新型吲哚胺2,3-双加氧酶1抑制剂的合成及活性研究

Synthesis and biological activity evaluation of novel indoleamine 2,3-dioxygenase 1 inhibitors

目的设计合成2类1H-吲唑类新化合物,并测试其吲哚胺2,3-双加氧酶1(IDO1)抑制活性。方法以肿瘤免疫关键调控蛋白IDO1作为靶标,依据IDO1活性位点的关键药效团特征,利用合理药物设计方法,以前期研究获得的高活性化合物作为先导化合物,设计合成了2类1H-吲唑类衍生物,并测试其体外IDO1酶抑制活性。采用分子对接软件DOCK6进行分子对接模拟并分析化合物的构效关系。结果与结论合成了5个1H-吲唑类衍生物,均表现出不同程度的IDO1抑制活性,其中化合物2a和3b的抑制活性较好,在100μmol·L^(-1)时的抑制率均为69%。构效关系和分子对接研究显示,4位连接基团的结构对化合物活性影响很大,1H-吲唑类化合物还有很大结构优化空间,极具开发潜力,可为靶向IDO1的肿瘤免疫治疗提供候选化合物。

Cancer immunotherapies promise to be an innovation in the treatment of cancer following surgical treatment, chemotherapy, radiotherapy, and targeted therapy, because of distinguished effectiveness and novelty. Indoleamine 2,3-dioxygenase 1 （IDOl） is an attractive target of cancer immunotherapy,and it has demonstrated remarkable value in the cancer treatment. Based on the key pharmacophore features of IDO active sites, two series of new 1H-indazoles were designed and synthesized via rational drug design methods. These 1H-indazole derivatives were determined the enzyme inhibitory activities, and compounds 2a and 3b exhibited the highest activities with inhibition ratio 69% at 100 ~nol .L-1. The structure-activity relationships （SARs） analysis and docking model of the 1H-indazole derivatives as novel IDOl inhibitors indicated thatthe linker groups at the 4-position largely affect inhibitory activity. In view of structural optimized potential of 1H-indazoles, the study suggested that 1H-indazoles have the potential to be the novel IDO pharmacologi- cal inhibitors and thus to provide the candidate compounds of IDO-targeted cancer immunotherapy agents.