波谱学杂志, 2021, 38(4): 503-513 doi: 10.11938/cjmr20212928

 

靶向肿瘤因子c-MYC基因启动区G4-DNA的小分子药物设计及核磁共振研究进展

胡晓东, 蓝文贤, 王春喜, 曹春阳,

中国科学院分子合成卓越中心, 中国科学院上海有机化学研究所生命有机国家重点实验室, 上海 200032

Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA

HU Xiao-dong, LAN Wen-xian, WANG Chun-xi, CAO Chun-yang,

State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

通讯作者: 曹春阳, Tel: 021-54925491, E-mail:ccao@mail.sioc.ac.cn

收稿日期: 2021-06-29  

基金资助: 国家重点研发计划资助项目.  2017YFE0108200
国家自然科学基金资助项目.  21977110
国家自然科学基金资助项目.  21778065
国家自然科学基金资助项目.  21807105
中国科学院先导项目.  XDB20000000
中国科学院分子合成卓越中心资助项目.  FZHCZY020600

Received: 2021-06-29  

摘要

肿瘤基因MYC在人类70%癌细胞中高表达，抑制其转录是治疗肿瘤的有效手段.c-MYC启动子区P1近端的核酸酶超敏元件Ⅲ1(NHE Ⅲ1)控制MYC基因近90%的转录激活.NHE Ⅲ1区域富含碱基G序列并且形成G-四链体(G4)，调控c-MYC基因转录，是抗肿瘤药物靶标.但G4-DNA和G4-RNA的三维结构高度相似，小分子与其他G4(如端粒G4、mRNA G4、c-Kit G4等)的非特异性作用会产生小分子药物“脱靶”效应，同时小分子药物会诱导其他G4形成从而干扰正常细胞的功能，造成靶向c-MYC G4抗癌药物设计困难.本文综述了近些年靶向肿瘤因子c-MYC G4-DNA的小分子药物研究进展，及核磁共振(NMR)技术在G4-DNA和G4-RNA结构确定中的作用，为靶向c-MYC G4-DNA的小分子药物设计等相关研究工作提供参考.

关键词： 肿瘤基因 ; c-MYC ; G-四链体(G4) ; 小分子药物 ; 核磁共振(NMR)

Abstract

MYC is a highly expressed oncogene in about 70% of human cancer cells and inhibition of its transcription serves as an effective tumor treatment. The P1 proximal nuclease hypersensitive element (NHE) Ⅲ1 of c-MYC promoter region controls nearly 90% transcriptional activation of MYC gene. This region enriched with base G forms G-quadruplex (G4) structure, which regulates c-MYC gene transcription and is a target of anti-tumor drugs. However, the three-dimensional structures of G4-DNA and G4-RNA are highly similar. Non-specific interactions between small molecules and other G4s, such as telomere G4, mRNA G4, c-Kit G4, etc., yield "off-target" effects. Meanwhile, small molecules can induce the formation of other G4s, thus interfering with the function of normal cells. All of these hinder the design of anti-cancer drugs targeting c-MYC G4. In this paper, we summarize the recent research progress of small molecules targeting tumor factor c-MYC G4-DNA, and the role of nuclear magnetic resonance (NMR) in determining G4-DNA and G4-RNA structure. This review provides a reference for designing drugs targeting c-MYC G4-DNA and other related research works.

Keywords： tumor gene ; c-MYC ; G-quadruplex (G4) ; small molecular drug ; nuclear magnetic resonance (NMR)

PDF (1615KB) 元数据 多维度评价 相关文章 导出 EndNote| Ris| Bibtex  收藏本文

本文引用格式

胡晓东, 蓝文贤, 王春喜, 曹春阳. 靶向肿瘤因子c-MYC基因启动区G4-DNA的小分子药物设计及核磁共振研究进展. 波谱学杂志[J], 2021, 38(4): 503-513 doi:10.11938/cjmr20212928

HU Xiao-dong. Research Advance and NMR Studies of Anti-Cancer Small Molecules Targeting c-MYC G4-DNA. Chinese Journal of Magnetic Resonance[J], 2021, 38(4): 503-513 doi:10.11938/cjmr20212928

引言

脱氧核糖核酸(DNA)是重要的遗传物质，不仅可以形成规整的B型双螺旋结构，还可以形成十余种不规整的非B型DNA结构，如Z-DNA、DNA错配、三螺旋(triplex)、四螺旋(quadruplex)、发卡式结构等[1].G-四链体(G4)是由Gellert等[2]于1962年发现的一种不规整的核酸二级结构，主要由富含鸟嘌呤(G)的DNA或RNA序列在一价阳离子(K+、Na+或NH4+等)的作用下，通过Hoogsteen氢键形成G-四集体(G-tetrad)(图 1)，并进一步堆积而成.

图1

新窗口打开| 下载原图ZIP| 生成PPT

图1   G-四链体结构组成.(a) G-四集体通过Hoogsteen氢键形成；(b) G-四链体结构中心被一价阳离子稳定

Fig.1   The structural composition of G-quadruplex. (a) G-tetrad formed by Hoogsteen hydrogen-bond; (b) The central structure of G-quadruplex is stabilized by monovalent cation


G-四链体结构形式多样，包括：(1)链排列方向多样性.四条链有三种组合方式：四条链都平行、三条链平行与另一条链反平行、两条链平行与另外两条反平行[图 2(a)]；(2)连接两条链的loop几何结构多样性.当G-四链体为分子内或者双分子结构时，用以连接链的loop的不同跨越会导致其多样性.比如在双分子G-四链体结构中，loop可以连接相邻或对角的链，两个loop可以头-尾或头-头方式排列[图 2(b)]；(3)链数量多样性.形成G-四链体同一寡核苷酸可以分子内折叠，也可以分子间折叠，形成单体、二聚体或者四聚体G-四链体[图 2(c)].

