Markovits J, Wilmańska D, Lescot E, Studzian K, Szmigiero L, Gniazdowski M
Laboratoire de Pharmacologie Moléculaire, UA 147 (CNRS), U 140 (INSERM) Institut Gustave Roussy, Villejuif, France.
Chem Biol Interact. 1989;70(1-2):73-87. doi: 10.1016/0009-2797(89)90064-1.
Two 1-nitro-9-aminoacridine dimers were prepared: one bearing a spermine flexible linking chain, compound 4, the other a rigid dipiperidine-type linker, compound 7. Both dimers elicited a higher affinity constant for DNA than the parent monomeric drug nitracrine 2. This affinity was several orders lower than what was found for other dimeric compounds having the same linkers and no nitro group on the acridine ring (3, 5, 6 and 8). Bisintercalation was evidenced for compound 4 by viscosimetric measurements. In the absence of dithiothreitol, an inhibitory effect of RNA synthesis in vitro was observed for all the tested compounds except 2 and 7. In the presence of dithiothreitol, 4 and 7 formed irreversible complexes with DNA of decreased template properties. The level of the dimers binding was lower than that of the parent compound 2. Cross-links were detected by means of hydroxylapatite chromatography in a complex of the dimer bearing a flexible linking chain, compound 4 with DNA, while the compound 7-DNA complex eluted in the single-stranded DNA region. The extent of cytotoxicity of the two 1-nitro-9-aminoacridine dimers against L1210 cultured cells was different.
制备了两种1-硝基-9-氨基吖啶二聚体：一种带有精胺柔性连接链，即化合物4；另一种带有刚性双哌啶型连接基，即化合物7。与母体单体药物硝吖啶2相比，这两种二聚体对DNA的亲和常数更高。但这种亲和力比具有相同连接基且吖啶环上无硝基的其他二聚体化合物（3、5、6和8）低几个数量级。通过粘度测量证明化合物4存在双插入作用。在没有二硫苏糖醇的情况下，除2和7外，所有测试化合物在体外均观察到对RNA合成的抑制作用。在有二硫苏糖醇的情况下，4和7与DNA形成模板性质降低的不可逆复合物。二聚体的结合水平低于母体化合物2。通过羟基磷灰石色谱法在带有柔性连接链的二聚体化合物4与DNA的复合物中检测到交联，而化合物7与DNA的复合物在单链DNA区域洗脱。两种1-硝基-9-氨基吖啶二聚体对L1210培养细胞的细胞毒性程度不同。
