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首页> 外文期刊>Anti-Cancer Drug Design >5,7-Disubstituted analogues of the mixed topoisomerase I/II poison N-(2-(dimethylamino)ethyl)acridine-4-carboxamide (DACA): DNA binding and patterns of cytotoxicity.
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5,7-Disubstituted analogues of the mixed topoisomerase I/II poison N-(2-(dimethylamino)ethyl)acridine-4-carboxamide (DACA): DNA binding and patterns of cytotoxicity.

机译：混合拓扑异构酶I / II的5,7-二取代类似物会毒化N-（2-（二甲基氨基）乙基）ac啶-4-羧酰胺（DACA）：DNA结合和细胞毒性模式。

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摘要

DACA is a DNA-intercalating agent and dual topoisomerase (topo) I/II inhibitor currently in clinical trial as an anticancer drug. Substitutions in the acridine ring of DACA have significant effects on biological activity, with 5-substituted analogues being more potent but relatively less active against cell lines that underexpress topo II, and the converse for 7-substituted analogues. A small series of 5,7-disubstituted analogues was therefore prepared and evaluated. The compounds were prepared by CDI-assisted coupling of the appropriate acridine acids. When these contained no or only one halogen atom, they could be prepared by Al/Hg amalgam reduction of the corresponding acridine acids. However, this method could not be used to prepare dihalogen-substituted acridine acids due to substantial dehalogenation, and these intermediates were synthesized via cyclization of the appropriate aldehydes to give the acridines directly. These compounds showed enhanced DNA binding compared with the parent DACA, indicating that the known favourable influence of 5-substituents on DNA binding is retained. Cell line studies showed that the 5,7-disubstituted compounds retained both the broad-spectrum effectiveness of the 7-monosubstituted analogues and the higher cytotoxic potency of the 5-monosubstituted analogues. The 7-chloro-5-methyl and 5-chloro-7-methyl analogues showed comparable in vivo antitumour activity to DACA in the subcutaneous colon 38 model, but were substantially more potent (optimal doses of 60 mg/kg compared with 200 mg/kg for DACA).
机译：DACA是一种DNA嵌入剂和双重拓扑异构酶（topo）I / II抑制剂，目前在临床试验中用作抗癌药物。 DACA idine啶环中的取代对生物活性具有显着影响，其中5-取代的类似物对未充分表达topo II的细胞系更有效，但活性相对较低，而7-取代的类似物则相反。因此，制备并评估了少量的5,7-二取代的类似物。通过CDI辅助偶联合适的a啶酸来制备化合物。当它们不包含或仅包含一个卤素原子时，它们可以通过Al / Hg汞齐还原相应的cr啶酸来制备。然而，由于大量的脱卤作用，该方法不能用于制备二卤素取代的a啶酸，这些中间体是通过适当醛的环化合成的，直接得到directly啶。与母体DACA相比，这些化合物显示出增强的DNA结合，表明保留了5-取代基对DNA结合的已知有利影响。细胞系研究表明，5,7-二取代化合物既保留了7-单取代类似物的广谱有效性，又保留了5-单取代类似物的更高细胞毒性。 7-氯-5-甲基和5-氯-7-甲基类似物在皮下结肠38模型中显示出与DACA相当的体内抗肿瘤活性，但效果更强（最佳剂量为60 mg / kg，而200 mg / kg公斤（DACA）。

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