Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark.
Chemistry. 2012 Aug 27;18(35):10892-902. doi: 10.1002/chem.201200081. Epub 2012 Jul 17.
Small molecules capable of stabilizing the G-quadruplex (G4) structure are of interest for the development of improved anticancer drugs. Novel 4,7-diamino-substituted 1,10-phenanthroline-2,9-dicarboxamides that represent hybrid structures of known phenanthroline-based ligands have been designed. An efficient synthetic route to the compounds has been developed and their interactions with various G4 sequences have been evaluated by Förster resonance energy transfer (FRET) melting assays, fluorescent intercalator displacement (FID), electrospray ionization mass spectrometry (ESI-MS), and circular dichroism (CD) spectroscopy. The preferred compounds have high aqueous solubility and are strong and potent G4 binders with a high selectivity over duplex DNA; thus, they represent a significant improvement over the lead compounds. Two of the compounds are inhibitors of HeLa and HT1080 cell proliferation.
小分子能够稳定 G-四链体 (G4) 结构，因此它们被广泛应用于开发新型抗癌药物。本研究设计了一系列新型 4,7-二氨基取代的 1,10-菲咯啉-2,9-二羧酸酰胺化合物，这些化合物是基于已知菲咯啉配体的杂化结构。此外，还开发了一种有效的合成路线，并通过荧光共振能量转移 (FRET) 熔融实验、荧光嵌入剂置换 (FID)、电喷雾电离质谱 (ESI-MS) 和圆二色光谱 (CD) 对这些化合物与各种 G4 序列的相互作用进行了评估。研究结果表明，优选的化合物具有高水溶性，并且是强有效的 G4 结合物，对双链 DNA 具有高选择性；因此，与先导化合物相比，这些化合物具有显著的改善作用。其中两种化合物能够抑制 HeLa 和 HT1080 细胞的增殖。
