Bailly F, Bailly C, Helbecque N, Pommery N, Colson P, Houssier C, Hénichart J P
INSERM U.16, Lille, France.
Anticancer Drug Des. 1992 Feb;7(1):83-100.
The synthesis of two peptidic derivatives, including an anilinoacridine chromophore (related to the antileukemic drug amsacrine) and either the tetrapeptide SPKK (a nucleic acid-binding unit) (1) or the octapeptide SPKKSPKK (2), has been carried out. The interaction of both drugs with DNA has been studied. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the tetrapeptidic or octapeptidic portion is located in the DNA minor groove. Compound 1 fully intercalates into DNA. In contrast, minor groove binding of the octapeptide SPKKSPKK seems to partially modify the intercalative properties of the acridine moiety of 2. In vitro cytostatic and cytotoxic activities against a murine leukemia cell line (L1210), as well as inhibition of [3H]thymidine incorporation, are reported. Compound 1, which is a better inhibitor of DNA synthesis than 2, is also 2.8-fold more potent in terms of growth inhibition. Both drugs are efficient cytostatic agents, but are weakly cytotoxic. The DNA-binding abilities of the two molecules are well correlated to their biological properties. Thus, DNA can be considered as the primary target for these new ligands.
已合成了两种肽衍生物，其中包括一个苯胺基吖啶发色团（与抗白血病药物安吖啶有关）以及四肽SPKK（一种核酸结合单元）(1)或八肽SPKKSPKK(2)。已研究了这两种药物与DNA的相互作用。结合数据与一种模型相符，在该模型中吖啶核占据一个嵌入位点，而四肽或八肽部分位于DNA小沟中。化合物1完全嵌入DNA。相比之下，八肽SPKKSPKK的小沟结合似乎部分改变了2中吖啶部分的嵌入特性。报告了对小鼠白血病细胞系（L1210）的体外细胞生长抑制和细胞毒性活性，以及对[3H]胸苷掺入的抑制作用。化合物1作为DNA合成的抑制剂比2更好，在生长抑制方面的效力也高2.8倍。两种药物都是有效的细胞生长抑制剂，但细胞毒性较弱。这两种分子的DNA结合能力与其生物学特性密切相关。因此，DNA可被视为这些新配体主要靶点。
