Hartley J A, Lown J W, Mattes W B, Kohn K W
Department of Chemistry, University of Alberta, Edmonton, Canada.
Acta Oncol. 1988;27(5):503-10. doi: 10.3109/02841868809093578.
An examination of the DNA sequence specificity of guanine-N7 alkylation for nitrogen mustards and chlorethylnitrosoureas revealed that large variations in alkylation intensities existed among different guanines in the DNA sequence. The most striking finding was that most agents reacted preferentially at runs of G's, the degree of preference being much greater than would be expected from the number of G's alone. This correlated with the molecular electrostatic potential induced at the guanine-N7 position by the nearest neighbor base pairs. Uracil and quinacrine mustards, however, showed distinctly different reaction patterns from other mustards and a detailed examination has led to structural hypotheses to account for the differences. Certain regions of the genome including regions in some oncogenes and the Epstein-Barr virus have unusually high GC contents (greater than 80% GC) which suggests that the antitumor effectiveness of alkylating agents may in part be due to selective reaction at certain regions in the genome. In fact certain mustards have been shown to exhibit enhanced reactivities with such regions in DNA fragments derived from the c-H-ras oncogene. The above findings point to the possibility of design of alkylating agents to optimise the selectivity of reaction with critical DNA regions. An alternative approach presently under investigation has emerged from an understanding of the characteristics of the sequence specific interaction of the natural oligopeptide antibiotics netropsin and distamycin in the minor groove of DNA. This has led to the synthesis of novel agents (lexitropsins) in which the binding specificity can be shifted from (AT)n in (GC)n in a predictable fashion. Thus the rational design of DNA sequence specific vectors linked to DNA reactive groups, such as alkylating or cleaving agents, could enable DNA damage to be delivered selectively to predetermined critical sites on the genome.
对氮芥和氯乙基亚硝脲的鸟嘌呤 - N7 烷基化的 DNA 序列特异性进行的研究表明，DNA 序列中不同鸟嘌呤之间的烷基化强度存在很大差异。最显著的发现是，大多数试剂优先与连续的鸟嘌呤发生反应，其优先程度远高于仅由鸟嘌呤数量所预期的程度。这与最近邻碱基对在鸟嘌呤 - N7 位置诱导的分子静电势相关。然而，尿嘧啶和喹吖因氮芥显示出与其他氮芥明显不同的反应模式，详细研究已得出结构假说来解释这些差异。基因组的某些区域，包括一些癌基因和爱泼斯坦 - 巴尔病毒中的区域，具有异常高的 GC 含量（大于 80% GC），这表明烷化剂的抗肿瘤有效性可能部分归因于在基因组某些区域的选择性反应。事实上，已表明某些氮芥与源自 c - H - ras 癌基因的 DNA 片段中的此类区域表现出增强的反应活性。上述发现指出了设计烷化剂以优化与关键 DNA 区域反应选择性的可能性。目前正在研究的另一种方法源于对天然寡肽抗生素纺锤菌素和偏端霉素在 DNA 小沟中序列特异性相互作用特征的理解。这导致了新型试剂（类纺锤菌素）的合成，其中结合特异性可以以可预测的方式从（AT）n 转移到（GC）n。因此，与 DNA 反应性基团（如烷化剂或切割剂）相连的 DNA 序列特异性载体的合理设计，可以使 DNA 损伤选择性地传递到基因组上预定的关键位点。