图2

新窗口打开| 下载原图ZIP| 生成PPT

图2   G-四链体结构多样性.(a) G-四集体的四种链朝向；(b)三种主要的Loop连接方式；(c)单体分子内和双分子分子间G-四链体.红色箭头代表链从5’到3’朝向[3]

Fig.2   Structural diversity of G4 structures. (a) Four orientation of chains in G-tetrads; (b) Main three connection modes of loops; (c) Monomer or dimer G4 structure. The red arrow indicates the orientation from 5'-end to 3'-end[3]


真核和原核生物基因组都含有大量G-四链体结构.有研究[4]表明，人类基因组含有约37万条可以形成G-四链体的基因序列，分布在以下几类与基因功能密切相关的区域.(1)细胞核内基因的启动子区域，特别是致癌因子(如c-MYC、c-MYB、BCL-2、RET、VEGF、KRAS、HIF-1α)的启动子区. G-四链体可参与基因转录调控，是抗癌药物靶标[5]；也可在转录时产生单链DNA，影响mRNA合成. (2) 端粒区域.端粒DNA是真核生物染色体线性DNA，3’末端一段富含G重复序列，用以维持染色体的稳定.当该G链悬突中有G-四链体形成时，会影响端粒酶的逆转录活性，从而导致端粒不能正常延伸.(3)细胞质中单链mRNA区域也能形成G-四链体，使得核糖体无法识别mRNA上密码子，导致翻译停止，从而下调基因表达[6].(4)外显子及内含子区域.当转录通过编码链上富含G的序列时，G-四链体的形成会导致基因组的不稳定，触发机体转录偶联修复(TCR)途径，修补基因组中具有转录活性的基因编码链上不正常结构引起的损伤.G-四链体的形成会使RNA聚合酶II发生停滞，使mRNA合成受阻.修复过程会招募TCR因子，但此过程较容易引起不必要的TCR，造成无损伤部位产生重复的修复补丁；在高转录区域，这种情况会导致自发突变水平增加[7].

基于G-四链体分布的广泛性，及其在抗肿瘤药物筛选等方面的潜在应用，本文对与人类70%恶性肿瘤相关的c-MYC基因G-四链体结构及相关的小分子药物筛选进行了综述，以期为相关领域的研究人员提供参考.

1 c-MYC基因的分布、结构与功能

c-MYC基因在人类70%恶性肿瘤(如乳腺癌、结肠癌、胶质母细胞瘤、宫颈癌、小细胞肺癌、骨髓性白血病等)细胞中过量表达.MYC基因产物是一个转录因子，在目标启动子区与MYC关联因子MAX形成杂二聚体，结合特定的E-boxes，控制多种肿瘤靶基因的表达.该功能对许多生理过程非常必要，如细胞增殖、分化、粘附、凋亡、血管生成和转移等等.MYC表达水平的增加，会直接导致与癌症发生与恶化相关的基因表达，降低癌症临床治愈率.而MYC基因的转录抑制，会减少大多数肿瘤细胞的繁殖与生长，但不影响正常细胞的功能.因此，靶向MYC基因进行合理的抗肿瘤药物设计，有望有效和安全地治疗人类各种肿瘤及其相关的疾病.

异常的MYC基因在肿瘤细胞中的表达主要在转录水平被调节.c-MYC启动子P1近端核酸酶超敏元件Ⅲ1(NHE Ⅲ1)控制该基因高达90%的转录激活，而NHE Ⅲ1区域富含碱基G，可以形成G-四链体结构，对c-MYC转录具有负调控作用，这表明NHE Ⅲ1序列二级结构处于B型双螺旋和非B型结构动态平衡中[8, 9].天然状态下，该区域形成四种平行G-四链体结构混合体，四种结构的区别在于形成loop碱基数不同(图 3).当这些G-四链体与小分子配体TMPyP4相互作用时，转变成平行与反平行混合的G-四链体结构.

图3

新窗口打开| 下载原图ZIP| 生成PPT

图3   已报道的c-MYC基因启动子的G4结构.(a) MYC基因的启动子结构和不同的相关元素；(b) MYC-1245、MYC-1234、MYC-2345、Pu22(4/14/23T) G4-DNA结构示意图.箭头指示5’到3’方向的DNA链；碱基G用圆圈表示，碱基A和T用正方形表示

Fig.3   Reported G4 structures in the c-MYC gene promoter. (a) The promoter structure of the MYC gene and different related elements; (b) Schematic demonstration of MYC-1245, MYC-1234, MYC-2345, and Pu22(4/14/23T) G4-DNA structures. The arrowheads indicate 5'-to-3' direction of DNA strands; guanines are shown by circles, and adenines and thymines are shown by boxes


2 靶向c-MYC启动区G4-DNA的抗肿瘤药物设计

2.1 靶向c-MYC启动区G4-DNA的抗肿瘤药物分子机制

当NHE Ⅲ1富含G区域的序列处于单链状态时，转录激活因子CNBP(CCHC-type zinc finger Nucleic acid-Binding Protein)及hnRNP K(heterogeneous nuclear RiboNucleoProtein K)和单链DNA结合，促进MYC转录进行；当该序列被TMPyP4或Se2SAP稳定时，G-四链体阻碍CNBP及hnRNP K与NHE Ⅲ1结合，转录被抑制[10, 11](图 4).

