Antonini Ippolito, Polucci Paolo, Magnano Amelia, Gatto Barbara, Palumbo Manlio, Menta Ernesto, Pescalli Nicoletta, Martelli Sante
Department of Chemical Sciences, University of Camerino, Via S Agostino 1, 62032 Camerino, Italy.
J Med Chem. 2003 Jul 3;46(14):3109-15. doi: 10.1021/jm030820x.
To enhance the outstanding biological response shown by the corresponding monomers 4 and 5, two classes of bis-acridine-4-carboxamides, 9, with a linker between the 4,4' positions, and 13, with a linker between the 1,1' positions, have been prepared as DNA-binding and potential antitumor agents. The noncovalent DNA-binding properties of these compounds have been examined using gel-electrophoresis and fluorometric techniques. The results indicate that (i). target compounds intercalate DNA; (ii). the bis derivatives with the optimal linker are considerably more DNA-affinic than corresponding monomers; (iii). overall affinity is sensitive to the nature of the linker, of the chromophores, and of the substituents at 7,7'; (iv). often, the bis derivatives show a marked AT-preferential binding. 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. Some highly DNA-affinic and potent cytotoxic compounds, 9b,f and 13b,c, have been selected for the National Cancer Institute (NCI) screening on 60 human tumor cell lines and identified as new leads in the antitumor strategies.
为了增强相应单体4和5所表现出的出色生物响应，已制备了两类双吖啶-4-羧酰胺，即在4,4'位之间带有连接基的9和在1,1'位之间带有连接基的13，作为DNA结合剂和潜在的抗肿瘤剂。已使用凝胶电泳和荧光技术研究了这些化合物的非共价DNA结合特性。结果表明：（i）. 目标化合物可插入DNA；（ii）. 带有最佳连接基的双衍生物对DNA的亲和力远高于相应的单体；（iii）. 总体亲和力对连接基、发色团以及7,7'位取代基的性质敏感；（iv）. 双衍生物通常表现出明显的AT优先结合。描述了这些衍生物对人结肠腺癌细胞系（HT29）的体外细胞毒性效力，并与参考药物进行了比较。讨论了构效关系。已选择一些具有高度DNA亲和力和强效细胞毒性的化合物9b、f和13b、c，用于美国国立癌症研究所（NCI）对60种人类肿瘤细胞系的筛选，并被确定为抗肿瘤策略中的新先导物。
