Koeppel F, Riou J F, Laoui A, Mailliet P, Arimondo P B, Labit D, Petitgenet O, Hélène C, Mergny J L
Laboratoire de Biophysique, Muséum National d'Histoire Naturelle, INSERM U201, CNRS UMR 8646, 43 rue Cuvier, 75005 Paris, France.
Nucleic Acids Res. 2001 Mar 1;29(5):1087-96. doi: 10.1093/nar/29.5.1087.
The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to directly inhibit telomerase activity. The reactivation of this enzyme in immortalized and most cancer cells suggests that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. In this paper, we describe ethidium derivatives that stabilize G-quadruplexes. These molecules were shown to increase the melting temperature of an intramolecular quadruplex structure, as shown by fluorescence and absorbance measurements, and to facilitate the formation of intermolecular quadruplex structures. In addition, these molecules may be used to reveal the formation of multi-stranded DNA structures by standard fluorescence imaging, and therefore become fluorescent probes of quadruplex structures. This recognition was associated with telomerase inhibition in vitro: these derivatives showed a potent anti-telomerase activity, with IC(50) values of 18-100 nM in a standard TRAP assay.
富含鸟嘌呤的端粒单链DNA在体外可形成分子内四链体结构，该结构已被证明能直接抑制端粒酶活性。在永生化细胞和大多数癌细胞中该酶的重新激活表明端粒酶是肿瘤学中的一个相关靶点，并且端粒酶抑制剂已被提议作为新的潜在抗癌药物。在本文中，我们描述了能稳定G-四链体的乙锭衍生物。如荧光和吸光度测量所示，这些分子能提高分子内四链体结构的解链温度，并促进分子间四链体结构的形成。此外，这些分子可用于通过标准荧光成像揭示多链DNA结构的形成，因此成为四链体结构的荧光探针。这种识别与体外端粒酶抑制有关：这些衍生物表现出强大的抗端粒酶活性，在标准TRAP分析中的IC(50)值为18 - 100 nM。