图4

新窗口打开| 下载原图ZIP| 生成PPT

图4   c-MYC启动子NHE Ⅲ1形成的G-四链体结构对转录的调控[10, 11]

Fig.4   Transcriptional regulation of G-quadruplex structure formed in c-MYC promoter NHE Ⅲ1[10, 11]


c-MYC G4-DNA本身不能参与肿瘤细胞生长与发育过程，需要在相关蛋白存在下才能发挥调节功能.如图 5所示，这些蛋白通过与c-MYC G4-DNA结合，促进、稳定或解开其G4-DNA结构来介导MYC基因的转录[12-14].如蛋白nucleolin(NCL)的RNA结合结构域(RBDs)3、(RBDs)4，及RGG(Arg-Gly-Gly)结构域与NHE Ⅲ1区富含G序列作用能促进c-MYC G4-DNA形成，稳定其结构[15, 16]，抑制MYC基因转录.CNBP蛋白是首个报道的富含G的DNA或RNA结合蛋白，能促进G4-DNA形成，致使MYC基因转录片刻内被抑制，同时招募NM23-H2，激活MYC基因转录.核仁磷酸蛋白NPM1(NucleoPhosMin 1)C端NPM1-C70[17-19]及作用于双链RNA 1的腺苷脱氨基化酶ADR1(Adenosine Deaminase acting on RNA 1)的Z-DNA结合域[20]都能结合单链NHE Ⅲ1富含G序列，促进c-MYC G4-DNA形成，抑制MYC基因转录.肿瘤抑制因子P53突变体C端片段320-393 aa与c-MYC G4-DNA结合作用很强[21]，可在肿瘤细胞中调节基因表达.解螺旋酶Pif1[22-24]、BLM[25-27]、WRN[28, 29]、DDX5[30]、NM23-H2[31, 32]及PARP-1[33]等通过与c-MYC G4-DNA作用，使其去折叠，抑制癌症转移.

图5

新窗口打开| 下载原图ZIP| 生成PPT

图5   与c-MYC G4相互作用的蛋白的结合方式.提升(a)和稳定(b)G4结构稳定性结合方式；(c)解螺旋G4结构的结合方式

Fig.5   Binding modes of the proteins interacting with c-MYC G4. Binding modes that promotes (a) and stabilizes (b) the G4 structural stability; (c) Binding mode that unwinds G4 structure


2.2 靶向c-MYC G4-DNA的小分子药物作用模式及缺陷

基于c-MYC G4-DNA结构作为转录的沉默元件的特点，抗肿瘤药物分子通过与其结合并稳定其结构，从而降低癌细胞中c-MYC表达，可用作治疗肿瘤.核磁共振(NMR)波谱、X-单晶衍射及计算分析研究表明，药物分子与G4-DNA可以在5’端、3’端、G-四集体之间、loop区及G4-DNA表面的沟槽等不同位置结合，如图 6所示.

图6

新窗口打开| 下载原图ZIP| 生成PPT

图6   四种配体与G4-DNA的结合模型.(a)配体在5’端、3’端或两端叠加的复合物结构模型；(b)配体插入G-四集体之间的结构模型；(c)配体在沟槽或loop上结合的结构模型；(d)配体停留在G4-DNA结构中心的复合物结构模型

Fig.6   Four binding models of the ligands with G4-DNA. (a) Ligands stack to the 5'-end, 3'-end, or both termini; (b) Ligands insert into G-tetrads; (c) Ligands bind to the groove and loop regions; (d) Ligands stay in the center of G4 structure


目前蛋白质结构数据库(PDB)库中与c-MYC G4相关的结构数量有197个，其中c-MYC G4与小分子复合物的结构数量为十余个.这为理解相关的分子识别机制奠定了基础.如图 7所示，文献报道的能够结合并稳定c-MYC G4-DNA结构，并且已进入临床前或者临床II期研究的小分子药物包括：喹叨啉类(quindoline)化合物(如SYUIO-05[34]、7a4[35]、T-BFQs[34-37])，阳离子卟啉类(cationic porphyrins)[10, 38-41]，咪唑类[42, 43]，喹喔啉类(quinoxalines)[44]，咔唑类(carbazoles)[45-47](如Cz-1[46])，小檗碱衍生物[48-50]，isaindigotone衍生物[50]，bisaryldiketene衍生物[49]，环萘二酰亚胺类(cyclic naphthalene diimide)衍生物[51, 52]，亚甲蓝(methylene blue)衍生物[52]，氨基酞菁(amido phthalocyanine)[53]等.但是，尽管这么多化合物能够靶向c-MYC G4-DNA，显示抑制MYC基因转录的效果，但迄今为止仍然没有一个小分子化合物被批准上市，主要原因如下：(1)目前所有报道的G4-DNA、G4-RNA结构具有很高的相似性；因此设计出来的小分子有可能与其他G4-DNA或者G4-RNA相互作用，造成“脱靶”效应；(2)靶向c-MYC G4-DNA的小分子，一方面可以促进c-MYC G4-DNA结构的形成，另一方面也会促进其他G4结构的形成，从而干扰正常细胞发挥功能.因此靶向c-MYC G4-DNA的小分子药物的设计需要新的思路.

