Rational design, synthesis, and biological evaluation of bis(pyrimido[5,6,1-de]acridines) and bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as new anticancer agents
Rational design, synthesis, and biological evaluation of bis(pyrimido[5,6,1-de]acridines) and bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as new anticancer agents
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DOI：
10.1021/jm049706k
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发表时间：
2004-10-07
影响因子：
7.3
通讯作者：
Martelli, S
中科院分区：
文献类型：
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作者：
Antonini, I;Polucci, P;Martelli, S
化合物5与吡唑并[3，4，5-酮]并[3，4，5-吡唑]并[3，4，5-吡啶甲酰胺]8反应良好，合成了两个新系列的嘧啶衍生物：双(嘧啶并吖啶)5和双(吡唑并吖啶甲酰胺)6。化合物5也可以看作是双(吖啶-4-甲酰胺)3的环化衍生物，化合物6是双(吖啶-4-甲酰胺)4的环化衍生物。用计量学方法研究了这些化合物的非共价DNA结合性质。结果表明：(1)目标化合物是很好的DNA配体；(2)His衍生物5和6比相应的单体7和8具有更强的DNA亲和性；(3)新的双5和6的结合效率总是低于相关的双(吖啶-4-甲酰胺)3和4；并且在5和6系列中都有明显的结合，在某些情况下，可以注意到更倾向于与富含AT的双链结合。描述了这些衍生物对人结肠腺癌细胞株(HT29)的体外细胞毒作用，并与参比药物进行了比较。讨论了构效关系。我们可以确定六种非常有效的细胞毒性化合物用于进一步的体外研究：针对六种人类癌细胞株的细胞毒性筛选和美国国家癌症研究所(NCI)对60种人类肿瘤细胞株的筛选。最后，化合物6a被选为NCI体内中空纤维试验的评价对象。
The good results obtained with pyrimido[5,6,1-de]acridines 7 and with pyrazolo[3,4,5-kl]-acridinecarboxamides 8 prompted us to the synthesis of two new series of his acridine derivatives: the bis(pyrimidoacridines) 5 and the bis(pyrazoloacridinecarboxamides) 6. Compounds 5 can be regarded also as cyclized derivatives of bis(acridine-4-carboxamides) 3 and compounds 6 as cyclized derivatives of bis(acridine-4-carboxamides) 4. The noncovalent DNA-binding properties of these compounds have been examined using fluorometric techniques. The results indicate that (i) the target compounds are excellent DNA ligands; (ii) the his derivatives 5 and 6 are more DNA-affinic than corresponding monomers 7 and 8; (iii) the new bis 5 and 6 result always less efficient in binding than related bis(acridine-4-carboxamides) 3 and 4; and GO in both series 5 and 6 a clear, remarkable in some cases, preference for binding to AT rich duplexes can be noted. In vitro cytotoxic potency of these derivatives toward the human colon adenocarcinoma cell line (HT29) is described and compared to that of reference drugs. Structure- activity relationships are discussed. We could identify six very potent cytotoxic compounds for further in vitro studies: a cytotoxic screening against six human cancer cell lines and the National Cancer Institute (NCI) screening on 60 human tumor cell lines. Finally, compound 6a was selected for evaluation in a NCI in vivo hollow fiber assay.