胡曉東，藍(lán)文賢，王春喜，曹春陽

靶向腫瘤因子c-基因啟動(dòng)區(qū)G4-DNA的小分子藥物設(shè)計(jì)及核磁共振研究進(jìn)展

胡曉東，藍(lán)文賢，王春喜，曹春陽*

中國科學(xué)院分子合成卓越中心，中國科學(xué)院上海有機(jī)化學(xué)研究所生命有機(jī)國家重點(diǎn)實(shí)驗(yàn)室，上海 200032

腫瘤基因在人類70%癌細(xì)胞中高表達(dá)，抑制其轉(zhuǎn)錄是治療腫瘤的有效手段．c-啟動(dòng)子區(qū)P1近端的核酸酶超敏元件III1（NHE III1）控制基因近90%的轉(zhuǎn)錄激活．NHE III1區(qū)域富含堿基G序列并且形成G-四鏈體（G4），調(diào)控c-基因轉(zhuǎn)錄，是抗腫瘤藥物靶標(biāo)．但G4-DNA和G4-RNA的三維結(jié)構(gòu)高度相似，小分子與其他G4（如端粒G4、mRNA G4、c-G4等）的非特異性作用會(huì)產(chǎn)生小分子藥物“脫靶”效應(yīng)，同時(shí)小分子藥物會(huì)誘導(dǎo)其他G4形成從而干擾正常細(xì)胞的功能，造成靶向c-G4抗癌藥物設(shè)計(jì)困難．本文綜述了近些年靶向腫瘤因子c-G4-DNA的小分子藥物研究進(jìn)展，及核磁共振（NMR）技術(shù)在G4-DNA和G4-RNA結(jié)構(gòu)確定中的作用，為靶向c-G4-DNA的小分子藥物設(shè)計(jì)等相關(guān)研究工作提供參考．

腫瘤基因；c-；G-四鏈體（G4）；小分子藥物；核磁共振（NMR）

引 言

脫氧核糖核酸（DNA）是重要的遺傳物質(zhì)，不僅可以形成規(guī)整的B型雙螺旋結(jié)構(gòu)，還可以形成十余種不規(guī)整的非B型DNA結(jié)構(gòu)，如Z-DNA、DNA錯(cuò)配、三螺旋（triplex）、四螺旋（quadruplex）、發(fā)卡式結(jié)構(gòu)等[1]．G-四鏈體（G4）是由Gellert等[2]于1962年發(fā)現(xiàn)的一種不規(guī)整的核酸二級(jí)結(jié)構(gòu)，主要由富含鳥嘌呤（G）的DNA或RNA序列在一價(jià)陽離子（K+、Na+或NH4+等）的作用下，通過Hoogsteen氫鍵形成G-四集體（G-tetrad）（圖1），并進(jìn)一步堆積而成．

圖1 G-四鏈體結(jié)構(gòu)組成．(a) G-四集體通過Hoogsteen氫鍵形成；(b) G-四鏈體結(jié)構(gòu)中心被一價(jià)陽離子穩(wěn)定

G-四鏈體結(jié)構(gòu)形式多樣，包括：（1）鏈排列方向多樣性．四條鏈有三種組合方式：四條鏈都平行、三條鏈平行與另一條鏈反平行、兩條鏈平行與另外兩條反平行[圖2(a)]；（2）連接兩條鏈的loop幾何結(jié)構(gòu)多樣性．當(dāng)G-四鏈體為分子內(nèi)或者雙分子結(jié)構(gòu)時(shí)，用以連接鏈的loop的不同跨越會(huì)導(dǎo)致其多樣性．比如在雙分子G-四鏈體結(jié)構(gòu)中，loop可以連接相鄰或?qū)堑逆湥瑑蓚€(gè)loop可以頭-尾或頭-頭方式排列[圖2(b)]；（3）鏈數(shù)量多樣性．形成G-四鏈體同一寡核苷酸可以分子內(nèi)折疊，也可以分子間折疊，形成單體、二聚體或者四聚體G-四鏈體[圖2(c)]．

圖2 G-四鏈體結(jié)構(gòu)多樣性．(a) G-四集體的四種鏈朝向；(b)三種主要的Loop連接方式；(c)單體分子內(nèi)和雙分子分子間G-四鏈體．紅色箭頭代表鏈從5’到3’朝向[3]