图7

新窗口打开| 下载原图ZIP| 生成PPT

图7   直接或间接与c-MYC G4-DNA结合的化合物的结构

Fig.7   Structures of the compounds that directly or indirectly interact with c-MYC G4-DNA


3 G-四链体结构及其与小分子相互作用机制的NMR研究

研究G-四链体结构常用的技术手段有：(1)圆二色谱(CD)与其他技术的联用.CD可以作为一个首选方法用来判断有无G-四链体形成[54]，电泳、层析及质谱法可以给出分子的大小[55, 56].但这些方法均不能给出原子分辨率的结构信息.(2)X-ray单晶衍射技术.但是G-四链体分子在水溶液中不易结晶，因此不是首选方法.(3)NMR技术.NMR可以监测和分辨多种构象.G-四链体中鸟嘌呤的亚氨基质子，其化学位移在一般在δ 10~12范围内；而Watson-Crick碱基互补配对中亚氨基质子的化学位移则位于更低场(δ 13~14).位于中间G-四集体上的鸟嘌呤的亚氨基质子与溶剂重水交换非常慢(图 8)，利于G-四链体拓扑结构测定.

图8

新窗口打开| 下载原图ZIP| 生成PPT

图8   (a) 三片层G-四链体在H2O(下)中及交换到D2O中1 h(上)后的亚氨基质子的一维氢谱；(b) RET G-四链体的拓扑结构[57]

Fig.8   (a) Imino proton region of one-dimensional 1H NMR spectra in H2O (down) and D2O (upper, exchanged from H2O sample 1 h later), respectively. (b) RET G4-DNA structure[57]


利用NMR技术可以非常方便地解析分子量比较小、不易长单晶的G4-DNA或G4-RNA与小分子配体复合物结构.有研究[58]报道，VEGFR-2在肿瘤生长过程中表达上调，抑制VEGFR-2的表达可以抑制血管生成，进而阻止肿瘤生长，而且VEGFR-2还与增殖性视网膜疾病密切相关.因此VEGF和VEGFR-2可以作为潜在的抗肿瘤相关药物的靶点，阻断VEGF/VEGFR-2信号通路，或者阻止VEGF与VEGFR-2蛋白的结合均可作为抗肿瘤药物设计的着手点[58].vegfr-2基因启动子区-120到-90之间存在一段GC富集区，位于该基因的转录起始位点上游，对其转录具有调控作用.2018年，Liu等[59]利用NMR技术确定了该区域碱基序列突变体VEGFR-17T的G4-DNA结构(图 9)，它由三个叠置的G-tetrad组成，包含三个syn鸟嘌呤.第一个鸟嘌呤G1位于中央G-四分体内.一个非典型的v形环跨越三个G-四集体平面的loop，不含有任何碱基.此外，还含有一个碱基序列较长的且呈现对角线形状的环状loop，包括六个核苷酸，连接着反向的双链.

图9

新窗口打开| 下载原图ZIP| 生成PPT

图9   vegfr-2 17T G4-DNA的溶液结构.(a)飘带图，(b) carton示意图.其中，紫色表示syn构象的碱基G，蓝色表示anti构象的碱基G，黄色表示G-C碱基对[59]

Fig.9   Solution structure of vegfr-2 17T G4-DNA displayed in ribbon mode (a) and cartoon mode (b), respectively, in which syn-G bases are shown in purple, anti-G bases are shown in cyan, G-C base-pairs are shown in yellow[59]


2018年，Calabrese等[60]利用NMR技术解析了小分子化合物DC-34与c-MYC G4-DNA复合物的溶液三维结构(图 10)，发现两个DC-34分子以满负荷的方式分别结合在c-MYC G4-DNA的5’及3’端.

图10

新窗口打开| 下载原图ZIP| 生成PPT

图10   DC-34与c-MYC G4复合物NMR结构(PDB：5W77).所有的分子以杆状图显示.两个DC-34分子分别为绿色和黄色，K+以紫色小球表示[60]

Fig.10   NMR structure of DC-34 complex with c-MYC G4. (PDB: 5W77). All molecules are shown as sticks. Two DC-34 molecules are shown in green and yellow, and K+ cations are shown as purple spheres[60]


2020年，Wang等[61]利用NMR技术筛选1 000多个小分子后，发现天然产物秋水仙素(colchicine)能够特异性结合肿瘤因子RET启动子区G4-DNA结构(图 11).他们利用NMR技术进一步确定了colchicine结合RET G4-DNA的复合物结构[61]，发现colchicine结合在RET G4-DNA的3’端，通过破坏碱基G14与RET G4-DNA原有的骨架G-tetrad之间的π-π堆积作用而与RET G4-DNA的3’端的G-tetrad发生堆积作用.这种作用方式与非特异性结合的配体berberine类似[62]，并没有因为小分子结构的差异结合方式发生变化.小分子结构分析表明，导致秋水仙素能够特异性结合RET G4-DNA的原因在于，秋水仙素的小分子结构刚性不及berberine，精细的柔性结构导致其不能与c-MYC G4-DNA、Tel G4-DNA、c-Kit G4-DNA相互作用，而只与RET G4-DNA相互作用.

