To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty–five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure–activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71–90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.

为了通过靶向吲哚胺 2,3-双加氧酶 1 (IDO1) 来发现小分子癌症免疫疗法候选物，合成了 25 种新的小檗碱 (BBR) 衍生物，其在 3 位或 9 位具有取代基，并检查了对 IFN- γ诱导的抑制IDO1 启动子活动。构效关系 (SAR) 表明 9 位的大体积基团可能对效力有益。其中，化合物2f、2i、2n、2o和8b的活性增加，与BBR相比抑制率为71-90%。它们对 IDO1 表达的影响也通过蛋白质水平得到进一步证实。此外，化合物2i和2n通过增强 NK 细胞通过 IDO1 对 A549 的特异性裂解而表现出抗癌活性，但没有细胞毒性。初步机制表明，它们都通过激活 AMPK 和随后抑制 STAT1 磷酸化来抑制 IFN- γ诱导的 IDO1 表达。因此，化合物2i和2n已被选为 IDO1 调节剂，用于小分子癌症免疫治疗以进行下一步研究。