Jin-Xia Lan , Le-Jun Huang , Si-Shuang Kang , Hao-Huang , Sheng-Lan Liu , Wei Dai , Xin-Liang Xu , Jin-Yang Wang , Guang-Zhao Shu , Wen Hou
{"title":"Design, synthesis, biological evaluation, and mechanism of action of new pyrazines as anticancer agents in vitro and in vivo","authors":"Jin-Xia Lan , Le-Jun Huang , Si-Shuang Kang , Hao-Huang , Sheng-Lan Liu , Wei Dai , Xin-Liang Xu , Jin-Yang Wang , Guang-Zhao Shu , Wen Hou","doi":"10.1016/j.bmc.2025.118108","DOIUrl":null,"url":null,"abstract":"<div><div>Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. <em>N</em>-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity <em>in vitro</em> and <em>in vivo</em>. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds <strong>B-11</strong> and <strong>C-27</strong> demonstrated significant anticancer activity <em>in vivo</em> in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118108"},"PeriodicalIF":3.3000,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089625000495","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. N-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity in vitro and in vivo. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds B-11 and C-27 demonstrated significant anticancer activity in vivo in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.