Institute for Organic Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141 Essen, Germany.
Chemistry. 2010 Mar 8;16(10):3036-56. doi: 10.1002/chem.200901999.
We present a systematic study of different guanidiniocarbonylpyrrole-aryl derivatives designed to interact with DNA or RNA both through intercalation of an aromatic moiety into the base stack of the nucleotide and through groove binding of a guanidiniocarbonylpyrrole cation. We varied 1) the size of the aromatic ring (benzene, naphthalene, pyrene and acridine), 2) the length and flexibility of the linker connecting the two binding groups, and 3) the total number of positive charges present at different pH values. The compounds and their interactions with DNA and RNA were studied by UV/Vis, fluorescence and CD spectroscopy. Antiproliferative activities against human tumour cell lines were also determined. Our studies show that efficient interaction with, for example, DNA requires a significantly large aromatic ring (pyrene) connected through a flexible linker to the pyrrole moiety. However, a positive charge, as in 12, is also needed. Compound 12 allows for base-pair-selective recognition of ds-DNA at physiological pH values. The antiproliferative activities of these compounds correlate with their binding affinities towards DNA, suggesting that their biological effects are most probably due to DNA binding.
我们进行了一项系统的研究，设计了不同的胍基羰基吡咯-芳基衍生物，旨在通过芳基部分嵌入核苷酸的碱基堆积来与 DNA 或 RNA 相互作用，同时通过胍基羰基吡咯阳离子与沟结合。我们改变了 1）芳环的大小（苯、萘、芘和吖啶），2）连接两个结合基团的连接体的长度和灵活性，以及 3）在不同 pH 值下存在的正电荷总数。通过紫外/可见分光光度法、荧光和 CD 光谱研究了化合物及其与 DNA 和 RNA 的相互作用。还测定了它们对人肿瘤细胞系的抗增殖活性。我们的研究表明，与例如 DNA 的有效相互作用需要通过柔性连接体连接的非常大的芳环（芘）连接到吡咯部分。然而，还需要正电荷，如在 12 中。化合物 12 允许在生理 pH 值下对 ds-DNA 进行碱基对选择性识别。这些化合物的抗增殖活性与其对 DNA 的结合亲和力相关，表明其生物学效应很可能归因于 DNA 结合。
