School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
Org Biomol Chem. 2011 Apr 21;9(8):2975-86. doi: 10.1039/c0ob00921k. Epub 2011 Mar 3.
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.
一系列具有烷基氨基侧链的 2-苯基-苯并吡喃并嘧啶（PBPP）衍生物被合成出来，并被发现是一种与端粒 G-四链体 DNA 结合的新型高选择性配体，其生物特性也被首次报道。通过荧光共振能量转移（FRET）熔融、表面等离子体共振（SPR）、圆二色（CD）光谱和分子建模等方法研究了它们与端粒 G-四链体 DNA 的相互作用。我们的结果表明，二取代的 PBPP 衍生物能够强烈结合并有效地稳定端粒 G-四链体结构，并且对 G-四链体具有显著的选择性，而对双链 DNA 的选择性则较小。相比之下，单取代的衍生物对 G-四链体的影响要小得多，这表明 PBPP 的二取代对于其与 G-四链体的相互作用是必不可少的。此外，还研究了 PBPP 衍生物对端粒酶的抑制作用及其细胞效应，发现化合物 11b 作为端粒酶抑制剂和端粒 G-四链体结合配体具有很大的发展潜力，可用于癌症治疗。