真核和原核生物基因組都含有大量G-四鏈體結(jié)構(gòu)．有研究[4]表明，人類基因組含有約37萬條可以形成G-四鏈體的基因序列，分布在以下幾類與基因功能密切相關(guān)的區(qū)域．（1）細(xì)胞核內(nèi)基因的啟動(dòng)子區(qū)域，特別是致癌因子（如c-、c-、、、、、）的啟動(dòng)子區(qū)．G-四鏈體可參與基因轉(zhuǎn)錄調(diào)控，是抗癌藥物靶標(biāo)[5]；也可在轉(zhuǎn)錄時(shí)產(chǎn)生單鏈DNA，影響mRNA合成．（2）端粒區(qū)域．端粒DNA是真核生物染色體線性DNA，3’末端一段富含G重復(fù)序列，用以維持染色體的穩(wěn)定．當(dāng)該G鏈懸突中有G-四鏈體形成時(shí)，會(huì)影響端粒酶的逆轉(zhuǎn)錄活性，從而導(dǎo)致端粒不能正常延伸．（3）細(xì)胞質(zhì)中單鏈mRNA區(qū)域也能形成G-四鏈體，使得核糖體無法識(shí)別mRNA上密碼子，導(dǎo)致翻譯停止，從而下調(diào)基因表達(dá)[6]．（4）外顯子及內(nèi)含子區(qū)域．當(dāng)轉(zhuǎn)錄通過編碼鏈上富含G的序列時(shí)，G-四鏈體的形成會(huì)導(dǎo)致基因組的不穩(wěn)定，觸發(fā)機(jī)體轉(zhuǎn)錄偶聯(lián)修復(fù)（TCR）途徑，修補(bǔ)基因組中具有轉(zhuǎn)錄活性的基因編碼鏈上不正常結(jié)構(gòu)引起的損傷．G-四鏈體的形成會(huì)使RNA聚合酶II發(fā)生停滯，使mRNA合成受阻．修復(fù)過程會(huì)招募TCR因子，但此過程較容易引起不必要的TCR，造成無損傷部位產(chǎn)生重復(fù)的修復(fù)補(bǔ)丁；在高轉(zhuǎn)錄區(qū)域，這種情況會(huì)導(dǎo)致自發(fā)突變水平增加[7]．

基于G-四鏈體分布的廣泛性，及其在抗腫瘤藥物篩選等方面的潛在應(yīng)用，本文對(duì)與人類70%惡性腫瘤相關(guān)的c-基因G-四鏈體結(jié)構(gòu)及相關(guān)的小分子藥物篩選進(jìn)行了綜述，以期為相關(guān)領(lǐng)域的研究人員提供參考．

1 c-MYC基因的分布、結(jié)構(gòu)與功能

c基因在人類70%惡性腫瘤（如乳腺癌、結(jié)腸癌、膠質(zhì)母細(xì)胞瘤、宮頸癌、小細(xì)胞肺癌、骨髓性白血病等）細(xì)胞中過量表達(dá)．基因產(chǎn)物是一個(gè)轉(zhuǎn)錄因子，在目標(biāo)啟動(dòng)子區(qū)與MYC關(guān)聯(lián)因子MAX形成雜二聚體，結(jié)合特定的E-boxes，控制多種腫瘤靶基因的表達(dá)．該功能對(duì)許多生理過程非常必要，如細(xì)胞增殖、分化、粘附、凋亡、血管生成和轉(zhuǎn)移等等．表達(dá)水平的增加，會(huì)直接導(dǎo)致與癌癥發(fā)生與惡化相關(guān)的基因表達(dá)，降低癌癥臨床治愈率．而基因的轉(zhuǎn)錄抑制，會(huì)減少大多數(shù)腫瘤細(xì)胞的繁殖與生長，但不影響正常細(xì)胞的功能．因此，靶向基因進(jìn)行合理的抗腫瘤藥物設(shè)計(jì)，有望有效和安全地治療人類各種腫瘤及其相關(guān)的疾?。?/p>

