Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding
Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding
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DOI：
10.1016/j.bmcl.2004.09.037
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发表时间：
2004-12-06
影响因子：
2.7
通讯作者：
Neidle, S
中科院分区：
文献类型：
--
作者：
Harrison, RJ;Reszka, AP;Neidle, S
报道了一组 2,6-、2,7- 和 3,6-双氨基烷基酰胺吖啶酮的合成和评估，与吖啶对应物相比，它们在体外表现出相似的抗端粒酶活性水平。计算机建模和相对结合能的计算表明与人分子内 G-四链体 DNA 具有等效的结合模式，但亲和力显着降低；与吖啶系统相比，吖啶酮发色团的离域有限。使用 FRET 方法对吖啶酮和吖啶四链体复合物进行的热熔化研究支持了这些预测。使用 SKOV3 细胞系使用两种代表性吖啶酮进行的亚细胞毒性剂量的长期细胞增殖研究表明，两种化合物均不会产生生长停滞，这与三取代吖啶化合物 BRACO-19 产生的效果形成鲜明对比。结论是，为了在亚毒性浓度下发生细胞生长停滞，端粒酶抑制活性是必要的，但其本身并不充分，并且还需要紧密的四链体结合。 (C) 2004 Elsevier Ltd. 保留所有权利。
The synthesis and evaluation of a group of 2,6-, 2,7- and 3,6-bis-aminoalkylamido acridones are reported, which show a similar level of activity against telomerase in vitro compared to their acridine counterparts. Computer modelling and calculations of relative binding energies suggest an equivalent binding mode to human intramolecular G-quadruplex DNA, but with significantly reduced affinity; as a result of the limited delocalisation of the acridone chromophore compared to the acridine system. Thermal melting studies on acridone and acridine quadruplex complexes using a FRET approach support these predictions. Long-term cell proliferation studies at sub-cytotoxic doses with two representative acridones using the SKOV3 cell line, show that neither compound produces growth arrest, in contrast with the effects produced by the tri-substituted acridine compound BRACO-19. It is concluded that telomerase inhibitory activity is a necessary though by itself insufficient property in order for cellular growth arrest to occur at sub-toxic concentrations, and that tight quadruplex binding is also required. (C) 2004 Elsevier Ltd. All rights reserved.