Fu Yuan-Te, Keppler Brian R, Soares Joana, Jarstfer Michael B
Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Bioorg Med Chem. 2009 Mar 1;17(5):2030-7. doi: 10.1016/j.bmc.2009.01.015. Epub 2009 Jan 15.
Human chromosomes terminate with telomeres, which contain double-stranded G-rich, repetitive DNA followed by a single-stranded overhang of the G-rich sequence. Single-stranded oligonucleotides containing G-rich telomeric repeats have been observed in vitro to fold into a variety of G-quadruplex topologies depending on the solution conditions. G-quadruplex structures are notable in part because G-quadruplex ligands inhibit both the enzyme telomerase and other telomere-binding proteins. Because telomerase is required for growth by the majority of cancers, G-quadruplex-stabilizing ligands have become an attractive platform for anticancer drug discovery. Here, we present the preparation and biochemical activities of a novel series of 3,6-disubstituted acridine dimers modeled after the known G-quadruplex ligand BRACO19. These BRACO19 Analog Dimer (BAD) ligands were shown to bind to human telomeric DNA and promote the formation of intramolecular G-quadruplexes in the absence of monovalent cations. As expected, the BAD ligands bound to telomeric DNA with a 1:1 stoichiometry, whereas the parent compound BRACO19, a monomer, bound with a 2:1 stoichiometry. The BAD ligands exhibited potent inhibition of human telomerase with IC(50) values similar to or lower than those of BRACO19. Furthermore, the BAD ligands displayed greater potency in the inhibition of hPot1 and increased selectivity for G-quadruplex DNA when compared to BRACO19. Collectively, these experiments support the hypothesis that there is an increased potency and selectivity to be gained in the design of G-quadruplex-stabilizing agents that incorporate multiple interactions.
人类染色体以端粒结尾，端粒包含富含鸟嘌呤的双链重复DNA，后面跟着富含鸟嘌呤序列的单链突出端。在体外观察到，含有富含鸟嘌呤端粒重复序列的单链寡核苷酸会根据溶液条件折叠成多种G-四链体拓扑结构。G-四链体结构之所以引人注目，部分原因是G-四链体配体既能抑制端粒酶，也能抑制其他端粒结合蛋白。由于大多数癌症的生长都需要端粒酶，因此G-四链体稳定配体已成为抗癌药物发现的一个有吸引力的平台。在这里，我们展示了一系列以已知的G-四链体配体BRACO19为模型的新型3,6-二取代吖啶二聚体的制备及其生化活性。这些BRACO19类似物二聚体（BAD）配体被证明能与人端粒DNA结合，并在没有单价阳离子的情况下促进分子内G-四链体的形成。正如预期的那样，BAD配体以1:1的化学计量比与端粒DNA结合，而母体化合物BRACO19（一种单体）以2:1的化学计量比结合。BAD配体对人端粒酶表现出强效抑制作用，其IC(50)值与BRACO19相似或更低。此外，与BRACO19相比，BAD配体在抑制hPot1方面表现出更大的效力，并且对G-四链体DNA的选择性增加。总的来说，这些实验支持了这样一种假设，即在设计包含多种相互作用的G-四链体稳定剂时，可以提高效力和选择性。
