A series of 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione was synthesized by Mannich reaction or by the transamination of 3-dimethylaminomethyl 4,11-dihydroxy- or 4,11-dimethoxynaphtho[2,3-f]indole-5,10-dione. The potency of novel derivatives was tested on a National Cancer Institute panel of 60 human tumor cell lines as well as in cells with genetically defined determinants of cytotoxic drug resistance, P-glycoprotein (Pgp) expression, and p53 inactivation. Mannich derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione with an additional amino function in their side chain, demonstrated equal cytotoxicity against the parental K562 leukemia cells and their Pgp-positive subline, whereas the latter showed approximately 7-fold resistance to adriamycin, a Pgp transported drug. 3-(1-Piperazinyl)methyl and 3-(quinuclidin-3-yl)aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione killed HCT116 colon carcinoma cells (carrying wild type p53) and their p53-null variant within the similar range of concentrations. We conclude that Mannich modification of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione, especially when cyclic diamine (e.g., piperazine, quinuclidine) is used, confers an important feature to the resulting compounds, namely, the potency for tumor cells otherwise resistant to a variety of anticancer drugs.
机译：通过曼尼希反应或3-二甲基氨基甲基4,11-二羟基-或4,11的氨基转移反应合成了一系列4,11-二羟基萘[2,3-f]吲哚-5,10-二酮的3-氨基甲基衍生物。 -二甲氧基萘并[2,3-f]吲哚-5,10-二酮。在国家癌症研究所的60个人类肿瘤细胞系以及具有细胞毒性药物抗药性，P-糖蛋白（Pgp）表达和p53失活的基因决定因素的细胞中测试了新型衍生物的效价。 4,11-二羟基萘并[2,3-f]吲哚-5,10-二酮的曼尼希衍生物在侧链具有额外的氨基功能，对亲代K562白血病细胞及其Pgp阳性亚系表现出相同的细胞毒性，而后者对Pgp转运药物阿霉素的抵抗力约为7倍。 4,11-二羟基萘[2,3-f]吲哚-5,10-二酮杀死的HCT116结肠癌细胞（携带野生型p53）的3-（1-哌嗪基）甲基和3-（奎宁环烯基-3-基）氨基甲基衍生物）及其在相似浓度范围内的p53-null变体。我们得出的结论是，特别是当使用环状二胺（例如，哌嗪，奎尼丁）时，曼尼希对4,11-二羟基萘并[2,3-f]吲哚-5,10-二酮的修饰赋予了重要的特征，即，对肿瘤细胞的效力，否则对多种抗癌药物具有抵抗力。

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