State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Bioorg Med Chem. 2018 Sep 15;26(17):4886-4897. doi: 10.1016/j.bmc.2018.08.028. Epub 2018 Aug 24.
Indoleamine 2,3-dioxygenase 1 (IDO1) is regarded as a promising target for cancer immunotherapy. Many naphthoquinone derivatives have been reported as IDO1 inhibitors so far. Herein, two series of naphthoquinone derivatives, naphthoindolizine and indolizinoquinoline-5,12-dione derivatives, were synthesized and evaluated for their IDO1 inhibitory activity. Most of the target compounds showed significant inhibition potency and high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). The structure-activity relationship was also summarized. The most potent compounds 5c (IC 23 nM, IDO1 enzyme), and 5b' (IC 372 nM, HeLa cell) were identified as promising lead compounds.
吲哚胺 2,3-双加氧酶 1（IDO1）被认为是癌症免疫治疗的有前途的靶点。到目前为止，已经报道了许多萘醌衍生物作为 IDO1 抑制剂。本文合成了两个系列的萘醌衍生物，萘并吲哚嗪和吲哚嗪并喹啉-5,12-二酮衍生物，并评估了它们对 IDO1 的抑制活性。大多数目标化合物对 IDO1 的抑制活性显著，对色氨酸 2,3-双加氧酶（TDO）具有高选择性。还总结了构效关系。最有效的化合物 5c（IC 23 nM，IDO1 酶）和 5b'（IC 372 nM，HeLa 细胞）被鉴定为有前途的先导化合物。
