Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1
Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1
复制标题
靶向IDO1的新型小檗碱衍生物作为癌症免疫治疗剂的合成及生物学评价
DOI：
10.1016/j.ejmech.2017.10.078
复制
发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Song, Dan-Qing
中科院分区：
文献类型：
--
作者：
Wang, Yan-Xiang;Pang, Wei-Qiang;Song, Dan-Qing
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药物，合成了 25 种在 3 或 9 位上带有取代基的新型小檗碱 (BBR) 衍生物，并检查了其对 IFN-γ 诱导的 IDO1 启动子活性的抑制情况。结构活性关系 (SAR) 表明 9 位的大体积组可能有利于效力。其中，化合物21、2i、2n、20和8b的活性增强，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了进一步证实。此外，化合物2i和2n通过IDO1增强NK细胞对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，两者均通过激活 AMPK 并随后抑制 STAT1 磷酸化来抑制 IFN-γ 诱导的 IDO1 表达。因此，化合物2i和2n被选为IDO1调节剂，用于小分子癌症免疫治疗，以供下一步研究。 (C) 2017 年作者。由 Elsevier Masson SAS 出版。
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-gamma-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 21, 2i, 2n, 20 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-gamma-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. (C) 2017 The Authors. Published by Elsevier Masson SAS.