Isaindigotone derivatives: a new class of highly selective ligands for telomeric G-quadruplex DNA.
Isaindigotone derivatives: a new class of highly selective ligands for telomeric G-quadruplex DNA.
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DOI：
10.1021/jm801600m
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发表时间：
2009-04
影响因子：
7.3
通讯作者：
Jia-Heng Tan;Tian-Miao Ou;Jin-Qiang Hou;Yu-jing Lu;Shi-Liang Huang;Hai-bin Luo;Jian-Yong Wu;
中科院分区：
文献类型：
--
作者：
Jia-Heng Tan;Tian-Miao Ou;Jin-Qiang Hou;Yu-jing Lu;Shi-Liang Huang;Hai-bin Luo;Jian-Yong Wu;
合成并表征了四种设计为端粒G-四链配体的异吲哚二酮衍生物(5a，b和6a，b)。这些化合物中的未融合芳环允许在G-四链识别中灵活和自适应的构象。通过FRET熔融、荧光滴定、圆二色谱、连续变化和分子模拟研究了人端粒G-四链DNA与所设计的配体的相互作用。我们的结果表明，这种自适应支架不仅可以让配体很好地占据G-四联体，而且可以完美地结合到G-四链体的沟槽上。多种结合模式的协同作用可能是这些配体对G-四链体结合能力和选择性提高的原因。HL60和CA46癌细胞长期暴露于化合物5a后，细胞群体增长、细胞衰老表型和端粒长度显著减少，这与有效的端粒G-四链配体和端粒酶抑制剂的行为一致。
Four isaindigotone derivatives (5a,b and 6a,b) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The unfused aromatic rings in these compounds allow a flexible and adaptive conformation in G-quadruplex recognition. The interaction of human telomeric G-quadruplex DNA with these designed ligands was explored by means of FRET melting, fluorescence titration, CD spectroscopy, continuous variation, and molecular modeling studies. Our results showed that the adaptive scaffold might not only allow the ligands to well occupy the G-quartet but also perfectly bind to the grooves of the G-quadruplex. The synergetic effect of the multiple binding modes might be responsible for the improved binding ability and high selectivity of these ligands toward G-quadruplex over duplex DNA. Long-term exposure of HL60 and CA46 cancer cells to compound 5a showed a remarkable decrease in population growth, cellular senescence phenotype, and shortening of the telomere length, which is consistent with the behavior of an effective telomeric G-quadruplex ligand and telomerase inhibitor.