Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA
Disubstituted 2-phenyl-benzopyranopyrimidine derivatives as a new type of highly selective ligands for telomeric G-quadruplex DNA
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双取代2-苯基-苯并吡喃并嘧啶衍生物作为端粒G-四链体DNA的新型高选择性配体
DOI：
10.1039/c0ob00921k
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发表时间：
2011-01-01
影响因子：
3.2
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
--
作者：
Wu, Wei-Bin;Chen, Shu-Han;Huang, Zhi-Shu
合成了一系列具有烷氨基侧链的2-苯基苯并吡喃嘧啶（PBPP）衍生物，发现其是一种新型的高选择性配体，可与端粒G-四链体DNA结合，并首次报道了它们的生物学性质。用FRET熔解、表面等离子体共振、CD光谱和分子模拟研究了它们与端粒G-四链体DNA的相互作用。我们的研究结果表明，二取代PBPP衍生物可以强烈结合并有效地稳定端粒G-四链体结构，并对G-四链体有显着的选择性超过双链体DNA。相比之下，单取代衍生物对G-四链体的影响要小得多，这表明PBPP的双取代是其与G-四链体相互作用所必需的。此外，研究了PBPP衍生物的端粒酶抑制及其细胞效应，发现化合物11b是作为端粒酶抑制剂和端粒G-四链体结合配体用于进一步开发用于癌症治疗的最有前景的化合物。
A series of 2-phenyl-benzopyranopyrimidine (PBPP) derivatives with alkylamino side chains were synthesized and found to be a new type of highly selective ligand to bind with telomeric G-quadruplex DNA, and their biological properties were reported for the first time. Their interactions with telomeric G-quadruplex DNA were studied with FRET melting, surface plasmon resonance, CD spectroscopy, and molecular modeling. Our results showed that the disubstituted PBPP derivatives could strongly bind to and effectively stabilize the telomeric G-quadruplex structure, and had significant selectivity for G-quadruplex over duplex DNA. In comparison, the mono substituted derivatives had much less effect on the G-quadruplex, suggesting that the disubstitution of PBPP is essential for its interaction with the G-quadruplex. Furthermore, telomerase inhibition of the PBPP derivatives and their cellular effects were studied, and compound 11b was found to be the most promising compound as a telomerase inhibitor and telomeric G-quadruplex binding ligand for further development for cancer treatment.