Guo Pu, Farahat Abdelbasset A, Paul Ananya, Kumar Arvind, Boykin David W, Wilson W David
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, 50 Decatur Street Southeast, Atlanta, Georgia 30303, United States.
Master of Pharmaceutical Sciences Program, California Northstate University, 9700 West Taron Drive, Elk Grove, California 95757, United States.
Biochemistry. 2020 May 12;59(18):1756-1768. doi: 10.1021/acs.biochem.0c00090. Epub 2020 Apr 20.
The majority of current drugs against diseases, such as cancer, can bind to one or more sites in a protein and inhibit its activity. There are, however, well-known limits on the number of druggable proteins, and complementary current drugs with compounds that could selectively target DNA or RNA would greatly enhance the availability of cellular probes and therapeutic progress. We are focusing on the design of sequence-specific DNA minor groove binders that, for example, target the promoter sites of transcription factors involved in a disease. We have started with AT-specific minor groove binders that are known to enter human cells and have entered clinical trials. To broaden the sequence-specific recognition of these compounds, several modules that have H-bond acceptors that strongly and specifically recognize G·C base pairs were identified. A lead module is a thiophene--alkyl-benzimidazole σ-hole-based system with terminal phenyl-amidines that have excellent affinity and selectivity for a G·C base pair in the minor groove. Efforts are now focused on optimizing this module. In this work, we are evaluating modifications to the compound aromatic system with the goal of improving GC selectivity and affinity. The lead compounds retain the thiophene--alkyl-BI module but have halogen substituents adjacent to an amidine group on the terminal phenyl-amidine. The optimum compounds must have strong affinity and specificity with a residence time of at least 100 s.
目前大多数治疗疾病（如癌症）的药物能够与蛋白质中的一个或多个位点结合并抑制其活性。然而，可成药蛋白质的数量存在众所周知的限制，将现有药物与能够选择性靶向DNA或RNA的化合物相结合，将极大地提高细胞探针的可用性并推动治疗进展。我们专注于设计序列特异性DNA小沟结合剂，例如靶向参与某种疾病的转录因子的启动子位点。我们从已知能够进入人体细胞并已进入临床试验的AT特异性小沟结合剂入手。为了拓宽这些化合物的序列特异性识别能力，我们鉴定了几个具有氢键受体的模块，这些受体能够强烈且特异性地识别G·C碱基对。一个先导模块是基于噻吩 - 烷基 - 苯并咪唑σ-空穴的体系，其末端苯脒对小沟中的G·C碱基对具有优异的亲和力和选择性。目前的工作重点是优化这个模块。在这项研究中，我们正在评估对化合物芳香体系的修饰，目标是提高对GC的选择性和亲和力。先导化合物保留了噻吩 - 烷基 - 苯并咪唑模块，但在末端苯脒的脒基附近有卤素取代基。最佳化合物必须具有强亲和力和特异性，停留时间至少为100秒。
