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首页> 外文期刊>Chemistry: A European journal >Factors Affecting DNA—DNA Interstrand Cross-Links in the Antiparallel3'-3' Sense: A Comparison with the 5'-5' Directional Isomer
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Factors Affecting DNA—DNA Interstrand Cross-Links in the Antiparallel3'-3' Sense: A Comparison with the 5'-5' Directional Isomer

机译：反平行3'-3'方向影响DNA-DNA链间交联的因素：与5'-5'定向异构体的比较

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摘要

Reported herein is a study ofthe unusual 3'-3' 1,4-GG interstrandcross-link (IXL) formation in duplexDNA by a series of polynuclear plati-num anticancer complexes. To examinethe effect of possible preassociationthrough charge and hydrogen-bondingeffects the closely related compounds[{trans-PtCl(NH_3)_2}_2(μ-trans-Pt(NH_3)_2- {NH_2(CH_2)_6NH_2}_2)]~4+(BBR3464, 1),[{trans-PtCl(NH_3)_2}_2(μ-NH_2(CH_2)_6-NH_2)]~2+(BBR3005, 2),Htrans-PtCl-(NH_3)_2}_2(μ-H_2N(CH_2)_3NH_2(CH_2)_4)]~3+(BBR3571, 3) and Wrans-PtC1(NH_3)_2}_2-{μ-H_2N(CH_2)_3-N(COCF_3)(CH_2)_4}]~2+(BBR3571-COCF_3,4) were studied.Two different molecular biology ap-proaches were used to investigate theeffect of DNA template upon IXL for-mation in synthetic 20-base-pair du-plexes. In the "hybridisation directed"method the monofunctionally adductedtop strands were hybridised with theircomplementary 5'-end labelled strands;after 24 h the efficiency of interstrandcross-linking in the 5'-5' direction wasslightly higher than in the 3'-3' direc-tion. The second method involved"postsynthetic modification" of theintact duplex; significantly less cross-linking was observed, but again a slightpreference for the 5'-5' duplex waspresent. 2D [~1H,~15N] HSQC NMRspectroscopy studies of the reaction of[~15N]-1 with the sequence 5'-d{TATAC-ATGTATA}_2allowed direct compari-son of the stepwise formation of the 3'-3' IXL with the previously studied 5'-5'IXL on the analogous sequence 5'-d(ATATGTACATAT)_2.Whereas thepreassociation and aquation steps weresimilar, differences were evident at themonofunctional binding step. The reac-tion did not yield a single distinct 3'-3'1,4-GG IXL, but numerous cross-linked adducts formed. Similar resultswere found for the reaction with the di-nuclear [~15N]-2.Molecular dynamics simulations for the 3'-3' IXLs formedby both 1 and 2 showed a highly dis-torted structure with evident fraying ofthe end base pairs and considerablewidening of the minor groove.
机译：本文报道了通过一系列多核铂抗癌复合物在双链DNA中形成异常3'-3'1,4-GG链间交联（IXL）的研究。要研究可能通过电荷和氢键进行的预缔合效应对密切相关的化合物[{trans-PtCl（NH_3）_2} _2（μ-trans-Pt（NH_3）_2- {NH_2（CH_2）_6NH_2} _2）]〜4 +的影响（BBR3464，1），[{trans-PtCl（NH_3）_2} _2（μ-NH_2（CH_2）_6-NH_2）]〜2 +（BBR3005，2），Htrans-PtCl-（NH_3）_2} _2（μ -H_2N（CH_2）_3NH_2（CH_2）_4）]〜3 +（BBR3571、3）和Wrans-PtC1（NH_3）_2} _2- {μ-H_2N（CH_2）_3-N（COCF_3）（CH_2）_4}]研究了〜2 +（BBR3571-COCF_3,4）。使用两种不同的分子生物学方法研究了DNA模板对合成20个碱基对双链体中IXL形成的影响。在“杂交导向”方法中，将单官能加合的上链与它们的互补5'-末端标记链杂交;在24小时后，沿5'-5'方向的链间交联效率略高于3'-3'方向。 -tion。第二种方法涉及完整双链体的“合成后修饰”。观察到显着较少的交联，但是再次略微偏爱5'-5'双链体。 [〜15N] -1与序列5'-d {TATAC-ATGTATA} _2的反应的二维[〜1H，〜15N] HSQC NMR光谱研究可逐步比较3'-3'IXL的形成与先前研究的5'-5'IXL相似的序列5'-d（ATATGTACATAT）_2。虽然预缔合和水合步骤相似，但在单功能结合步骤上却存在明显差异。反应没有产生单一的独特的3'-3'1,4-GG IXL，但形成了许多交联的加合物。与双核[〜15N] -2的反应也发现了相似的结果。由分子1和分子2形成的3'-3'IXL的分子动力学模拟显示结构高度扭曲，末端碱基对明显磨损，并显着扩展小凹槽的

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