A New Design Strategy and Diagnostic to Tailor the DNA-Binding Mechanism of Small Organic Molecules and Drugs
A New Design Strategy and Diagnostic to Tailor the DNA-Binding Mechanism of Small Organic Molecules and Drugs
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DOI：
10.1021/acschembio.6b00448
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发表时间：
2016-11-01
影响因子：
4
通讯作者：
Goodson, Theodore, III
中科院分区：
文献类型：
--
作者：
Doan, Phi;Pitter, Demar R. G.;Goodson, Theodore, III
DNA沟结合的经典模型指出，沟结合分子应该采用与DNA的螺旋沟紧密匹配的新月形。在这里，我们提出了一个新的设计策略，不服从这个经典模型。通过合成和检测一系列与DNA结合的新型化合物，研究了有机小分子与DNA的结合机理。这项研究导致了DNA结合分子和/或药物的结构性质关系的出现，这表明可以通过修改中心杂环核心的电子受体性质来设计结构以嵌入或沟槽结合小牛胸腺dsDNA。这表明，中央核的电子接受能力在DNA结合机制中起着关键作用。这些小分子的特征在于稳态和超快非线性光谱。在活细胞中进行生物成像实验，以评估新型小分子的细胞摄取和定位。该报告为设计和开发针对DNA的小有机分子（如治疗剂）铺平了新的途径，因为它们的性能和特异性取决于DNA结合机制。
The classical model for DNA groove binding states that groove binding molecules should adopt a crescent shape that closely matches the helical groove of DNA. Here, we present a new design strategy that does not obey this classical model. The DNA-binding mechanism of small organic molecules was investigated by synthesizing and examining a series of novel compounds that bind with DNA. This study has led to the emergence of structure property relationships for DNA-binding molecules and/or drugs, which reveals that the structure can be designed to either intercalate or groove bind with calf thymus dsDNA by modifying the electron acceptor properties of the central heterocyclic core. This suggests that the electron accepting abilities of the central core play a key role in the DNA-binding mechanism. These small molecules were characterized by steady-state and ultrafast nonlinear spectroscopies. Bioimaging experiments were performed in live cells to evaluate cellular uptake and localization of the novel small molecules. This report paves a new route for the design and development of small organic molecules, such as therapeutics, targeted at DNA as their performance and specificity is dependent on the DNA-binding mechanism.