Dihydroimidazophenanthridinium (DIP)‐Based DNA Binding Agents with Tuneable Structures and Biological Activity
Dihydroimidazophenanthridinium (DIP)‐Based DNA Binding Agents with Tuneable Structures and Biological Activity
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DOI：
10.1002/cbic.200600205
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发表时间：
2006-11
期刊：
影响因子：
3.2
通讯作者：
Louise V. Smith;Alexis D. C. Parenty;Kevin M. Guthrie;J. Plumb;Robert Brown;L. Cronin
中科院分区：
文献类型：
--
作者：
Louise V. Smith;Alexis D. C. Parenty;Kevin M. Guthrie;J. Plumb;Robert Brown;L. Cronin
我们使用“一锅法”方法合成了具有较大结构多样性 (1-29) 的二氢咪唑菲啶鎓阳离子 (DIP) 库。 DIP的DNA结合常数范围为2×104至1.3×105 M−1，结合自由能范围为-5.9至-6.40 kcal mol−1。粘度测量表明，化合物的结合导致 DNA 延长，因此表明通过嵌入进行结合。这些化合物的细胞毒性通过基于四唑染料的微量滴定测定进行测定，并显示出较大的值范围（0.09-11.7 μM）。 DNA-DIP 相互作用的初步分子模型研究表明，DIP 部分可以通过嵌入与 DNA 相互作用，并且一些 R 基团可能有助于通过小凹槽结合进行结合。这些结果让我们深入了解如何设计能够以这些方式相互作用的生物活性 DNA 结合剂。
We have synthesised a library of dihydroimidazophenanthridinium cations (DIPs) with large structural diversity (1–29) using a “one‐pot” approach. The DNA binding constants of DIPs range from 2×104 to 1.3×105 M−1, and the free energies for binding range from −5.9 to −6.40 kcal mol−1. Viscosity measurements demonstrated that the binding of the compounds caused DNA lengthening, thus signifying binding by intercalation. The cytotoxicities of the compounds were determined by tetrazolium dye‐based microtitration assays and showed a large range of values (0.09–11.7 μM). Preliminary molecular modelling studies of the DNA–DIP interactions suggested that the DIP moieties can interact with DNA by intercalation, and some R groups might facilitate binding by minor‐groove binding. The results provide insight into how to design biologically active DNA binding agents that can interact in these ways.