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Cell active and functionally-relevant small-molecule agonists of calcitonin receptor.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2020-01-21 , DOI: 10.1016/j.bioorg.2020.103596
Shuai Zhao 1 , Shengchao Guo 2 , Chan Yang 3 , Zheng Gong 2 , Yaomin Wang 1 , Yingli Jia 3 , Xinyu Jiang 1 , Liwei Xu 4 , Li Shi 4 , Xiao Yu 5 , Jinpeng Sun 6 , Yan Zhang 7 , Xin Chen 1
Affiliation  

The natural calcitonin (CT) receptor and its peptide agonists are considered validated targets for drug discovery. A small molecule agonist, SUN-B8155, has previously been shown to efficiently activate cellular CTR. Herein, we report the synthesis of a series of compounds (S8155 1-9) derived from SUN-B8155, and investigate the structural-functional relationship, bias properties and their cellular activity profile. We discover that the N-hydroxyl group from the pyridone ring is required for G protein activity and its affinity to the CT receptor. Among the compounds studied, S8155-7 exhibits improved G protein activity while S8155-4 displays a significant β-arrestin-2 signaling bias. Finally, we show that both S8155-4 and S8155-7 inhibit tumour cell invasion through CTR activation. These two compounds are anticipated to find extensive applications in chemical biology research as well drug development efforts targeting CT receptor.

中文翻译:

降钙素受体的细胞活性和与功能相关的小分子激动剂。

天然降钙素(CT)受体及其肽激动剂被认为是药物发现的有效靶标。先前已证明小分子激动剂SUN-B8155可有效激活细胞CTR。在这里,我们报告了一系列衍生自SUN-B8155的化合物(S8155 1-9)的合成,并研究了结构-功能关系,偏倚性质及其细胞活性概况。我们发现,吡啶酮环的N-羟基是G蛋白活性及其对CT受体亲和力所必需的。在研究的化合物中,S8155-7表现出改善的G蛋白活性,而S8155-4表现出显着的β-arrestin-2信号偏向。最后,我们显示S8155-4和S8155-7均通过CTR激活抑制肿瘤细胞的侵袭。
更新日期:2020-01-21
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