药学学报, 2019, 54(11): 2039-2048
引用本文:
王太禹, 王利娜, 赵力挥, 王国成. 吲哚胺2,3-双加氧酶1抑制剂的设计、合成及初步活性研究

[J]. 药学学报, 2019, 54(11): 2039-2048.
WANG Tai-yu, WANG Li-na, ZHAO Li-hui, WANG Guo-cheng. Design, synthesis and inhibitory activity of indoleamine 2,3-dioxygenase 1 inhibitors[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 2039-2048.

吲哚胺2,3-双加氧酶1抑制剂的设计、合成及初步活性研究

王太禹1, 王利娜1, 赵力挥1, 王国成2
1. 天士力控股集团有限公司天士力研究院, 天津 300410;
2. 江苏天士力帝益药业有限公司, 江苏 淮安 223003
摘要:
吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase 1,IDO1)是人体色氨酸代谢通路中的关键酶,可介导肿瘤免疫应答的关键性免疫抑制酶,IDO1抑制剂是一种潜在的肿瘤免疫治疗药物。本研究在新近报道的IDO1蛋白-抑制剂复合物晶体(PDBID:6AZV)基础上,通过分析抑制剂与IDO1的相互作用模式,参考复合物晶体中的抑制剂结构,设计合成了11个化合物,其结构经图谱数据确认。初步活性研究表明,在目标化合物中含有联苯(吡啶)四唑结构的化合物(B1B2)与含有磺酰胺结构的联苯化合物(D1D2D3),在酶和细胞水平的抑制活性实验中,均具有优良的IDO1抑制活性,与阳性对照INCB24360相当或更优。
关键词:    吲哚胺2,3-双加氧酶1      IDO1      抑制剂      合成      肿瘤免疫     
Design, synthesis and inhibitory activity of indoleamine 2,3-dioxygenase 1 inhibitors
WANG Tai-yu1, WANG Li-na1, ZHAO Li-hui1, WANG Guo-cheng2
1. Tasly Institute, Tasly Holding Group, Tianjin 300410, China;
2. Jiangsu Tasly Diyi Pharmaceutical Co., Ltd., Huaian 223003, China
Abstract:
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme in the human tryptophan metabolism pathway, which can mediate tumor immune response. An IDO1 inhibitor would be a potential cancer immunotherapy drug. Based on the recently reported crystal of an IDO1 protein-inhibitor complex (PDBID:6AZV), the structure of reported inhibitor, and by analyzing the interaction mode between the inhibitor and IDO1, new inhibitor molecules were designed and synthesized. All structures were confirmed by spectral data. Preliminary activity studies showed that compounds containing an azabiphenyl tetrazole structure (B1 and B2) and biphenyl compounds containing a sulfonamide structure (D1, D2 and D3) had excellent inhibitory activity of IDO1 at the enzyme and cell level, and were comparable or even better than the control drug INCB24360.
Key words:    indoleamine2,3-dioxygenase1    IDO1    inhibitor    synthesis    tumor immunology   
收稿日期: 2019-08-27
DOI: 10.16438/j.0513-4870.2019-0685
基金项目: 江苏省基础研究计划资助项目(面上项目BK20181209).
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