图11

新窗口打开| 下载原图ZIP| 生成PPT

图11   RET G4-DNA与秋水仙碱复合物的结构(橙色).(a)能量最低的20个结构的集合，碱基G14构象是灵活的；(b)一个复合物的构象，芳香七元环与苯环之间呈27.5°；(c)自由态RET G4-DNA的结构；(d)秋水仙素(橙色球棍模型显示)在复合物结构中位置与自由态RET G4-DNA中的G3-G9-G13-G19四集体平面中的碱基G14对比.在图(a)~(c)中，由4个syn鸟嘌呤组成的G-四集体分别为洋红色线和卡通模式，anti鸟嘌呤组成的G-四集体分别以青色和卡通模式显示.在所有图中：碱基G14是深灰色的线条和卡通模式展示；碱基G16和T20分别为绿线和卡通模式展示；碱基G4、C5、G6和C10为小麦色或卡通模式展示.所有非极性质子都没有显示出来[61]

Fig.11   Structure of RET G4-DNA in complex with colchicine (in orange). (a) The ensemble of 20 structures with the lowest energy. Base G14 is flexible; (b) One conformer of the complex. An angle 27.5° was formed between aromatic seven-membered ring and phenyl ring; (c) The structure of free RET G4-DNA; (d) The position of colchicine (in orange) relative to G14 (in green) above G3-G9-G13-G19 tetrad (in cyan) at 3'-end in the complex structure, compared to structure of free RET G4-DNA (in line mode, except the base G14 which was termed as G14 free and displayed in blue stick). In (a)~(c), the G-tetrad composed by four syn guanines was in magenta line and cartoon modes, respectively. The G-tetrads composed by anti- guanines were shown in cyan lines and cartoon modes, respectively. In all figures, base G14 was in deep-gray lines and cartoon modes. Bases G16 and T20 were in green lines and cartoon modes, respectively. Bases G4, C5, G6 and C10 in loops were in wheat lines or cartoon modes. All nonpolar protons were not displayed[61]


4 总结与展望

MYC在人类大部分癌细胞中高表达，抑制其转录是治疗肿瘤的有效手段.c-MYC启动子区P1近端NHE Ⅲ1区域富含碱基G序列形成G-四链体，调控c-MYC基因转录，是抗肿瘤药物靶标.目前靶向c-MYC G4抗癌药物因为“脱靶”效应，存在很多困难.研究MYC启动区G4-DNA的结构，有利于靶向c-MYC基因启动子区G4-DNA的抗癌药物的开发和临床推进，从而提高癌症病人的存活率.NMR在分子量较小的G4-DNA及G4-RNA结构确定中具有冷冻电镜、X-单晶衍射不可取代的特色作用，在靶向G4-DNA小分子药物筛选方面也能发挥前期引导应用，因此，结合NMR、小分子药物有机合成和药物选择性相互作用确认等技术，靶向c-MYC G4-DNA的抗肿瘤药物的开发将会迎来新局面.

利益冲突

无

参考文献

WELLS R D , DERE R , HEBERT M L , et al.

Advances in mechanisms of genetic instability related to hereditary neurological diseases

[J]. Nucleic Acids Res, 2005, 33 (12): 3785- 3798.

DOI:10.1093/nar/gki697      [本文引用: 1]

GELLERT M , LIPSETT M N , DAVIES D R .

Helix formation by guanylic acid

[J]. Proc Natl Acad Sci U S A, 1962, 48 (12): 2013- 2018.

DOI:10.1073/pnas.48.12.2013      [本文引用: 1]

ADRIAN M , HEDDI B , PHAN A T .

NMR spectroscopy of G-quadruplexes

[J]. Methods, 2012, 57 (1): 11- 24.

DOI:10.1016/j.ymeth.2012.05.003      [本文引用: 2]

HUPPERT J L .

Four-stranded nucleic acids: structure, function and targeting of G-quadruplexes

[J]. Chem Soc Rev, 2008, 39 (40): 1375- 1384.

[本文引用: 1]

BALASUBRAMANIAN S , HURLEY L H , NEIDLE S .

Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?

[J]. Nat Rev Drug Discov, 2011, 10, 261- 275.

DOI:10.1038/nrd3428      [本文引用: 1]

LIPPS H J , RHODES D .

G-quadruplex structures: in vivo evidence and function

[J]. Trends Cell Biol, 2009, 19 (8): 414- 422.

DOI:10.1016/j.tcb.2009.05.002      [本文引用: 1]

TORNALETTI S .

Transcriptional processing of G4 DNA

[J]. Mol Carcinog, 2009, 48 (4): 326- 335.

DOI:10.1002/mc.20513      [本文引用: 1]

COONEY M , CZERNUSZEWICZ G , POSTEL E H , et al.

Site-specific oligonucleotide binding represses transcription of the human c-myc gene in vitro

[J]. Science, 1988, 241 (4864): 456- 459.

DOI:10.1126/science.3293213      [本文引用: 1]

TOMONAGA T , LEVENS D .

Activating transcription from single stranded DNA

[J]. Proc Natl Acad Sci U S A, 1996, 93, 5830- 5835.

