TRPA1 Inhibition Effects by 3-Phenylcoumarin Derivatives

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-07-02 DOI:10.1021/acsmedchemlett.4c00072

Carita Sallomy, Paul Awolade, Minna Rahnasto-Rilla, Mari Hämäläinen, Liisa P. Nousiainen, Niklas G. Johansson, Sanna Hiltunen, Petri Turhanen, Eeva Moilanen, Maija Lahtela-Kakkonen, Juri M. Timonen

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Abstract

Transient receptor potential ankyrin 1 (TRPA1) protein plays an important role in the inflammatory response, and it has been associated with different pain conditions and pain-related diseases, making TRPA1 a valid target for painkillers. In this study, we identified potential TRPA1 inhibitors and located their binding sites utilizing computer-aided drug design (CADD) techniques. The designed 3-phenylcoumarin-based TRPA1 inhibitors were successfully synthesized using a microwave assisted synthetic strategy. 3-(3-Bromophenyl)-7-acetoxycoumarin (5), 7-hydroxy-3-(3-hydroxyphenyl)coumarin (12) and 3-(3-hydroxyphenyl)coumarin (23) all showed inhibitory activity toward TRPA1 in vitro. Compound 5 also decreased the size and formation of breast cancer cells. Hence, targeting TRPA1 may represent a promising alternative for the treatment of pain and inflammation.

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3- 苯基香豆素衍生物对 TRPA1 的抑制作用

瞬态受体电位炔诺酮 1（TRPA1）蛋白在炎症反应中起着重要作用，它与不同的疼痛状况和疼痛相关疾病有关，因此 TRPA1 是止痛药的一个有效靶点。在这项研究中，我们利用计算机辅助药物设计（CADD）技术确定了潜在的 TRPA1 抑制剂并找到了它们的结合位点。利用微波辅助合成策略成功合成了所设计的基于 3-苯基香豆素的 TRPA1 抑制剂。3-(3-溴苯基)-7-乙酰氧基香豆素（5）、7-羟基-3-(3-羟基苯基)香豆素（12）和 3-(3-羟基苯基)香豆素（23）在体外均显示出对 TRPA1 的抑制活性。化合物 5 还能减少乳腺癌细胞的大小和形成。因此，靶向 TRPA1 可能是治疗疼痛和炎症的一种有前途的替代方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.