端粒G-四链体配体:天然产物Schizocommunin衍生物的设计、合成与评价
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- 英文论文题名：Design,Synthesis,and Biological Evaluation of Schizocommunin Derivatives as Telomeric G-quadruplex ligands
- 论文作者：车通 ; 谭嘉恒 ; 黄志纾
- 英文论文作者：Tong Che ; Jia-Heng Tan ; Zhi-Shu Huang ; School of Pharmaceutical Sciences ; Sun Yat-sen University
- 年：2016
- 作者机构：中山大学药学院;
- 论文关键词：Schizocommunin衍生物 ; 端粒G-四链体
- 会议召开时间：2016-07-01
- 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
- 语种：中文
- 分类号：O629;O641.4
- 学会代码：ZGHY
- 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
- 会议地点：中国辽宁大连
- 主办单位：中国化学会
- 学会名称：中国化学会
- 页数：1
- 文件大小：331k
- 原文格式：D
- 会议级别：全国
摘要
端粒是位于真核细胞线性染色体末端的DNA-蛋白质复合体。端粒DNA是由一段TTAGGG重复序列组成,其中鸟嘌呤碱基可通过Hoogsteen氢键维系形成的一种特殊二级结构——G-四链体。小分子配体通过结合稳定端粒G-四链体DNA可以影响端粒长度维持机制,抑制端粒酶活性,引起端粒功能紊乱,最终导致肿瘤细胞衰老凋亡。因此,通过稳定端粒G-四链体结构,是潜在抗肿瘤靶点。天然产物Schizocommunin~([1])其母体结构由喹唑酮与共轭的靛红连接而成,其分子内氢键使化合物形成一个大的芳香共平面结构,可以与G-四链体平面发生π-π堆积作用。因此,我们设计、合成了一系列天然产物Schizocommunin衍生物作为端粒G-四链体小分子配体。研究结果表明化合物通过稳定端粒G-四链体结构,抑制端粒酶活性,引起端粒DNA损伤,导致肿瘤细胞衰老和凋亡。
Human telomeres which are located on the ends of chromosomes are composed of repetitive TTAGGG sequences and associated proteins,when the telomeric DNA forms quadruplex structure it cannot be elongated by telomerase.Therefore,small molecules that can induce and stabilize human telomeric G-quadruplex are considered as promising anticancer agents.The structure of Schizocommunin comprises a quinazoline moiety conjugated with a isatin group.It can form intramolecular hydrogen bonding and large planar aromatic surfaces binding with G-quadruplexes via π-π stacking.Therefore,we designed and synthetized a series of Schizocommunin derivatives as telomeric DNA G-quadruplex ligands.Our results showed that the compound induces cancer cell senescence by stabilizing telomeric G-quadruplexes and sparking a DNA damage response at the telomere region.
Human telomeres which are located on the ends of chromosomes are composed of repetitive TTAGGG sequences and associated proteins,when the telomeric DNA forms quadruplex structure it cannot be elongated by telomerase.Therefore,small molecules that can induce and stabilize human telomeric G-quadruplex are considered as promising anticancer agents.The structure of Schizocommunin comprises a quinazoline moiety conjugated with a isatin group.It can form intramolecular hydrogen bonding and large planar aromatic surfaces binding with G-quadruplexes via π-π stacking.Therefore,we designed and synthetized a series of Schizocommunin derivatives as telomeric DNA G-quadruplex ligands.Our results showed that the compound induces cancer cell senescence by stabilizing telomeric G-quadruplexes and sparking a DNA damage response at the telomere region.
引文
[1]Uehata,K.;Kimura,N.;Hasegawa,K.;Arai,S.;Nishida,M.;Hosoe,T.;Kawai,K.;Nishida,A.J Nat Prod.2013,76(11),2034-9.