DOI:10.1073/pnas.93.12.5830      [本文引用: 1]

SEENISAMY J , BASHYAM S , GOKHALE V , et al.

Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure

[J]. J Am Chem Soc, 2005, 127 (9): 2944- 2959.

DOI:10.1021/ja0444482      [本文引用: 4]

SIDDIQUI-JAIN A , GRAND C L , BEARSS D J , et al.

Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription

[J]. Proc Natl Acad Sci U S A, 2002, 99, 11593- 11598.

DOI:10.1073/pnas.182256799      [本文引用: 3]

SUN Z Y , WANG X N , CHENG S Q , et al.

Developing novel G-quadruplex ligands: from interaction with nucleic acids to interfering with nucleic acid(-)protein interaction

[J]. Molecules, 2019, 24 (3): 396.

DOI:10.3390/molecules24030396      [本文引用: 1]

BRAZDA V , HARONIKOVA L , LIAO J C , et al.

DNA and RNA quadruplex-binding proteins

[J]. Int J Mol Sci, 2014, 15, 17493- 17517.

DOI:10.3390/ijms151017493     

VARSHNEY D , SPIEGEL J , ZYNER K , et al.

The regulation and functions of DNA and RNA G-quadruplexes

[J]. Nat Rev Mol Cell Biol, 2020, 21, 459- 474.

DOI:10.1038/s41580-020-0236-x      [本文引用: 1]

GONZALEZ V , GUO K X , HURLEY L , et al.

Identification and characterization of nucleolin as a c-MYC G-quadruplex-binding protein

[J]. J Biol Chem, 2009, 284 (35): 23622- 23635.

DOI:10.1074/jbc.M109.018028      [本文引用: 1]

GONZALEZ V , HURLEY L H .

The C-terminus of nucleolin promotes the formation of the c-MYC G-quadruplex and inhibits c-MYC promoter activity

[J]. Biochemistry, 2010, 49 (45): 9706- 9714.

DOI:10.1021/bi100509s      [本文引用: 1]

FEDERICI L , ARCOVITO A , SCAGLIONE G L , et al.

Nucleophosmin C-terminal leukemia-associated domain interacts with G-rich quadruplex forming DNA

[J]. J Biol Chem, 2010, 285 (48): 37138- 37149.

DOI:10.1074/jbc.M110.166736      [本文引用: 1]

Scognamiglio P L , Di Natale C , Leone M , et al.

G-quadruplex DNA recognition by nucleophosmin: new insights from protein dissection

[J]. Biochim Biophys Acta, 2014, 1840 (6): 2050- 2059.

DOI:10.1016/j.bbagen.2014.02.017     

GALLO A , STERZO CL , MORI M , et al.

Structure of nucleophosmin DNA-binding domain and analysis of its complex with a G-quadruplex sequence from the c-MYC promoter

[J]. J Biol Chem, 2012, 287 (32): 26539- 26548.

DOI:10.1074/jbc.M112.371013      [本文引用: 1]

KANG H J , LE TVT , KIM K , et al.

Novel interaction of the Z-DNA binding domain of human ADAR1 with the oncogenic c-MYC promoter G-quadruplex

[J]. J Mol Biol, 2014, 426 (14): 2594- 2604.

DOI:10.1016/j.jmb.2014.05.001      [本文引用: 1]

PETR M , HELMA R , POLÁŠKOVÁ A , et al.

Wild-type p53 binds to MYC promoter G-quadruplex

[J]. Biosci Rep, 2016, 36 (5): e00397.

DOI:10.1042/BSR20160232      [本文引用: 1]

SANDERS C M .

Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity

[J]. Biochem J, 2010, 430, 119- 128.

DOI:10.1042/BJ20100612      [本文引用: 1]

BYRD A K , RANEY K D .

A parallel quadruplex DNA is bound tightly but unfolded slowly by pif1 helicase

[J]. J Biol Chem, 2015, 290 (10): 6482- 6494.

DOI:10.1074/jbc.M114.630749     

BYRD A K , BELL M R , RANEY K D .

Pif1 helicase unfolding of G-quadruplex DNA is highly dependent on sequence and reaction conditions

[J]. J Biol Chem, 2018, 293 (46): 17792- 17802.

DOI:10.1074/jbc.RA118.004499      [本文引用: 1]

LEE S , LEE A R , RYU K S , et al.

NMR investigation of the interaction between the RecQ C-terminal domain of human bloom syndrome protein and G-quadruplex DNA from the human c-MYC promoter

[J]. J Mol Biol, 2019, 431 (4): 794- 806.

DOI:10.1016/j.jmb.2019.01.010      [本文引用: 1]

BUDHATHOKI J B , RAY S , URBAN V , et al.

RecQ-core of BLM unfolds telomeric G-quadruplex in the absence of ATP

[J]. Nucleic Acids Res, 2014, 42 (18): 11528- 11545.

DOI:10.1093/nar/gku856     

CHATTERJEE S , ZAGELBAUM J , SAVITSKY P , et al.

Mechanistic insight into the interaction of BLM helicase with intra-strand G-quadruplex structures

[J]. Nat Commun, 2014, 5, 5556.

DOI:10.1038/ncomms6556      [本文引用: 1]

KAROW J K , WU L , HICKSON I D .

