Design, synthesis, and evaluation of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine derivatives as potential glutaminyl cyclase isoenzyme inhibitors for the treatment of cancer

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-11-01 DOI:10.1016/j.ejmech.2024.117019
Qingqing Zhou , Zhenxin Wu , Feixia Qin , Pan He , Zhuoran Wang , Fangyi Zhu , Ying Gao , Wei Xiong , Chenyang Li , Haiqiang Wu
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Abstract

Upregulated glutaminyl cyclase isoenzyme (isoQC) contributes to cancer development by catalyzing pE-CD47 generation and thus enhancing CD47-SIRPα binding and subsequent “don't eat me” signals. We thus consider that isoQC could represent a novel target for cancer therapy. We previously prepared a series of diphenyl conjugated imidazole derivatives (DPCIs) and evaluated their use as glutaminyl cyclase (QC) inhibitors. Here, a new series of DPCIs was rationally designed and synthesized. As anticipated, the analogues exhibited considerably improved inhibitory potency against both QC and isoQC. Crucially, these chemicals exhibited marked selectivity toward isoQC. Further assessments established that one selected compound (27) did not affect the viability of A549, H1299, PC9, or HEK293T cells or the body weight of mice. This compound did, however, reduce pE-CD47 levels in infected A549 cells (isoQC_OE and isoQC_KD) and exhibited apparent anti-cancer effects in vivo by downregulating the level of pE-CD47 via the inhibition of isoQC activity. Taken together, these findings indicated that the compounds synthesized in this study could represent potential QC/isoQC inhibitors for the treatment of cancers.

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设计、合成和评估 4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶衍生物作为治疗癌症的潜在谷氨酰胺环化酶同工酶抑制剂
上调的谷氨酰胺酰环酶同工酶(isoQC)可催化 pE-CD47 的生成,从而增强 CD47-SIRPα 的结合和随后的 "别吃我 "信号,从而促进癌症的发展。因此,我们认为异QC可能是癌症治疗的一个新靶点。我们之前制备了一系列二苯基共轭咪唑衍生物(DPCIs),并评估了它们作为谷氨酰胺酰环化酶(QC)抑制剂的用途。在此,我们合理地设计并合成了一系列新的 DPCIs。正如预期的那样,这些类似物对 QC 和异 QC 的抑制效力都有显著提高。最重要的是,这些化学物质对异QC具有明显的选择性。进一步的评估表明,一种被选中的化合物(27)不会影响 A549、H1299、PC9 或 HEK293T 细胞的活力或小鼠的体重。不过,这种化合物确实降低了受感染的 A549 细胞(isoQC_OE 和 isoQC_KD)中 pE-CD47 的水平,并通过抑制 isoQC 活性下调 pE-CD47 的水平,在体内表现出明显的抗癌效果。综上所述,这些发现表明本研究合成的化合物可能是治疗癌症的潜在 QC/isoQC 抑制剂。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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