Heterocyclic dications as a new class of telomeric G-quadruplex targeting agents.
Heterocyclic dications as a new class of telomeric G-quadruplex targeting agents.
复制标题
DOI：
10.2174/138161212799958422
复制
发表时间：
2012
影响因子：
3.1
通讯作者：
Wilson WD
中科院分区：
文献类型：
--
作者：
Nanjunda R;Musetti C;Kumar A;Ismail MA;Farahat AA;Wang S;Sissi C;Palumbo M;Boykin DW;Wilson WD
能够诱导和稳定G-四链DNA结构的小分子为抗癌和抗寄生虫治疗提供了一种新的途径，人们已经在寻找能够稳定四链结构的先导化合物方面做出了广泛的努力。本研究的目的是探索一系列杂环化合物的构象修饰，以发现能够选择性结合和稳定特定G-四链体的结构基序，例如那些存在于人类端粒中的结构基序。G-四链体对小分子具有不同的潜在识别位点；然而，大多数这些配体的主要相互作用部位是末端四元体。与双链DNA沟槽识别类似，小分子的四链沟槽识别提供了增强选择性的潜力，可以发展成为一种可行的治疗策略。所研究的化合物是基于对DB832的初步研究而选择的，DB832是一种具有独特端粒相互作用的联苯二胺。这种化合物提供了一个范例，可以帮助理解导致四链槽识别的最佳化合物-DNA相互作用。通过热熔融、圆二色谱、质谱学和核磁共振等生物物理实验，研究了DB832衍生物对DNA的识别作用。还进行了生物学研究，以补充生物物理数据。结果表明，这是一种复杂的结合机制，包括对某些配体的沟槽的识别以及对大多数配体的在人端粒G-四联体末端四分体的堆积。这些分子代表了一个很好的起点，为进一步分析不同模式的四链识别和随后的药物开发结构优化奠定了基础。
Small molecules that can induce and stabilize G-quadruplex DNA structures represent a novel approach for anti-cancer and anti-parasitic therapy and extensive efforts have been directed towards discovering lead compounds that are capable of stabilizing quadruplexes. The purpose of this study is to explore conformational modifications in a series of heterocyclic dications to discover structural motifs that can selectively bind and stabilize specific G-quadruplexes, such as those present in the human telomere. The G-quadruplex has various potential recognition sites for small molecules; however, the primary interaction site of most of these ligands is the terminal tetrads. Similar to duplex-DNA groove recognition, quadruplex groove recognition by small molecules offers the potential for enhanced selectivity that can be developed into a viable therapeutic strategy. The compounds investigated were selected based on preliminary studies with DB832, a bifuryl-phenyl diamidine with a unique telomere interaction. This compound provides a paradigm that can help in understanding the optimum compound-DNA interactions that lead to quadruplex groove recognition. DNA recognition by the DB832 derivatives was investigated by biophysical experiments such as thermal melting, circular dichroism, mass spectrometry and NMR. Biological studies were also performed to complement the biophysical data. The results suggest a complex binding mechanism which involves the recognition of grooves for some ligands as well as stacking at the terminal tetrads of the human telomeric G-quadruplex for most of the ligands. These molecules represent an excellent starting point for further SAR analysis for diverse modes of quadruplex recognition and subsequent structure optimization for drug development.
登录
查看更多内容
影响因子：
15
作者：
Han, FXG;Wheelhouse, RT;Hurley, LH
通讯作者：
Hurley, LH
影响因子：
14.9
作者：
Ambrus A;Chen D;Dai J;Bialis T;Jones RA;Yang D
通讯作者：
Yang D
影响因子：
4
作者：
Colgin, LM;Reddel, RR
通讯作者：
Reddel, RR
影响因子：
15
作者：
Collie, Gavin W.;Sparapani, Silvia;Neidle, Stephen
通讯作者：
Neidle, Stephen
影响因子：
3.6
作者：
Cookson, JC;Dai, FP;Burger, AM
通讯作者：
Burger, AM