(+)-CC-1065 produces bending of DNA that appears to resemble adenine/thymine tracts.
(+)-CC-1065 produces bending of DNA that appears to resemble adenine/thymine tracts.
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( )-CC-1065 产生类似于腺嘌呤/胸腺嘧啶束的 DNA 弯曲。
DOI：
10.1021/tx00019a003
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发表时间：
1991
影响因子：
4.1
通讯作者：
Hurley,LH
中科院分区：
文献类型：
--
作者：
Lin,CH;Sun,DY;Hurley,LH
在upjohn科学家合成的大量类似物的帮助下（12），结构-活性关系得到了明确的定义（图1）。特别重要的是，我们观察到(+)-CC-1065的A亚基具有足够的结构信息来引出整个药物分子的序列特异性，尽管B和C亚基的性质可以调节或微调这种特异性（图1）（6b）。在以前的出版物（6b, c, 10b）中，我们认为(+)-CC-1065的序列选择性的主要基础是序列依赖的催化活化和/或序列依赖的构象灵活性。与此结果相反，我们最近证明了(-)- cc -1065（合成的对映体）的序列选择性在很大程度上取决于非共价结合相互作用。凝胶电泳（13）、电子显微镜（14）、x射线衍射（15）和羟基自由基足迹（16）已经证明DNA中的腺嘌呤/胸腺嘧啶束（a -束）可以在DNA中产生弯曲。DNA中a束相关弯曲的精确结构基础仍然存在争议（17），但连接弯曲模型（13）似乎是最可能的。高场XH NMR（19）和羟基自由基足迹（20）的结果都表明，由于AT碱基对的高螺旋桨扭转角导致小凹槽变窄，这是这种效应的结构基础。在这篇文章中，我们利用羟基自由基足迹和高场质子核磁共振证明，DNA中的弯曲，被(+)-CC-1065捕获或诱导，似乎在总体上类似于自然的弧形a束弯曲。讨论了这种弯曲与序列选择性的可能关系以及与强效dna反应性药物相关的这种特征的生物学后果。
Facilitated by the extensive array of analogues synthesized byUpjohn scientists (12), structure-activity re-lationships have been sharply defined (Figure 1). Of particular significance is our observation that the A subunit of (+)-CC-1065 has sufficient structural information to elicit the sequence specificity of the entire drug molecule, although the nature of B and C subunits can modulate or fine tune this specificity (Figure 1)(6b). In previous publications (6b, c, 10b) we have argued that the primary basis for the sequence selectivity of (+)-CC-1065 is a se-quence-dependent catalytic activation and/or a se-quence-dependent conformational flexibility. In contrast to this result, we have recently demonstrated that the sequence selectivity of (-)-CC-1065, the synthetic enan-tiomer, is largely determined by noncovalent binding interactions. Adenine/thymine tracts (A-tracts) in DNA have been demonstrated by gel electrophoresis (13), elec-tron microscopy (14), X-ray diffraction (15), and hydroxyl-radical footprinting (16) to produce bends in DNA. The precise structural basis for the A-tract-associatedbend in DNA is still controversial (17), but the junction bend model (13) seems to be the most probable. Both high-field XH NMR (19) and hydroxyl-radical footprinting (20) results are consistent with narrowing of the minor groove due to a high propeller twist angle in an AT base pair at the junction site as a structural basis for thiseffect. In this communication we demonstrate, using hydroxyl-radical footprinting and high-field proton NMR, that the bend in DNA, which is entrapped or induced by (+)-CC-1065, appears to resemble in overall respects a naturally oc-curring A-tract bend. The possible relationship of this bend to sequence selectivity and biological consequences of such a feature associated with a potent DNA-reactive drug are discussed.