Targeting telomerase and telomeres: a click chemistry approach towards highly selective G-quadruplex ligands
Targeting telomerase and telomeres: a click chemistry approach towards highly selective G-quadruplex ligands
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DOI：
10.1039/b801822g
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发表时间：
2008-01-01
影响因子：
--
通讯作者：
Moses, John E.
中科院分区：
文献类型：
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作者：
Moorhouse, Adam D.;Haider, Shozeb;Moses, John E.
端粒-保护染色体末端的特化复合物的维持由酶复合物端粒酶进行，其是在超过80%的癌细胞中激活的关键因子，但在大多数正常细胞中不存在。靶向端粒维持机制可能会在广泛的癌症类型中阻止肿瘤生长，而在癌细胞外几乎没有细胞毒性作用。在这里，我们详细描述了一类新的G-四链体结合配体使用点击化学方法合成。这些配体包含1，3-二（1，2，3-三唑-4-基）苯药效团，并显示出与G-四链体DNA相对于双链体DNA相互作用的高水平选择性。这些配体抑制端粒酶的酶活性的能力与它们稳定四链体DNA的能力相关，并且与通过分子建模计算的亲和力的估计相关。
Maintenance of telomeres - specialized complexes that protect the ends of chromosomes, is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but is absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types, with little cytotoxic effect outside cancer cells. Here, we describe in detail a new class of G-quadruplex binding ligands synthesized using a click chemistry approach. These ligands comprise a 1,3di(1,2,3-triazol-4-yl)benzene pharmacophore, and display high levels of selectivity for interaction with G-quadruplex DNA vs. duplex DNA. The ability of these ligands to inhibit the enzymatic activity of telomerase correlates with their ability to stabilize quadruplex DNA, and with estimates of affinity calculated by molecular modeling.