Assa-Munt N, Leupin W, Denny W A, Kearns D R
Department of Chemistry, University of California, San Diego, La Jolla, California 92093, USA.
Biochemistry. 1985 Mar 12;24(6):1449-60. doi: 10.1021/bi00327a025.
Measurements of the 1H NMR spectra and relaxation rates were used to study the dynamic properties of 9-aminoacridine (9AA) and four bis(acridine) complexes with d(AT)5.d(AT)5. The behavior of the 9AA (monointercalator) and that of C8 (bisintercalator containing an eight-carbon atom linker chain) are entirely similar. For both compounds, the lifetime of the drug in a particular binding site is 2-3 ms at approximately 20 degrees C, and neither affects the A.T base pair opening rates. The complex with C10 (bisintercalator containing a 10-carbon atom linker chain) is slightly more stable than the C8 complex since its estimated binding site lifetime is 5-10 ms at 29 degrees C. Base pairs adjacent to the bound C10 are destabilized, relative to free d(AT)5.d(AT)5, but other base pairs in the C10 complex are little affected. Bis(acridine) pyrazole (BAPY) and bis(acridine) spermine (BAS) considerably stabilize those base pairs that are sandwiched between the two acridine chromophores, but in the BAS complex proton exchange from the two flanking base pairs appears to be accelerated, relative to free d(AT)5.d(AT)5. The lifetime of these drugs in specific binding sites is too long (>10 ms) to be manifested in increased line widths, at least up to 41 degrees C. An important conclusion from this study is that certain bisintercalators rapidly migrate along DNA, despite having large binding constants (K>10(6) M-1). For C8 and C10 complexes, migration rates are little different from those deduced for 9AA. The rigid linker chain in BAPY and the charge interactions in BAS retard migration of these two bisintercalators. These results provide new parameters that are useful in understanding the biochemical and biological properties of these and other bisintercalating drugs.
利用1H NMR光谱和弛豫速率测量来研究9-氨基吖啶（9AA）以及四种与d(AT)5.d(AT)5形成的双（吖啶）配合物的动力学性质。9AA（单嵌入剂）和C8（含有八个碳原子连接链的双嵌入剂）的行为完全相似。对于这两种化合物，在约20℃时，药物在特定结合位点的寿命为2 - 3毫秒，且两者均不影响A.T碱基对的打开速率。与C10（含有十个碳原子连接链的双嵌入剂）形成的配合物比C8配合物稍稳定，因为在29℃时其估计的结合位点寿命为5 - 10毫秒。相对于游离的d(AT)5.d(AT)5，与结合的C10相邻的碱基对不稳定，但C10配合物中的其他碱基对受影响较小。双（吖啶）吡唑（BAPY）和双（吖啶）精胺（BAS）极大地稳定了夹在两个吖啶发色团之间的那些碱基对，但在BAS配合物中，相对于游离的d(AT)5.d(AT)5，来自两个侧翼碱基对的质子交换似乎加速了。这些药物在特定结合位点的寿命太长（>10毫秒），以至于至少在41℃之前，线宽增加都不明显。这项研究的一个重要结论是，某些双嵌入剂尽管具有较大的结合常数（K>10(6) M-1），但仍能沿DNA快速迁移。对于C8和C10配合物，迁移速率与从9AA推导的迁移速率几乎没有差异。BAPY中的刚性连接链和BAS中的电荷相互作用阻碍了这两种双嵌入剂的迁移。这些结果提供了新的参数，有助于理解这些及其他双嵌入药物的生化和生物学性质。
