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NF-κB regulation by bisbenzylisoquinoline alkaloids in human T cells: a structure–activity relationship study
Medicinal Chemistry Research ( IF 2.6 ) Pub Date : 2020-09-19 , DOI: 10.1007/s00044-020-02624-2
Wencheng Xu , Shuhe Chen , Xiaoqin Wang , Junichi Kusano , Ryusei Yamamoto , Hiroto Matsuda , Yoshikazu Hara , Yoshiaki Fujii , Seiichi Hayashi , Sachiko Tanaka , Kentaro Sugiyama , Haruki Yamada , Toshihiko Hirano

Suppressive potencies of tetrandrine, isotetrandrine, fangchinoline, berbamine, dauricine, cepharanthine, and armepavine on expression and activation of NF-κB in MOLT-4 cells, MOLT-4/DNR cells, peripheral blood mononuclear cells (PBMCs) of healthy subjects and PBMCs of dialysis patients were compared. In MOLT-4 cells, the suppressive potencies evaluated by the IC50 values were isotetrandrine > cepharanthine > tetrandrine > dauricine > fangchinoline > berbamine or armepavine. In MOLT-4/DNR cells, the order was isotetrandrine > tetrandrine > cepharanthine > fangchinoline > dauricine > berbamine or armepavine. In PBMCs of healthy subjects, the order was isotetrandrine > dauricine > fangchinoline > tetrandrine > cepharanthine > berbamine or armepavine. In PBMCs of dialysis patients, the order was isotetrandrine > fangchinoline > tetrandrine > cepharanthine > dauricine > berbamine or armepavine. Among them, isotetrandrine showed the strongest inhibitory effects on the expression of NF-κB and p-NF-κB in these cells. Accordingly, both 7- and 12-substitutions are suggested to influence the suppressive potency of bisbenzylisoquinoline alkaloids, though 7-substitution is likely to have less contribution. Bisbenzylisoquinoline alkaloid seems to be more suitable than monobenzylisoquinoline alkaloid to serve as a lead compound. Bisbenzylisoquinoline alkaloids with an 18-membered ring formed by two oxygen bridges seem to be superior to those with one oxygen. However, the binding sites of two oxygen bridges on the phenyl ring appear to have limited influence. These findings provide further insight into structure–activity relationships to the development of active analogs of this promising class of drugs for the treatment of diseases mediated by abnormalities of T cell activation.



中文翻译:

双苄基异喹啉生物碱在人T细胞中对NF-κB的调节作用:结构与活性关系的研究

粉防己碱,异粉防己碱,防己诺林碱,贝巴明,dauricine,头孢兰定和阿米帕品对健康受试者和PBMCs的MOLT-4细胞,MOLT-4 / DNR细胞,外周血单个核细胞(PBMC)中的NF-κB表达和激活的抑制作用对透析患者进行比较。在MOLT-4电池中,抑制强度由IC 50评估值分别为异粉防己碱>头孢兰氨酸>粉防己碱>达里辛>房果碱>贝巴明或阿米帕素。在MOLT-4 / DNR细胞中,顺序为异粉防己碱>粉防己碱>头孢兰氨酸>房车碱>达里辛>贝巴明或阿米帕韦。在健康受试者的PBMC中,其顺序为异粉防己碱>牛磺酸>房车碱>粉防己碱>头孢兰氨酸>贝巴明或阿米帕韦。在透析患者的PBMC中,其顺序为异粉防己碱>防己诺林碱>粉防己碱>头孢兰定>达里辛>贝巴明或阿马分开。其中,异粉防己碱对这些细胞中NF-κB和p-NF-κB的表达具有最强的抑制作用。因此,建议7和12取代都影响双苄基异喹啉生物碱的抑制能力,尽管7替代的贡献可能较小。双苄基异喹啉生物碱似乎比单苄基异喹啉生物碱更适合用作先导化合物。具有由两个氧桥形成的18元环的双苄基异喹啉生物碱似乎优于具有一个氧的那些。然而,苯环上两个氧桥的结合位点似乎具有有限的影响。这些发现为结构与活性之间的关系提供了进一步的见解,与这种有前途的药物活性类似物的开发有关,用于治疗由T细胞活化异常介导的疾病。具有由两个氧桥形成的18元环的双苄基异喹啉生物碱似乎优于具有一个氧的那些。然而,苯环上两个氧桥的结合位点似乎具有有限的影响。这些发现为与这种有前途的药物的活性类似物的开发之间的结构-活性关系的发展提供了进一步的见解,用于治疗由T细胞活化异常介导的疾病。具有由两个氧桥形成的18元环的双苄基异喹啉生物碱似乎优于具有一个氧的那些。然而,苯环上两个氧桥的结合位点似乎具有有限的影响。这些发现为结构与活性之间的关系提供了进一步的见解,与这种有前途的药物活性类似物的开发有关,用于治疗由T细胞活化异常介导的疾病。

更新日期:2020-10-07
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