Antonini I, Polucci P, Kelland L R, Menta E, Pescalli N, Martelli S
Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy.
J Med Chem. 1999 Jul 15;42(14):2535-41. doi: 10.1021/jm9805586.
A series of DNA-intercalating potential antitumor agents, (amino)alkyl-substituted 2,3-dihydro-1H,7H-pyrimido[5,6, 1-de]acridine-1,3,7-triones, has been prepared by aminolysis of the corresponding 6-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these compounds have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward eight tumor cell lines, including human colon adenocarcinoma (HT29, LoVo sensitive and LoVo/Dx (doxorubicin-resistant)) and human ovarian carcinoma (A2780 sensitive, A2780cisR (cisplatin-resistant), CH1, CH1cisR (cisplatin-resistant), and SKOV-3) cells, are described and compared to that of reference drugs. The cytotoxic activity often parallels the observed DNA affinities, for almost all the target compounds. Interesting structure-activity relationships have been found. The octanol/water partition coefficients have also been calculated, but there was no correlation either with cytotoxicity values or with resistance index. Three highly DNA-affinic analogues, 9 and 15f,15h, have been identified with a useful broad spectrum of cytotoxic activity.
通过用合适的ω-氨基烷基胺对相应的6-氯衍生物进行氨解反应，制备了一系列具有DNA嵌入能力的潜在抗肿瘤药物，即（氨基）烷基取代的2,3-二氢-1H,7H-嘧啶并[5,6,1-de]吖啶-1,3,7-三酮。已使用荧光技术研究了这些化合物的非共价DNA结合特性。描述了这些衍生物对包括人结肠腺癌（HT29、LoVo敏感型和LoVo/Dx（多柔比星耐药型））以及人卵巢癌（A27,80敏感型、A2780cisR（顺铂耐药型）、CH1、CH1cisR（顺铂耐药型）和SKOV-3）细胞在内的八种肿瘤细胞系的体外细胞毒性效力，并与参考药物进行了比较。对于几乎所有目标化合物，细胞毒性活性通常与观察到的DNA亲和力平行。发现了有趣的构效关系。还计算了正辛醇/水分配系数，但它与细胞毒性值或耐药指数均无相关性。已鉴定出三种具有高度DNA亲和力的类似物9以及15f、15h，它们具有有用的广谱细胞毒性活性。
