Department of Chemistry, School of Science , Tianjin University , Tianjin 300072 , P R China.
Collaborative Innovation Center of Chemical Science and Engineering , Tianjin 30072 , P R China.
ACS Appl Mater Interfaces. 2018 Apr 25;10(16):13350-13360. doi: 10.1021/acsami.8b01901. Epub 2018 Apr 16.
Porphyrins are promising candidates for nucleic acid G-quadruplex-specific optical recognition. We previously demonstrated that G-quadruplex recognition specificity of porphyrins could be improved by introducing bulky side arm substituents, but the enhanced protonation tendency limits their applications in some cases, such as under acidic conditions. Here, we demonstrated that the protonation tendency of porphyrin derivatives could be efficiently overcome by increasing molecular asymmetry. To validate this, an asymmetric, water-soluble, cationic porphyrin FA-TMPipEOPP (5-{4-[2-[[(2 E)-3-[3-methoxy-4-[2-(1-methyl-1-piperidinyl)ethoxy]phenyl]-1-oxo-2-propenyl]oxy]ethoxy]phenyl},10,15,20-tri{4-[2-(1-methyl-1-piperidinyl)ethoxy]-phenyl}porphyrin) was synthesized by introducing a ferulic acid (FA) unit at one side arm, and its structure was well-characterized. Unlike its symmetric counterpart TMPipEOPP that has a tendency to protonate under acidic conditions, FA-TMPipEOPP remained in the unprotonated monomeric form under the pH range of 2.0-8.0. Correspondingly, FA-TMPipEOPP showed better G-quadruplex recognition specificity than TMPipEOPP and thus might be used as a specific optical probe for colorimetric and fluorescent recognition of G-quadruplexes under acidic conditions. The feasibility was demonstrated by two proof-of-concept studies: probing structural competition between G-quadruplexes and duplexes and label-free and wash-free cancer cell-targeted bioimaging under an acidic tumor microenvironment. As G-quadruplex optical probes, FA-TMPipEOPP works well under acidic conditions, whereas TMPipEOPP works well under neutral conditions. This finding provides useful information for G-quadruplex probe research. That is, porphyrin-based G-quadruplex probes suitable for different pH conditions might be obtained by adjusting the molecular symmetry.
卟啉是核酸 G-四链体特异性光学识别的有前途的候选物。我们之前证明，通过引入大体积侧臂取代基可以提高卟啉对 G-四链体的识别特异性，但增强的质子化倾向限制了它们在某些情况下的应用，例如在酸性条件下。在这里，我们证明通过增加分子不对称性可以有效地克服卟啉衍生物的质子化倾向。为了验证这一点，合成了一种不对称的、水溶性的、阳离子卟啉 FA-TMPipEOPP（5-{4-[2-[[(2E)-3-[3-甲氧基-4-[2-(1-甲基-1-哌啶基)乙氧基]苯基]-1-氧代-2-丙烯基]氧基]乙氧基]苯基}，10,15,20-三{4-[2-(1-甲基-1-哌啶基)乙氧基]苯基}卟啉），在一侧臂上引入了阿魏酸（FA）单元，其结构得到了很好的表征。与在酸性条件下倾向于质子化的对称对照物 TMPipEOPP 不同，FA-TMPipEOPP 在 pH 值为 2.0-8.0 的范围内保持未质子化的单体形式。相应地，FA-TMPipEOPP 显示出比 TMPipEOPP 更好的 G-四链体识别特异性，因此可用于在酸性条件下作为 G-四链体的比色和荧光识别的特异性光学探针。通过两个概念验证研究证明了这种可行性：探测 G-四链体和双链体之间的结构竞争以及在酸性肿瘤微环境下无标记和无洗涤的癌细胞靶向生物成像。作为 G-四链体光学探针，FA-TMPipEOPP 在酸性条件下效果很好，而 TMPipEOPP 在中性条件下效果很好。这一发现为 G-四链体探针研究提供了有用的信息。也就是说，通过调整分子对称性，可能获得适合不同 pH 条件的基于卟啉的 G-四链体探针。
