Fujii Shinya, Kobayashi Takanobu, Nakatsu Aki, Miyazawa Hiroshi, Kagechika Hiroyuki
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University.
Chem Pharm Bull (Tokyo). 2014;62(7):700-8. doi: 10.1248/cpb.c14-00218.
Nuclear transcription factor nuclear factor-kappa B (NF-κB) has diverse pathophysiological functions, and NF-κB inhibitors are considered to be candidates for multiple therapeutic applications. We previously reported a novel triazine-based NF-κB inhibitor, 2-anilino-4,6-dichloro-1,3,5-triazine (NI241), that directly inhibits DNA binding of NF-κB. Here, we report synthesis of a series of triazine derivatives and evaluation of their structure-activity relationships for NF-κB inhibition. We found that 2-amino-4,6-dichloro-1,3,5-triazine substructure is essential for the inhibitory activity of the lead compound NI241, and modification of NI241 by introduction of an m-methoxy substituent on the phenyl ring afforded the more potent derivative 28. The structure-activity relationships identified in this study suggested a possible mechanism of irreversible NF-κB inhibition by NI241, and should be helpful in the design of other NF-κB inhibitors.
核转录因子核因子-κB（NF-κB）具有多种病理生理功能，NF-κB抑制剂被认为是多种治疗应用的候选药物。我们之前报道了一种新型的基于三嗪的NF-κB抑制剂，2-苯胺基-4,6-二氯-1,3,5-三嗪（NI241），它能直接抑制NF-κB与DNA的结合。在此，我们报道了一系列三嗪衍生物的合成及其对NF-κB抑制作用的构效关系评估。我们发现2-氨基-4,6-二氯-1,3,5-三嗪亚结构对先导化合物NI241的抑制活性至关重要，通过在苯环上引入间甲氧基取代基对NI241进行修饰，得到了活性更强的衍生物28。本研究中确定的构效关系提示了NI241不可逆抑制NF-κB的可能机制，这将有助于设计其他NF-κB抑制剂。
