Synthesis and characterization of novel phenyl carboxamide-selenium analogs: Identification of a potent DHODH inhibitor as a potential anticancer agent

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-23 DOI:10.1016/j.ejmech.2025.118193

Cristina Morán-Serradilla , Carmen Sanmartín , Asif Raza , Amandeep Singh , César Aliaga , Daniel Plano , Arun K. Sharma

{"title":"Synthesis and characterization of novel phenyl carboxamide-selenium analogs: Identification of a potent DHODH inhibitor as a potential anticancer agent","authors":"Cristina Morán-Serradilla , Carmen Sanmartín , Asif Raza , Amandeep Singh , César Aliaga , Daniel Plano , Arun K. Sharma","doi":"10.1016/j.ejmech.2025.118193","DOIUrl":null,"url":null,"abstract":"<div><div>Despite continued research efforts, cancer remains a growing public health problem. Herein, we have designed four different libraries of compounds by rationally introducing select Se moieties into the phenyl carboxamide backbone and characterized them <em>in vitro</em> to assess their antiproliferative activities. The identified lead compounds, <strong>A1</strong> and <strong>C3</strong>, displayed a discerning cytotoxicity against a panel of 60 cancer cell lines in the DTP of the NCI. Their ability to induce apoptosis and ROS and modulate the cell cycle was assessed in MDA-MB-231 breast cancer cells. In addition, both <strong>A1</strong> and <strong>C3</strong> inhibited tumor growth with no evident toxicity signs in a syngeneic breast cancer mouse model. Notably, in concordance with the COMPARE analysis, compound <strong>A1</strong> was found to act at the level of the <em>de novo</em> pyrimidine biosynthetic pathway by inhibiting <em>in vitro</em> the cellular dihydroorotate dehydrogenase (DHODH), which was also supported by the molecular modeling studies.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"301 ","pages":"Article 118193"},"PeriodicalIF":5.9000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523425009584","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Despite continued research efforts, cancer remains a growing public health problem. Herein, we have designed four different libraries of compounds by rationally introducing select Se moieties into the phenyl carboxamide backbone and characterized them in vitro to assess their antiproliferative activities. The identified lead compounds, A1 and C3, displayed a discerning cytotoxicity against a panel of 60 cancer cell lines in the DTP of the NCI. Their ability to induce apoptosis and ROS and modulate the cell cycle was assessed in MDA-MB-231 breast cancer cells. In addition, both A1 and C3 inhibited tumor growth with no evident toxicity signs in a syngeneic breast cancer mouse model. Notably, in concordance with the COMPARE analysis, compound A1 was found to act at the level of the de novo pyrimidine biosynthetic pathway by inhibiting in vitro the cellular dihydroorotate dehydrogenase (DHODH), which was also supported by the molecular modeling studies.

查看原文本刊更多论文

新型苯基羧胺-硒类似物的合成与表征：一种有效的DHODH抑制剂作为潜在抗癌剂的鉴定

尽管研究不断努力，癌症仍然是一个日益严重的公共卫生问题。在此基础上，我们设计了4个不同的化合物文库，通过在苯基羧基酰胺主链中合理地引入Se基团，并对其进行了体外表征，以评估其抗增殖活性。鉴定的先导化合物A1和C3对NCI DTP中的60个癌细胞系显示出明显的细胞毒性。在MDA-MB-231乳腺癌细胞中评估了它们诱导细胞凋亡和ROS以及调节细胞周期的能力。此外，在同基因乳腺癌小鼠模型中，A1和C3均能抑制肿瘤生长，且无明显的毒性迹象。值得注意的是，与COMPARE分析一致的是，化合物A1通过体外抑制细胞二氢羟酸脱氢酶（DHODH），在从头合成嘧啶生物合成途径水平上起作用，这也得到了分子模型研究的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

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.