天然香豆素Coladonin及其衍生物选择性抑制碳酸酐酶IX和XII：有前途的抗黑色素瘤和抗胶质母细胞瘤药物。

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-05-19 eCollection Date: 2025-06-12 DOI:10.1021/acsmedchemlett.5c00235

Muhamad Mustafa, Wiem Baccari, Alessio Nocentini, Maria Luisa Massardi, Michael Smietana, Eslam M Abbass, Ilyes Saidi, Mansour Znati, Hichem Ben Jannet, Roberto Ronca, Claudiu T Supuran, Jean-Yves Winum

{"title":"天然香豆素Coladonin及其衍生物选择性抑制碳酸酐酶IX和XII：有前途的抗黑色素瘤和抗胶质母细胞瘤药物。","authors":"Muhamad Mustafa, Wiem Baccari, Alessio Nocentini, Maria Luisa Massardi, Michael Smietana, Eslam M Abbass, Ilyes Saidi, Mansour Znati, Hichem Ben Jannet, Roberto Ronca, Claudiu T Supuran, Jean-Yves Winum","doi":"10.1021/acsmedchemlett.5c00235","DOIUrl":null,"url":null,"abstract":"Coladonin, a natural sesquiterpene coumarin ether isolated from Ferula tunetana, along with seven ester derivatives were investigated as inhibitors of human carbonic anhydrases IX and XII (hCA IX/XII). A series of coladonin-derived analogues (7a-g) was synthesized and tested against five CA isoforms (hCA I, II, IV, IX, XII). Coladonin 6 and its trifluoracetyl derivative 7e strongly and selectively inhibited hCA IX (K i = 90 and 70 nM, respectively) and hCA XII (K i = 210 and 110 nM, respectively). Compound 7e exhibited better selectivity on hCA IX than acetazolamide (AAZ). The antimelanoma and antiglioblastoma efficacy of coladonin 6 and 7e was evaluated in vitro under hypoxic conditions. Both compounds displayed significant antiproliferative effects, markedly better than those of the reference hCA IX/XII inhibitor SLC-0111 currently in clinical phase IIb. These results highlight coladonin 6 as a promising scaffold for developing selective hCA IX/XII inhibitors targeting hypoxic tumors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1190-1196"},"PeriodicalIF":4.0000,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169602/pdf/","citationCount":"0","resultStr":"{\"title\":\"Selective Inhibition of Carbonic Anhydrase IX and XII by Natural Coumarin Coladonin and Its Derivatives: Promising Antimelanoma and Antiglioblastoma Agents.\",\"authors\":\"Muhamad Mustafa, Wiem Baccari, Alessio Nocentini, Maria Luisa Massardi, Michael Smietana, Eslam M Abbass, Ilyes Saidi, Mansour Znati, Hichem Ben Jannet, Roberto Ronca, Claudiu T Supuran, Jean-Yves Winum\",\"doi\":\"10.1021/acsmedchemlett.5c00235\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Coladonin, a natural sesquiterpene coumarin ether isolated from Ferula tunetana, along with seven ester derivatives were investigated as inhibitors of human carbonic anhydrases IX and XII (hCA IX/XII). A series of coladonin-derived analogues (7a-g) was synthesized and tested against five CA isoforms (hCA I, II, IV, IX, XII). Coladonin 6 and its trifluoracetyl derivative 7e strongly and selectively inhibited hCA IX (K i = 90 and 70 nM, respectively) and hCA XII (K i = 210 and 110 nM, respectively). Compound 7e exhibited better selectivity on hCA IX than acetazolamide (AAZ). The antimelanoma and antiglioblastoma efficacy of coladonin 6 and 7e was evaluated in vitro under hypoxic conditions. Both compounds displayed significant antiproliferative effects, markedly better than those of the reference hCA IX/XII inhibitor SLC-0111 currently in clinical phase IIb. These results highlight coladonin 6 as a promising scaffold for developing selective hCA IX/XII inhibitors targeting hypoxic tumors.\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"16 6\",\"pages\":\"1190-1196\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-05-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169602/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsmedchemlett.5c00235\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/12 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.5c00235","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/12 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

从tunetana阿Ferula中分离的天然倍半萜香豆素醚Coladonin与7个酯衍生物一起作为人类碳酸酐酶IX和XII （hCA IX/XII）的抑制剂进行了研究。合成了一系列coladonin衍生的类似物（7a-g），并对5种CA异构体（hCA I， II， IV， IX， XII）进行了测试。Coladonin 6及其三氟乙酰基衍生物7e对hCA IX （K i分别为90 nM和70 nM）和hCA XII （K i分别为210 nM和110 nM）具有强选择性抑制作用。化合物7e对hcaix的选择性优于乙酰唑胺（AAZ）。在体外缺氧条件下，对coladonin 6和7e的抗黑色素瘤和抗胶质母细胞瘤效果进行了评价。两种化合物均显示出显著的抗增殖作用，明显优于目前处于临床IIb期的参考hCA IX/XII抑制剂SLC-0111。这些结果突出了coladonin 6作为一种有前途的支架，用于开发针对缺氧肿瘤的选择性hCA IX/XII抑制剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Selective Inhibition of Carbonic Anhydrase IX and XII by Natural Coumarin Coladonin and Its Derivatives: Promising Antimelanoma and Antiglioblastoma Agents.

Coladonin, a natural sesquiterpene coumarin ether isolated from Ferula tunetana, along with seven ester derivatives were investigated as inhibitors of human carbonic anhydrases IX and XII (hCA IX/XII). A series of coladonin-derived analogues (7a-g) was synthesized and tested against five CA isoforms (hCA I, II, IV, IX, XII). Coladonin 6 and its trifluoracetyl derivative 7e strongly and selectively inhibited hCA IX (K _i = 90 and 70 nM, respectively) and hCA XII (K _i = 210 and 110 nM, respectively). Compound 7e exhibited better selectivity on hCA IX than acetazolamide (AAZ). The antimelanoma and antiglioblastoma efficacy of coladonin 6 and 7e was evaluated in vitro under hypoxic conditions. Both compounds displayed significant antiproliferative effects, markedly better than those of the reference hCA IX/XII inhibitor SLC-0111 currently in clinical phase IIb. These results highlight coladonin 6 as a promising scaffold for developing selective hCA IX/XII inhibitors targeting hypoxic tumors.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

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.