RecQ family helicases: roles in cancer and aging

[J]. Curr Opin Genet Dev, 2000, 10 (1): 32- 38.

DOI:10.1016/S0959-437X(99)00039-8      [本文引用: 1]

SUN H , KAROW J K. , HICKSON I D , et al.

The Bloom's syndrome helicase unwinds G4 DNA

[J]. J Biol Chem, 1998, 273 (42): 27587- 27592.

DOI:10.1074/jbc.273.42.27587      [本文引用: 1]

WU G H , XING Z , TRAN E J , et al.

DDX5 helicase resolves G-quadruplex and is involved in MYC gene transcriptional activation

[J]. Proc Natl Acad Sci U S A, 2019, 116 (41): 20453- 20461.

DOI:10.1073/pnas.1909047116      [本文引用: 1]

POSTEL E H , BERBERICH S J , FLINT S J , et al.

Human c-MYC transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis

[J]. Science, 1993, 261 (5120): 478- 480.

DOI:10.1126/science.8392752      [本文引用: 1]

JI L , ARCINAS M , BOXER L M .

The transcription factor, Nm23H2, binds to and activates the translocated c-MYC allele in Burkitt's lymphoma

[J]. J Biol Chem, 1995, 270 (22): 13392- 13398.

DOI:10.1074/jbc.270.22.13392      [本文引用: 1]

FEKETE A , KENESI E , HUNYADI-GULYAS E , et al.

The guanine-quadruplex structure in the human c-myc gene's promoter is converted into B-DNA form by the human poly(ADP-ribose)polymerase-1

[J]. PLoS One, 2012, 7, e42690.

DOI:10.1371/journal.pone.0042690      [本文引用: 1]

OU T M , LIN J , LU Y J , et al.

Inhibition of cell proliferation by quindoline derivative (SYUIQ-05) through its preferential interaction with c-MYC promoter G-quadruplex

[J]. J Med Chem, 2011, 54 (16): 5671- 5679.

DOI:10.1021/jm200062u      [本文引用: 2]

DAI J X , CARVER M , HURLEY L H , et al.

Solution structure of a 2:1 quindoline-c-MYC G-quadruplex: insights into G-quadruplex-interactive small molecule drug design

[J]. J Am Chem Soc, 2011, 133 (44): 17673- 17680.

DOI:10.1021/ja205646q      [本文引用: 1]

ZENG D Y , KUANG G T , WANG S K , et al.

Discovery of Novel 11-triazole substituted benzofuro[3, 2-b]quinolone derivatives as c-MYC G-quadruplex specific stabilizers via click chemistry

[J]. J Med Chem, 2017, 60, 5407- 5423.

DOI:10.1021/acs.jmedchem.7b00016     

LIU H Y , CHEN A C , YIN Q K , et al.

New Disubstituted quindoline derivatives inhibiting Burkitt's lymphoma cell proliferation by impeding c-MYC transcription

[J]. J Med Chem, 2017, 60 (13): 5438- 5454.

DOI:10.1021/acs.jmedchem.7b00099      [本文引用: 1]

GABELICA V , BAKER E S , TEULADE-FICHOU M P , et al.

Stabilization and structure of telomeric and c-MYC region intramolecular G-quadruplexes: the role of central cations and small planar ligands

[J]. J Am Chem Soc, 2007, 129 (4): 895- 904.

DOI:10.1021/ja065989p      [本文引用: 1]

GRAND C L , HAN H Y , MUNOZ R M , et al.

The cationic porphyrin TMPyP4 down-regulates c-MYC and human telomerase reverse transcriptase expression and inhibits tumor growth in vivo

[J]. Mol Cancer Ther, 2002, 1, 565- 573.

URL    

SEENISAMY J , REZLER E M , POWELL T J , et al.

The dynamic character of the G-quadruplex element in the c-MYC promoter and modification by TMPyP4

[J]. J Am Chem Soc, 2004, 126 (28): 8702- 8709.

DOI:10.1021/ja040022b     

PHAN A T , KURYAVYI V , GAW H Y , et al.

Small-molecule interaction with a five-guanine-tract G-quadruplex structure from the human MYC promoter

[J]. Nat Chem Biol, 2005, 1, 167- 173.

DOI:10.1038/nchembio723      [本文引用: 1]

HU M H , WANG Y Q , YU Z Y , et al.

Discovery of a new four-leaf clover-like ligand as a potent c-MYC transcription inhibitor specifically targeting the promoter G-quadruplex

[J]. J Med Chem, 2018, 61 (6): 2447- 2459.

DOI:10.1021/acs.jmedchem.7b01697      [本文引用: 1]

WU T Y , HUANG Q , HUANG Z S , et al.

A drug-like imidazole-benzothiazole conjugate inhibits malignant melanoma by stabilizing the c-MYC G-quadruplex

[J]. Bioorg Chem, 2020, 99, 103866.

DOI:10.1016/j.bioorg.2020.103866      [本文引用: 1]

HU M H , WU T Y , HUANG Q , et al.

New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription

[J]. Nucleic Acids Res, 2019, 47 (20): 10529- 10542.

DOI:10.1093/nar/gkz835      [本文引用: 1]

GLUSZYNSKA A , JUSKOWIAK B , KUTA-SIEJKOWSKA M , et al.

Carbazole ligands as c-MYC G-quadruplex binders

[J]. Int J Biol Macromol, 2018, 114, 479- 490.

