Indoleamine 2,3-dioxygenase 1 (IDO1) as a key rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism plays an important role in tumour immune escape. Herein, a variety of secondary sulphonamides were synthesised and evaluated in the HeLa cell-based IDO1/kynurenine assay, leading to the identification of new IDO1 inhibitors. Among them, compounds 5d, 5l and 8g exhibited the strongest inhibitory effect with significantly improved activity over the hit compound BS-1. The in vitro results showed that these compounds could restore the T cell proliferation and inhibit the differentiation of naïve CD4+ T cell into highly immunosuppressive FoxP3+ regulatory T (Treg) cell without affecting the viability of HeLa cells and the expression of IDO1 protein. Importantly, the pharmacodynamic assay showed that compound 5d possessed potent antitumour effect in both CT26 and B16F1 tumours bearing immunocompetent mice but not in immunodeficient mice. Functionally, subsequent experiments demonstrated that compound 5d could effectively inhibit tumour cell proliferation, induce apoptosis, up-regulate the expression of IFN-γ and granzyme B, and suppress FoxP3+ Treg cell differentiation, thereby activate the immune system. Thus, compound 5d could be a potential and efficacious agent for further evaluation.

中文翻译：

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发现次磺酰胺作为IDO1抑制剂在体内具有强大的抗肿瘤作用。

吲哚胺2,3-二加氧酶1（IDO1）是色氨酸代谢的犬尿氨酸途径中的关键限速酶，在肿瘤免疫逃逸中起重要作用。本文中，合成了多种仲磺酰胺，并在基于HeLa细胞的IDO1 /犬尿氨酸测定中进行了评估，从而鉴定了新的IDO1抑制剂。其中，化合物5d，5l和8g显示出最强的抑制作用，并且与命中的化合物BS-1相比具有显着改善的活性。体外结果表明，这些化合物可恢复T细胞增殖并抑制幼稚CD4 + T细胞分化为高度免疫抑制的FoxP3 +调节性T（Treg）细胞，而不会影响HeLa细胞的活力和IDO1蛋白的表达。重要的，药效学分析表明，化合物5d在携带免疫功能小鼠的CT26和B16F1肿瘤中均具有有效的抗肿瘤作用，而在免疫缺陷小鼠中则没有。从功能上讲，后续实验表明化合物5d可有效抑制肿瘤细胞增殖，诱导细胞凋亡，上调IFN-γ和颗粒酶B的表达并抑制FoxP3 + Treg细胞分化，从而激活免疫系统。因此，化合物5d可能是进一步评估的潜在和有效试剂。并抑制FoxP3 + Treg细胞分化，从而激活免疫系统。因此，化合物5d可能是进一步评估的潜在和有效试剂。并抑制FoxP3 + Treg细胞分化，从而激活免疫系统。因此，化合物5d可能是进一步评估的潜在和有效试剂。