異常的基因在腫瘤細(xì)胞中的表達(dá)主要在轉(zhuǎn)錄水平被調(diào)節(jié)．c-啟動(dòng)子P1近端核酸酶超敏元件III1（NHE III1）控制該基因高達(dá)90%的轉(zhuǎn)錄激活，而NHE III1區(qū)域富含堿基G，可以形成G-四鏈體結(jié)構(gòu)，對(duì)c-轉(zhuǎn)錄具有負(fù)調(diào)控作用，這表明NHE III1序列二級(jí)結(jié)構(gòu)處于B型雙螺旋和非B型結(jié)構(gòu)動(dòng)態(tài)平衡中[8,9]．天然狀態(tài)下，該區(qū)域形成四種平行G-四鏈體結(jié)構(gòu)混合體，四種結(jié)構(gòu)的區(qū)別在于形成loop堿基數(shù)不同（圖3）．當(dāng)這些G-四鏈體與小分子配體TMPyP4相互作用時(shí)，轉(zhuǎn)變成平行與反平行混合的G-四鏈體結(jié)構(gòu)．

2 靶向c-MYC啟動(dòng)區(qū)G4-DNA的抗腫瘤藥物設(shè)計(jì)

2.1 靶向c-MYC啟動(dòng)區(qū)G4-DNA的抗腫瘤藥物分子機(jī)制

當(dāng)NHE III1富含G區(qū)域的序列處于單鏈狀態(tài)時(shí)，轉(zhuǎn)錄激活因子CNBP（CCHC-type zinc finger Nucleic acid-Binding Protein）及hnRNP K（heterogeneous nuclear RiboNucleoProtein K）和單鏈DNA結(jié)合，促進(jìn)轉(zhuǎn)錄進(jìn)行；當(dāng)該序列被TMPyP4或Se2SAP穩(wěn)定時(shí)，G-四鏈體阻礙CNBP及hnRNP K與NHE III1結(jié)合，轉(zhuǎn)錄被抑制[10,11]（圖4）．

圖3 已報(bào)道的c-MYC基因啟動(dòng)子的G4結(jié)構(gòu)．(a) MYC基因的啟動(dòng)子結(jié)構(gòu)和不同的相關(guān)元素；(b) MYC-1245、MYC-1234、MYC-2345、Pu22(4/14/23T) G4-DNA結(jié)構(gòu)示意圖．箭頭指示5’到3’方向的DNA鏈；堿基G用圓圈表示，堿基A和T用正方形表示

圖4 c-MYC啟動(dòng)子NHE III1形成的G-四鏈體結(jié)構(gòu)對(duì)轉(zhuǎn)錄的調(diào)控[10,11]

c-G4-DNA本身不能參與腫瘤細(xì)胞生長與發(fā)育過程，需要在相關(guān)蛋白存在下才能發(fā)揮調(diào)節(jié)功能．如圖5所示，這些蛋白通過與c-G4-DNA結(jié)合，促進(jìn)、穩(wěn)定或解開其G4-DNA結(jié)構(gòu)來介導(dǎo)基因的轉(zhuǎn)錄[12-14]．如蛋白nucleolin（NCL）的RNA結(jié)合結(jié)構(gòu)域(RBDs)3、(RBDs)4，及RGG（Arg-Gly-Gly）結(jié)構(gòu)域與NHE III1區(qū)富含G序列作用能促進(jìn)c-G4-DNA形成，穩(wěn)定其結(jié)構(gòu)[15,16]，抑制基因轉(zhuǎn)錄．CNBP蛋白是首個(gè)報(bào)道的富含G的DNA或RNA結(jié)合蛋白，能促進(jìn)G4-DNA形成，致使基因轉(zhuǎn)錄片刻內(nèi)被抑制，同時(shí)招募NM23-H2，激活基因轉(zhuǎn)錄．核仁磷酸蛋白NPM1（NucleoPhosMin 1）C端NPM1-C70[17-19]及作用于雙鏈RNA 1的腺苷脫氨基化酶ADR1（Adenosine Deaminase acting on RNA 1）的Z-DNA結(jié)合域[20]都能結(jié)合單鏈NHE III1富含G序列，促進(jìn)c-G4-DNA形成，抑制基因轉(zhuǎn)錄．腫瘤抑制因子P53突變體C端片段320-393 aa與c-G4-DNA結(jié)合作用很強(qiáng)[21]，可在腫瘤細(xì)胞中調(diào)節(jié)基因表達(dá)．解螺旋酶Pif1[22-24]、BLM[25-27]、WRN[28,29]、DDX5[30]、NM23-H2[31,32]及PARP-1[33]等通過與c-G4-DNA作用，使其去折疊，抑制癌癥轉(zhuǎn)移．