DOI:10.1016/j.ijbiomac.2018.03.135      [本文引用: 1]

DAS T , PANDA D , SAHA P , et al.

Small molecule driven stabilization of promoter G-quadruplexes and transcriptional regulation of c-MYC

[J]. Bioconjug Chem, 2018, 29 (8): 2636- 2645.

DOI:10.1021/acs.bioconjchem.8b00338      [本文引用: 1]

SCHMIDT A W , REDDY K R , KNOLKER H J .

Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids

[J]. Chem Rev, 2012, 112 (6): 3193- 3328.

DOI:10.1021/cr200447s      [本文引用: 1]

MA Y , OU T M , HOU J Q , et al.

9-N-substituted berberine derivatives: stabilization of G-quadruplex DNA and down-regulation of oncogene c-MYC

[J]. Bioorg Med Chem, 2008, 16 (16): 7582- 7591.

DOI:10.1016/j.bmc.2008.07.029      [本文引用: 1]

PENG D , TAN J H , CHEN S B , et al.

Bisaryldiketene derivatives: A new class of selective ligands for c-myc G-quadruplex DNA

[J]. Bioorg Med Chem, 2010, 18 (23): 8235- 8242.

DOI:10.1016/j.bmc.2010.10.021      [本文引用: 1]

SHAN C , YAN J W , WANG Y Q , et al.

Design, synthesis, and evaluation of isaindigotone derivatives to downregulate c-MYC transcription via disrupting the interaction of NM23-H2 with G-quadruplex

[J]. J Med Chem, 2017, 60 (4): 1292- 1308.

DOI:10.1021/acs.jmedchem.6b01218      [本文引用: 2]

Islam M M , Fujii S , Sato S , et al.

A selective G-quadruplex DNA-stabilizing ligand based on a cyclic naphthalene diimide derivative

[J]. Molecules, 2015, 20, 10963- 10979.

DOI:10.3390/molecules200610963      [本文引用: 1]

CHAN D S H , YANG H , KWAN M H T , et al.

Structure-based optimization of FDA-approved drug methylene blue as a c-MYC G-quadruplex DNA stabilizer

[J]. Biochimie, 2011, 93 (6): 1055- 1064.

DOI:10.1016/j.biochi.2011.02.013      [本文引用: 2]

ALZEER J , LUEDTKE N W .

pH-mediated fluorescence and G-quadruplex binding of amido phthalocyanines

[J]. Biochemistry, 2010, 49 (20): 4339- 4348.

DOI:10.1021/bi9020583      [本文引用: 1]

VORLICKOVA M , KEJNOVSKÁ I , SAGI J , et al.

Circular dichroism and guanine quadruplexes

[J]. Methods, 2012, 57 (1): 64- 75.

DOI:10.1016/j.ymeth.2012.03.011      [本文引用: 1]

SEN D , GILBERT W .

Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis

[J]. Nature, 1988, 334, 364- 366.

DOI:10.1038/334364a0      [本文引用: 1]

MARCHAND A , FERREIRA R , TATEISHI-KARIMATA H , et al.

Sequence and solvent effects on telomeric DNA bimolecular G-quadruplex folding kinetics

[J]. J Phys Chem B, 2013, 117 (41): 12391- 12401.

DOI:10.1021/jp406857s      [本文引用: 1]

TONG X T , LAN W X , ZHANG X , et al.

Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence

[J]. Nucleic Acids Res, 2011, 39 (15): 6753- 6763.

DOI:10.1093/nar/gkr233      [本文引用: 2]

LI M M , WU S , LIU Z , et al.

Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGF-mediated angiogenesis through suppression of VEGFR-2 signaling pathway

[J]. Biochem Pharmacol, 2012, 83 (9): 1251- 1260.

DOI:10.1016/j.bcp.2012.01.023      [本文引用: 2]

LIU Y P , LAN W X , WANG C X , et al.

A putative G-quadruplex structure in the proximal promoter of VEGFR-2 has implications for drug design to inhibit tumor angiogenesis

[J]. J Biol Chem, 2018, 293 (23): 8947- 8955.

DOI:10.1074/jbc.RA118.002666      [本文引用: 3]

CALABRESE D R , CHEN X , LEON E C , et al.

Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex

[J]. Nat Commun, 2018, 9, 4229.

DOI:10.1038/s41467-018-06315-w      [本文引用: 3]

WANG F , WANG C X , LIU Y P , et al.

Colchicine selective interaction with oncogene RET G-quadruplex revealed by NMR

[J]. Chem Commun (Camb), 2020, 56 (14): 2099- 2102.

DOI:10.1039/D0CC00221F      [本文引用: 4]

WANG F , WANG C X , LIU Y P , et al.

NMR studies on the interaction between oncogene RET G-quadruplex and berberine

[J]. Chinese J Chem, 2020, 38 (12): 1656- 1662.

DOI:10.1002/cjoc.202000301      [本文引用: 1]

/

〈 〉

网站设计版权所有 © 2017 《波谱学杂志》编辑部
地址：湖北省武汉市武昌区小洪山西30号 中科院精密测量科学与技术创新研究院波谱楼 《波谱学杂志》编辑部
邮编：430071　电话/传真：(086)027－87198791   E-mail: magres@wipm.ac.cn
本系统由北京玛格泰克科技发展有限公司设计开发