Synthesis of Oligonucleotides containing the cis-Interstrand Crosslink Produced by Mitomycins in their Reaction with DNA.
Synthesis of Oligonucleotides containing the cis-Interstrand Crosslink Produced by Mitomycins in their Reaction with DNA.
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DOI：
10.1002/chem.202002452
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发表时间：
2020-10-01
期刊：
影响因子：
--
通讯作者：
Champeil E
中科院分区：
文献类型：
--
作者：
Aguilar W;Zacarias O;Romaine M;Proni G;Petrovic AG;Abzalimov R;Paz MM;Champeil E
抗癌药物丝裂霉素C(MC)和去氨甲酰丝裂霉素C(DMC)是一种DNA烷基化试剂，可以在相对DNA链上的脱氧鸟苷残基之间形成DNA链间交联(ICL)。MC主要形成脱氧鸟苷加合物，在鸟嘌呤-丝裂糖键上具有1“-R立体化学(1”-α，反式)，而DMC主要形成具有1“-S立体化学(1”-β，顺式)的加合物。这种交联化反应是非对映专一性的：反式交联物只在CpG序列上形成，而顺式交联物只在GPC序列上形成。到目前为止，在特定位置含有1“-β-脱氧鸟苷加合物或ICL的寡核苷酸还不能被合成，从而限制了人们对这些化合物在其毒性中所起作用的研究。在这里，我们提出了一种新的仿生合成来获得这些底物。通过对核苷的酶消化、高分辨质谱分析、圆二色谱和紫外熔融温度的研究，证明了所加成的寡核苷酸和ICL的结构。最后，创建了合成的25聚1“-βICL的虚拟模型，以探索该交联双链的构象空间和结构特征。提出了一种新的仿生合成方法来获得具有S立体构型的丝裂霉素-DNA加合物。通过对核苷的酶消化、MS/MS裂解、圆二色谱和紫外熔融温度的研究，证明了所加成的寡核苷酸和ICL的结构。为了探索其构象空间和结构特征，建立了一个交联型DNA双链的虚拟模型。
Mitomycin C, (MC), an antitumor drug and decarbamoylmitomycin C, (DMC), a derivative of MC lacking the carbamoyl moiety, are DNA alkylating agents which can form DNA interstrand crosslinks (ICLs) between deoxyguanosine residues located on opposing DNA strands. MC forms primarily deoxyguanosine adducts with a 1”-R stereochemistry at the guanine-mitosene bond (1”-α, trans) whereas DMC forms mainly adducts with a 1”-S stereochemistry (1”-β, cis). The crosslinking reaction is diastereospecific: trans-crosslinks are formed exclusively at CpG sequences, while cis-crosslinks are formed only at GpC sequences. Until now, oligonucleotides containing 1”-β-deoxyguanosine adducts or ICL at a specific site could not be synthesized, thus limiting the investigation of the role played by the stereochemical configuration at C1“ in the toxicity of these compounds. Here, we present a novel biomimetic synthesis to access these substrates. Structural proof of the adducted oligonucleotides and ICL were provided by enzymatic digestion to nucleosides, high resolution mass spectral analysis, CD spectroscopy and UV melting temperature studies. Finally, a virtual model of the 25 mer 1”-β ICL synthesized was created to explore the conformational space and structural features of the crosslinked duplex. A novel biomimetic synthesis to access mitomycins-DNA adducts with a S stereochemical configuration at C1” is presented. Structural proof of the adducted oligonucleotides and ICL were provided by enzymatic digestion to nucleosides, MS/MS fragmentation, CD spectroscopy and UV melting temperature studies. A virtual model of the crosslinked DNA duplex was created to explore its conformational space and structural features.
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影响因子：
8.8
作者：
Kato N;Kawasoe Y;Williams H;Coates E;Roy U;Shi Y;Beese LS;Schärer OD;Yan H;Gottesman ME;Takahashi TS;Gautier J
通讯作者：
Gautier J
影响因子：
62.1
作者：
Bass, Phillip D.;Gubler, Daniel A.;Judd, Ted C.;Williams, Robert M.
通讯作者：
Williams, Robert M.
影响因子：
2.7
作者：
Champeil, Elise;Paz, Manuel M.;Sapse, Anne-Marie
通讯作者：
Sapse, Anne-Marie
影响因子：
5.1
作者：
Mustra, David J.;Warren, Amy J.;Hamilton, Joshua W.
通讯作者：
Hamilton, Joshua W.
DOI：
10.1002/chem.201802038
发表时间：
2018-09-06
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
--
作者：
Aguilar W;Paz MM;Vargas A;Zheng M;Cheng SY;Champeil E
通讯作者：
Champeil E