圖5 與c-MYC G4相互作用的蛋白的結(jié)合方式．提升(a)和穩(wěn)定(b)G4結(jié)構(gòu)穩(wěn)定性結(jié)合方式；(c)解螺旋G4結(jié)構(gòu)的結(jié)合方式

2.2 靶向c-MYC G4-DNA的小分子藥物作用模式及缺陷

基于c-G4-DNA結(jié)構(gòu)作為轉(zhuǎn)錄的沉默元件的特點(diǎn)，抗腫瘤藥物分子通過與其結(jié)合并穩(wěn)定其結(jié)構(gòu)，從而降低癌細(xì)胞中c-表達(dá)，可用作治療腫瘤．核磁共振（NMR）波譜、X-單晶衍射及計(jì)算分析研究表明，藥物分子與G4-DNA可以在5’端、3’端、G-四集體之間、loop區(qū)及G4-DNA表面的溝槽等不同位置結(jié)合，如圖6所示．

圖6 四種配體與G4-DNA的結(jié)合模型．(a)配體在5’端、3’端或兩端疊加的復(fù)合物結(jié)構(gòu)模型；(b)配體插入G-四集體之間的結(jié)構(gòu)模型；(c)配體在溝槽或loop上結(jié)合的結(jié)構(gòu)模型；(d)配體停留在G4-DNA結(jié)構(gòu)中心的復(fù)合物結(jié)構(gòu)模型

目前蛋白質(zhì)結(jié)構(gòu)數(shù)據(jù)庫（PDB）庫中與c-G4相關(guān)的結(jié)構(gòu)數(shù)量有197個(gè)，其中c-G4與小分子復(fù)合物的結(jié)構(gòu)數(shù)量為十余個(gè)．這為理解相關(guān)的分子識(shí)別機(jī)制奠定了基礎(chǔ)．如圖7所示，文獻(xiàn)報(bào)道的能夠結(jié)合并穩(wěn)定c-G4-DNA結(jié)構(gòu)，并且已進(jìn)入臨床前或者臨床II期研究的小分子藥物包括：喹叨啉類（quindoline）化合物（如SYUIO-05[34]、7a4[35]、T-BFQs[34-37]），陽離子卟啉類（cationic porphyrins）[10,38-41]，咪唑類[42,43]，喹喔啉類（quinoxalines）[44]，咔唑類（carbazoles）[45-47]（如Cz-1[46]），小檗堿衍生物[48-50]，isaindigotone衍生物[50]，bisaryldiketene衍生物[49]，環(huán)萘二酰亞胺類（cyclic naphthalene diimide）衍生物[51,52]，亞甲藍(lán)（methylene blue）衍生物[52]，氨基酞菁（amido phthalocyanine）[53]等．但是，盡管這么多化合物能夠靶向c-G4-DNA，顯示抑制基因轉(zhuǎn)錄的效果，但迄今為止仍然沒有一個(gè)小分子化合物被批準(zhǔn)上市，主要原因如下：（1）目前所有報(bào)道的G4-DNA、G4-RNA結(jié)構(gòu)具有很高的相似性；因此設(shè)計(jì)出來的小分子有可能與其他G4-DNA或者G4-RNA相互作用，造成“脫靶”效應(yīng)；（2）靶向c-G4-DNA的小分子，一方面可以促進(jìn)c-G4-DNA結(jié)構(gòu)的形成，另一方面也會(huì)促進(jìn)其他G4結(jié)構(gòu)的形成，從而干擾正常細(xì)胞發(fā)揮功能．因此靶向c-G4-DNA的小分子藥物的設(shè)計(jì)需要新的思路．

圖7 直接或間接與c-MYC G4-DNA結(jié)合的化合物的結(jié)構(gòu)

