Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-b]quinolone Derivatives as c-myc G-Quadruplex Specific Stabilizers via Click Chemistry
Discovery of Novel 11-Triazole Substituted Benzofuro[3,2-b]quinolone Derivatives as c-myc G-Quadruplex Specific Stabilizers via Click Chemistry
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通过点击化学发现新型 11-三唑取代苯并呋喃[3,2-b]喹诺酮衍生物作为 c-myc G-四联体特异性稳定剂
DOI：
10.1021/acs.jmedchem.7b00016
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发表时间：
2017
影响因子：
7.3
通讯作者：
Ou Tian-Miao
中科院分区：
文献类型：
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作者：
Zeng De-Ying;Kuang Guo-Tao;Wang Shi-Ke;Peng Wang;Lin Shu-Ling;Zhang Qi;Su Xiao-Xuan;Hu Ming-Hao;Wang Honggen;Tan Jia-Heng;Huang Zhi-Shu;Gu Lian-Quan;Ou Tian-Miao
核酸结合物的特异性对这类药物的开发至关重要，尤其是新型g -四联体结合物的开发。喹啉衍生物已被开发为具有良好相互作用活性的g -四联稳定剂。为了提高喹多啉衍生物asc- mygc -四联体结合配体的选择性和结合亲和力，采用一系列炔基和叠氮基的1,3-偶极环加成方法，设计合成了新型含三唑的苯并呋喃喹啉衍生物（T-BFQs）。这些新型T-BFQs对- mycg -四重体DNA的选择性显著提高，结合亲和力明显提高。进一步的细胞和体内实验表明，T-BFQs可能通过下调c-mycgene的转录来抑制肿瘤细胞的增殖。我们的发现拓宽了特定g -四联稳定剂的修饰策略。
The specificity of nucleic acids’ binders is crucial for developing this kind of drug, especially for novel G-quadruplexes’ binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivatives asc-mycG-quadruplex binding ligands, novel triazole containing benzofuroquinoline derivatives (T-BFQs) were designed and synthesized by using the 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks. The selectivity towardc-mycG-quadruplex DNA of these novel T-BFQs was significantly improved, together with an obvious increase on binding affinity. Further cellular and in vivo experiments indicated that the T-BFQs showed inhibitory activity on tumor cells’ proliferation, presumably through the down-regulation of transcription ofc-mycgene. Our findings broadened the modification strategies of specific G-quadruplex stabilizers.