Inhibition of human telomerase by a G-quadruplex-interactive compound
Inhibition of human telomerase by a G-quadruplex-interactive compound
复制标题
DOI：
10.1021/jm970199z
复制
发表时间：
1997-07-04
影响因子：
7.3
通讯作者：
Hurley, LH
中科院分区：
文献类型：
--
作者：
Sun, DY;Thompson, B;Hurley, LH
染色体的末端具有称为端粒的专门序列，其包括简单DNA序列的串联重复。人类端粒由5′-TTAGGG序列组成。端粒除了保护染色体末端外，还有几种功能，其中最重要的似乎与衰老，复制和细胞周期时钟有关。3细胞分裂的进行性循环导致端粒每循环缩短约50-200个核苷酸。几乎所有的肿瘤细胞都有缩短的端粒，其保持恒定的长度4，5，并与染色体不稳定性和细胞永生化有关。端粒酶将端粒重复序列添加到端粒末端，确保肿瘤细胞中端粒长度的净维持与细胞分裂的连续轮次相称。端粒酶是一种具有内源性RNA模板的DNA聚合酶，6新生端粒重复序列在其上合成。最近的一个重要发现是，在培养的肿瘤细胞和原发性肿瘤组织中，大约85-90%的人类癌症对端粒酶呈阳性，而大多数体细胞似乎缺乏可检测水平的端粒酶。[7]这一发现已被广泛应用于人类肿瘤（参见参考文献8和9），并可能用于诊断。端粒酶是一种新型的、高选择性的抗肿瘤药物靶点。6，10，11这一假设得到了HeLa细胞中端粒酶RNA反义结构实验的支持，该实验表明端粒缩短，以及这些永生细胞的死亡。6针对端粒酶RNA的序列特异性肽核酸也被发现对该酶发挥抑制作用。12我们的实验室已经启动了一种基于结构的方法，通过靶向核酸结构，如可能与人类端粒或端粒酶相关的G-四链体，13，14来发现选择性抑制人类端粒酶的非核苷化合物。在这份报告中，我们首先证明了2，6-二氨基蒽醌（化合物1）对人端粒酶的抑制作用。我们还通过1H-NMR显示了化合物1对G-四链体的稳定性，并且最后提供了该化合物通过与以下机制一致的机制抑制端粒酶的证据：
The ends of chromosomes have specialized sequences, termed telomeres, comprising tandem repeats of simple DNA sequences. Human telomeres consist of the sequence 5′-TTAGGG. 1, 2 Telomeres have several functions apart from protecting the ends of chromosomes, the most important of which appear to be associated with senescence, replication, and the cell cycle clock. 3 Progressive rounds of cell division result in a shortening of the telomeres by some 50-200 nucleotides per round. Almost all tumor cells have shortened telomeres, which are maintained at a constant length4, 5 and are associated with chromosome instability and cell immortalization. The enzyme telomerase adds the telomeric repeat sequences onto telomere ends, ensuring the net maintenance of telomere length in tumor cells commensurate with successive rounds of cell division. Telomerase is a DNA polymerase with an endogenous RNA template, 6 on which the nascent telomeric repeats are synthesized. A significant recent finding has been that approximately 85-90% of all human cancers are positive for telomerase, both in cultured tumor cells and primary tumor tissue, whereas most somatic cells appear to lack detectable levels of telomerase. 7 This finding has been extended to a wide range of human tumors (see, for example, refs 8 and 9) and is likely to be of use in diagnosis. Human telomerase has been proposed as a novel and potentially highly selective target for antitumor drug design. 6, 10, 11 This hypothesis is supported by experiments with antisense constructs against telomerase RNA in HeLa cells, which show that telomere shortening is produced, together with the death of these otherwise immortal cells. 6 Sequence-specific peptide nucleic acids directed against telomerase RNA have also been found to exert an inhibitory effect on the enzyme. 12Our laboratories have initiated a structure-based approach to discovering non-nucleoside compounds that will selectively inhibit human telomerase by targeting the nucleic acid structures, such as G-quadruplexes, 13, 14 that may be associated with human telomeres or telomerase. In this report we first demonstrate inhibition of human telomerase by the 2, 6-diamidoanthraquinone (compound 1). We also show by 1H-NMR the stabilization of a G-quadruplex by compound 1 and, finally, provide evidence that this compound inhibits the telomerase enzyme by a mechanism consistent with