肟联用多柔比星糖苷共轭物提高了胶质母细胞瘤在高级别胶质瘤治疗中的特异性靶向性

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 eCollection Date: 2024-11-14 DOI:10.1021/acsmedchemlett.4c00398

Anna Lisa Iorio, Elena Lenci, Chiara Marzano, Elisabetta Bucaletti, Bianca Tirinnanzi, Giacomo Casati, Laura Giunti, Caterina Dallari, Caterina Credi, Iacopo Sardi, Andrea Trabocchi

{"title":"肟联用多柔比星糖苷共轭物提高了胶质母细胞瘤在高级别胶质瘤治疗中的特异性靶向性","authors":"Anna Lisa Iorio, Elena Lenci, Chiara Marzano, Elisabetta Bucaletti, Bianca Tirinnanzi, Giacomo Casati, Laura Giunti, Caterina Dallari, Caterina Credi, Iacopo Sardi, Andrea Trabocchi","doi":"10.1021/acsmedchemlett.4c00398","DOIUrl":null,"url":null,"abstract":"The treatment of glioblastoma (GBM) represents an urgent challenge for public health due to the inability to effectively deliver anticancer agents, such as doxorubicin (DOX), through the blood-brain barrier (BBB). Herein we report the synthesis of two novel DOX glycoconjugates using an oxime linkage that maintained the intercalation capability of the planar anthracycline ring of DOX, as demonstrated by UV-vis and fluorescence experiments in the presence of DNA. The biological effect of DOX glycoconjugates was evaluated in GBM cell lines, showing an enhanced cytotoxic and pro-apoptotic effect of 7 as compared to 4 and to conventional DOX. These data were confirmed in an in vitro coculture BBB model in which DOX glycoconjugate 7 showed high capability to cross a cellular monolayer and exert its cytotoxic effect on GBM cells. The results show that conjugation with glucose may represent a helpful tool to increase chemotherapy effectiveness in poor-responding GBM patients.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1953-1960"},"PeriodicalIF":3.5000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571026/pdf/","citationCount":"0","resultStr":"{\"title\":\"Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy.\",\"authors\":\"Anna Lisa Iorio, Elena Lenci, Chiara Marzano, Elisabetta Bucaletti, Bianca Tirinnanzi, Giacomo Casati, Laura Giunti, Caterina Dallari, Caterina Credi, Iacopo Sardi, Andrea Trabocchi\",\"doi\":\"10.1021/acsmedchemlett.4c00398\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The treatment of glioblastoma (GBM) represents an urgent challenge for public health due to the inability to effectively deliver anticancer agents, such as doxorubicin (DOX), through the blood-brain barrier (BBB). Herein we report the synthesis of two novel DOX glycoconjugates using an oxime linkage that maintained the intercalation capability of the planar anthracycline ring of DOX, as demonstrated by UV-vis and fluorescence experiments in the presence of DNA. The biological effect of DOX glycoconjugates was evaluated in GBM cell lines, showing an enhanced cytotoxic and pro-apoptotic effect of 7 as compared to 4 and to conventional DOX. These data were confirmed in an in vitro coculture BBB model in which DOX glycoconjugate 7 showed high capability to cross a cellular monolayer and exert its cytotoxic effect on GBM cells. The results show that conjugation with glucose may represent a helpful tool to increase chemotherapy effectiveness in poor-responding GBM patients.\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"15 11\",\"pages\":\"1953-1960\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-10-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571026/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsmedchemlett.4c00398\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/14 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.4c00398","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/14 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

由于多柔比星（DOX）等抗癌药物无法通过血脑屏障（BBB）有效递送，胶质母细胞瘤（GBM）的治疗成为公共卫生面临的一项紧迫挑战。在此，我们报告了两种新型 DOX 糖共轭物的合成，它们采用肟连接，保持了 DOX 平面蒽环的插层能力，这一点已在 DNA 存在下的紫外可见光和荧光实验中得到证实。在 GBM 细胞系中对 DOX 糖结合物的生物效应进行了评估，结果显示，与 4 和传统 DOX 相比，7 增强了细胞毒性和促凋亡效应。这些数据在体外共培养 BBB 模型中得到了证实，在该模型中，DOX 糖共轭物 7 显示出很强的穿过细胞单层并对 GBM 细胞发挥细胞毒性作用的能力。结果表明，与葡萄糖共轭可作为一种有用的工具，提高对反应不佳的 GBM 患者的化疗效果。

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

Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy.

The treatment of glioblastoma (GBM) represents an urgent challenge for public health due to the inability to effectively deliver anticancer agents, such as doxorubicin (DOX), through the blood-brain barrier (BBB). Herein we report the synthesis of two novel DOX glycoconjugates using an oxime linkage that maintained the intercalation capability of the planar anthracycline ring of DOX, as demonstrated by UV-vis and fluorescence experiments in the presence of DNA. The biological effect of DOX glycoconjugates was evaluated in GBM cell lines, showing an enhanced cytotoxic and pro-apoptotic effect of 7 as compared to 4 and to conventional DOX. These data were confirmed in an in vitro coculture BBB model in which DOX glycoconjugate 7 showed high capability to cross a cellular monolayer and exert its cytotoxic effect on GBM cells. The results show that conjugation with glucose may represent a helpful tool to increase chemotherapy effectiveness in poor-responding GBM patients.

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.