3 G-四鏈體結(jié)構(gòu)及其與小分子相互作用機(jī)制的NMR研究

研究G-四鏈體結(jié)構(gòu)常用的技術(shù)手段有：（1）圓二色譜（CD）與其他技術(shù)的聯(lián)用．CD可以作為一個(gè)首選方法用來判斷有無G-四鏈體形成[54]，電泳、層析及質(zhì)譜法可以給出分子的大小[55,56]．但這些方法均不能給出原子分辨率的結(jié)構(gòu)信息．（2）X-ray單晶衍射技術(shù)．但是G-四鏈體分子在水溶液中不易結(jié)晶，因此不是首選方法．（3）NMR技術(shù)．NMR可以監(jiān)測(cè)和分辨多種構(gòu)象．G-四鏈體中鳥嘌呤的亞氨基質(zhì)子，其化學(xué)位移在一般在10～12范圍內(nèi)；而Watson-Crick堿基互補(bǔ)配對(duì)中亞氨基質(zhì)子的化學(xué)位移則位于更低場（13～14）．位于中間G-四集體上的鳥嘌呤的亞氨基質(zhì)子與溶劑重水交換非常慢（圖8），利于G-四鏈體拓?fù)浣Y(jié)構(gòu)測(cè)定．

圖8 (a)三片層G-四鏈體在H2O（下）中及交換到D2O中1 h（上）后的亞氨基質(zhì)子的一維氫譜；(b) RET G-四鏈體的拓?fù)浣Y(jié)構(gòu)[57]

利用NMR技術(shù)可以非常方便地解析分子量比較小、不易長單晶的G4-DNA或G4-RNA與小分子配體復(fù)合物結(jié)構(gòu)．有研究[58]報(bào)道，VEGFR-2在腫瘤生長過程中表達(dá)上調(diào)，抑制VEGFR-2的表達(dá)可以抑制血管生成，進(jìn)而阻止腫瘤生長，而且VEGFR-2還與增殖性視網(wǎng)膜疾病密切相關(guān)．因此VEGF和VEGFR-2可以作為潛在的抗腫瘤相關(guān)藥物的靶點(diǎn)，阻斷VEGF/VEGFR-2信號(hào)通路，或者阻止VEGF與VEGFR-2蛋白的結(jié)合均可作為抗腫瘤藥物設(shè)計(jì)的著手點(diǎn)[58]．基因啟動(dòng)子區(qū)-120到-90之間存在一段GC富集區(qū)，位于該基因的轉(zhuǎn)錄起始位點(diǎn)上游，對(duì)其轉(zhuǎn)錄具有調(diào)控作用．2018年，Liu等[59]利用NMR技術(shù)確定了該區(qū)域堿基序列突變體VEGFR-17T的G4-DNA結(jié)構(gòu)（圖9），它由三個(gè)疊置的G-tetrad組成，包含三個(gè)鳥嘌呤．第一個(gè)鳥嘌呤G1位于中央G-四分體內(nèi)．一個(gè)非典型的v形環(huán)跨越三個(gè)G-四集體平面的loop，不含有任何堿基．此外，還含有一個(gè)堿基序列較長的且呈現(xiàn)對(duì)角線形狀的環(huán)狀loop，包括六個(gè)核苷酸，連接著反向的雙鏈．

圖9 vegfr-2 17T G4-DNA的溶液結(jié)構(gòu)．(a)飄帶圖，(b) carton示意圖．其中，紫色表示syn構(gòu)象的堿基G，藍(lán)色表示anti構(gòu)象的堿基G，黃色表示G-C堿基對(duì)[59]

2018年，Calabrese等[60]利用NMR技術(shù)解析了小分子化合物DC-34與c-G4-DNA復(fù)合物的溶液三維結(jié)構(gòu)（圖10），發(fā)現(xiàn)兩個(gè)DC-34分子以滿負(fù)荷的方式分別結(jié)合在c-G4-DNA的5’及3’端．

圖10 DC-34與c-MYC G4復(fù)合物NMR結(jié)構(gòu)（PDB：5W77）．所有的分子以桿狀圖顯示．兩個(gè)DC-34分子分別為綠色和黃色，K+以紫色小球表示[60]

