Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin, 541199, China.
Guangxi Key Laboratory for Pharmaceutical Molecular Discovery and Druggability Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China; Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin, 541199, China.
Eur J Med Chem. 2023 Jun 5;254:115349. doi: 10.1016/j.ejmech.2023.115349. Epub 2023 Apr 11.
A series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed, synthesized and evaluated for their inhibitory activities against IDO1. These compounds displayed moderate to good inhibitory activity against IDO1 with IC values in low micromolar range. Among them, compound 10m bound effectively to IDO1 with good inhibitory activities (hIDO1 IC = 0.64 μM, HeLa IDO1 IC = 1.04 μM) and were selected for further investigation. Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein. Molecular docking study of the most active compound 10m revealed key interactions between 10m and IDO1 in which the chromone-oxime moiety coordinated to the heme iron and formed several hydrogen bonds with the porphyrin ring of heme and ALA264, consistent with the observation by UV-visible spectra that 10m induced a Soret peak shift from 403 to 421 nm. Moreover, compound 10m exhibited no cytotoxicity at its effective concentration in MTT assay. Consistently, in vivo assays results demonstrated that 10m displayed potent antitumor activity with low toxicity in CT26 tumor-bearing Balb/c mice, in comparison with 1-methyl-l-tryptophan (1-MT) and 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L). In brief, the results suggested that chromone-oxime derivatives containing sulfonamide moieties might serve as IDO1 inhibitors for the development of new antitumor agents.
一系列含有哌嗪磺酰胺部分的色酮肟衍生物被设计、合成并评估了它们对 IDO1 的抑制活性。这些化合物对 IDO1 表现出中等至良好的抑制活性，IC 值在低微摩尔范围内。其中，化合物 10m 与 IDO1 有效结合，具有良好的抑制活性（hIDO1 IC = 0.64 μM，HeLa IDO1 IC = 1.04 μM），并被选择进一步研究。表面等离子体共振分析证实了化合物 10m 与 IDO1 蛋白的直接相互作用。对最活跃的化合物 10m 的分子对接研究表明，10m 与 IDO1 之间存在关键相互作用，其中色酮肟部分与血红素铁配位，并与血红素的卟啉环和 ALA264 形成多个氢键，这与紫外可见光谱的观察结果一致，即 10m 诱导 Soret 峰从 403nm 位移至 421nm。此外，在 MTT 测定中，化合物 10m 在有效浓度下没有显示出细胞毒性。同样，体内试验结果表明，与 1-甲基-L-色氨酸（1-MT）和 4-氨基-N-（3-氯-4-氟苯基）-N'-羟基-1,2,5-恶二唑-3-甲脒（IDO5L）相比，化合物 10m 在 CT26 荷瘤 Balb/c 小鼠中具有较强的抗肿瘤活性和较低的毒性。总之，这些结果表明，含有磺酰胺部分的色酮肟衍生物可能作为 IDO1 抑制剂，用于开发新的抗肿瘤药物。