2020年，Wang等[61]利用NMR技術(shù)篩選1 000多個(gè)小分子后，發(fā)現(xiàn)天然產(chǎn)物秋水仙素（colchicine）能夠特異性結(jié)合腫瘤因子啟動(dòng)子區(qū)G4-DNA結(jié)構(gòu)（圖11）．他們利用NMR技術(shù)進(jìn)一步確定了colchicine結(jié)合G4-DNA的復(fù)合物結(jié)構(gòu)[61]，發(fā)現(xiàn)colchicine結(jié)合在G4-DNA的3’端，通過破壞堿基G14與G4-DNA原有的骨架G-tetrad之間的π-π堆積作用而與G4-DNA的3’端的G-tetrad發(fā)生堆積作用．這種作用方式與非特異性結(jié)合的配體berberine類似[62]，并沒有因?yàn)樾》肿咏Y(jié)構(gòu)的差異結(jié)合方式發(fā)生變化．小分子結(jié)構(gòu)分析表明，導(dǎo)致秋水仙素能夠特異性結(jié)合G4-DNA的原因在于，秋水仙素的小分子結(jié)構(gòu)剛性不及berberine，精細(xì)的柔性結(jié)構(gòu)導(dǎo)致其不能與c-G4-DNA、G4-DNA、c-G4-DNA相互作用，而只與G4-DNA相互作用．

圖11 RET G4-DNA與秋水仙堿復(fù)合物的結(jié)構(gòu)（橙色）．(a)能量最低的20個(gè)結(jié)構(gòu)的集合，堿基G14構(gòu)象是靈活的；(b)一個(gè)復(fù)合物的構(gòu)象，芳香七元環(huán)與苯環(huán)之間呈27.5?；(c)自由態(tài)RET G4-DNA的結(jié)構(gòu)；(d)秋水仙素（橙色球棍模型顯示）在復(fù)合物結(jié)構(gòu)中位置與自由態(tài)RET G4-DNA中的G3-G9-G13-G19四集體平面中的堿基G14對(duì)比．在圖(a)～(c)中，由4個(gè)syn鳥嘌呤組成的G-四集體分別為洋紅色線和卡通模式，anti鳥嘌呤組成的G-四集體分別以青色和卡通模式顯示．在所有圖中：堿基G14是深灰色的線條和卡通模式展示；堿基G16和T20分別為綠線和卡通模式展示；堿基G4、C5、G6和C10為小麥色或卡通模式展示．所有非極性質(zhì)子都沒有顯示出來[61]

4 總結(jié)與展望

在人類大部分癌細(xì)胞中高表達(dá)，抑制其轉(zhuǎn)錄是治療腫瘤的有效手段．c-啟動(dòng)子區(qū)P1近端NHE III1區(qū)域富含堿基G序列形成G-四鏈體，調(diào)控c-基因轉(zhuǎn)錄，是抗腫瘤藥物靶標(biāo)．目前靶向c-G4抗癌藥物因?yàn)椤懊摪小毙?yīng)，存在很多困難．研究啟動(dòng)區(qū)G4-DNA的結(jié)構(gòu)，有利于靶向c-基因啟動(dòng)子區(qū)G4-DNA的抗癌藥物的開發(fā)和臨床推進(jìn)，從而提高癌癥病人的存活率．NMR在分子量較小的G4-DNA及G4-RNA結(jié)構(gòu)確定中具有冷凍電鏡、X-單晶衍射不可取代的特色作用，在靶向G4-DNA小分子藥物篩選方面也能發(fā)揮前期引導(dǎo)應(yīng)用，因此，結(jié)合NMR、小分子藥物有機(jī)合成和藥物選擇性相互作用確認(rèn)等技術(shù)，靶向c-G4-DNA的抗腫瘤藥物的開發(fā)將會(huì)迎來新局面．

本工作得到基金委面上項(xiàng)目（91753119、21977110、21778065及21807105）支持．

無

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

，，，*

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

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) III1of c-promoter region controls nearly 90% transcriptional activation ofgene. This region enriched with base G forms G-quadruplex (G4) structure, which regulates c-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-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-G4. In this paper, we summarize the recent research progress of small molecules targeting tumor factor c-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-G4-DNA and other related research works.

tumor gene, c-,G-quadruplex (G4),small molecular drug, nuclear magnetic resonance (NMR)

O482.53

A

10.11938/cjmr20212928

2021-06-29;

2021-09-16

國家重點(diǎn)研發(fā)計(jì)劃資助項(xiàng)目(2017YFE0108200)；國家自然科學(xué)基金資助項(xiàng)目(21977110, 21778065, 21807105)；中國科學(xué)院先導(dǎo)項(xiàng)目(XDB20000000)；中國科學(xué)院分子合成卓越中心資助項(xiàng)目(FZHCZY020600).

* Tel: 021-54925491, E-mail: ccao@mail.sioc.ac.cn.