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Novel Plasma Kallikrein Inhibitors for Treating Multiple Diseases. 用于治疗多种疾病的新型血浆 Kallikrein 抑制剂。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00484
Ram W Sabnis
{"title":"Novel Plasma Kallikrein Inhibitors for Treating Multiple Diseases.","authors":"Ram W Sabnis","doi":"10.1021/acsmedchemlett.4c00484","DOIUrl":"10.1021/acsmedchemlett.4c00484","url":null,"abstract":"<p><p>Provided herein are novel plasma kallikrein inhibitors, pharmaceutical compositions, use of such compounds in treating hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1808-1809"},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold. 利用大环支架实现嗜环蛋白催化和守门口袋的双重定位
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00427
Johannes K Dreizler, Christian Meyners, Felix Hausch
{"title":"Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold.","authors":"Johannes K Dreizler, Christian Meyners, Felix Hausch","doi":"10.1021/acsmedchemlett.4c00427","DOIUrl":"10.1021/acsmedchemlett.4c00427","url":null,"abstract":"<p><p>Cyclophilins, especially cyclophilin A, are involved in a variety of diseases, including the life cycle of many viruses. An advanced macrocyclic inhibitor of cyclophilin was reported to bind the catalytic pocket but not the neighboring gatekeeper pocket. Here we describe macrocyclic cyclophilin inhibitors bearing side chains designed to reach out to the gatekeeper pocket. After establishing a suitable synthesis allowing for late-stage modification of the relevant positions, we explored this exit vector. This culminated in a rigid ornithine-resembling analogue as a versatile building block, which was also incorporated into the macrocyclic scaffold. The use of amines as the gatekeeper-engaging modality was invalidated, but the exit vector was successfully established as a promising position for future modifications. Further work is needed to identify suitable motifs to simultaneously engage the catalytic and gatekeeper pockets in this highly developed macrocyclic scaffold.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"2012-2018"},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel Plasma Kallikrein Inhibitors for Treating Multiple Diseases 治疗多种疾病的新型血浆 Kallikrein 抑制剂
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-27 DOI: 10.1021/acsmedchemlett.4c0048410.1021/acsmedchemlett.4c00484
Ram W. Sabnis*, 
{"title":"Novel Plasma Kallikrein Inhibitors for Treating Multiple Diseases","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0048410.1021/acsmedchemlett.4c00484","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00484https://doi.org/10.1021/acsmedchemlett.4c00484","url":null,"abstract":"<p >Provided herein are novel plasma kallikrein inhibitors, pharmaceutical compositions, use of such compounds in treating hereditary angioedema, uveitis, posterior uveitis, wet age-related macular degeneration, diabetic macular edema, diabetic retinopathy and retinal vein occlusion and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1808–1809 1808–1809"},"PeriodicalIF":3.5,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Semisynthetic Tetramate-Containing Fungal Metabolites with Activity against Trichomonas vaginalis and Mycoplasma genitalium. 具有抗阴道毛滴虫和生殖器支原体活性的半合成含四甲酸酯的真菌代谢物
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-24 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00386
Thilini Peramuna, Gwendolyn E Wood, Ziwei Hu, Karen L Wendt, Laarni Kendra T Aguila, Caroline M Kim, Adam S Duerfeldt, Robert H Cichewicz
{"title":"Semisynthetic Tetramate-Containing Fungal Metabolites with Activity against <i>Trichomonas vaginalis</i> and <i>Mycoplasma genitalium</i>.","authors":"Thilini Peramuna, Gwendolyn E Wood, Ziwei Hu, Karen L Wendt, Laarni Kendra T Aguila, Caroline M Kim, Adam S Duerfeldt, Robert H Cichewicz","doi":"10.1021/acsmedchemlett.4c00386","DOIUrl":"10.1021/acsmedchemlett.4c00386","url":null,"abstract":"<p><p>Tetramic acid-containing natural products are well known for their promising biological activity against various diseases. In our previous study, we reported fungal-derived tetramic acid-containing natural products with activity against <i>Trichomonas vaginalis</i>. Here, we demonstrate that <i>Mycoplasma genitalium</i> is also highly susceptible to this chemotype and we uncovered the initial structure activity relationships on disparate tetramate chemotypes in phomasetin (<b>6</b>) and pyrrolocin A (<b>10</b>). Further, <b>6</b> and <b>10</b> were modified using \"click\" chemistry to re-engineer bioactivity. Compounds <b>6</b> and <b>10</b> hold promise as a pipeline-diversifying chemotype for promising leads against <i>T</i>. <i>vaginalis</i> and <i>M</i>. <i>genitalium</i>.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1933-1939"},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Semisynthetic Tetramate-Containing Fungal Metabolites with Activity against Trichomonas vaginalis and Mycoplasma genitalium 具有抗阴道毛滴虫和生殖器支原体活性的半合成含四甲酸酯的真菌代谢物
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-24 DOI: 10.1021/acsmedchemlett.4c0038610.1021/acsmedchemlett.4c00386
Thilini Peramuna, Gwendolyn E. Wood, Ziwei Hu, Karen L. Wendt, Laarni Kendra T. Aguila, Caroline M. Kim, Adam S. Duerfeldt and Robert H. Cichewicz*, 
{"title":"Semisynthetic Tetramate-Containing Fungal Metabolites with Activity against Trichomonas vaginalis and Mycoplasma genitalium","authors":"Thilini Peramuna,&nbsp;Gwendolyn E. Wood,&nbsp;Ziwei Hu,&nbsp;Karen L. Wendt,&nbsp;Laarni Kendra T. Aguila,&nbsp;Caroline M. Kim,&nbsp;Adam S. Duerfeldt and Robert H. Cichewicz*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0038610.1021/acsmedchemlett.4c00386","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00386https://doi.org/10.1021/acsmedchemlett.4c00386","url":null,"abstract":"<p >Tetramic acid-containing natural products are well known for their promising biological activity against various diseases. In our previous study, we reported fungal-derived tetramic acid-containing natural products with activity against <i>Trichomonas vaginalis</i>. Here, we demonstrate that <i>Mycoplasma genitalium</i> is also highly susceptible to this chemotype and we uncovered the initial structure activity relationships on disparate tetramate chemotypes in phomasetin (<b>6</b>) and pyrrolocin A (<b>10</b>). Further, <b>6</b> and <b>10</b> were modified using “click” chemistry to re-engineer bioactivity. Compounds <b>6</b> and <b>10</b> hold promise as a pipeline-diversifying chemotype for promising leads against <i>T</i>. <i>vaginalis</i> and <i>M</i>. <i>genitalium</i>.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1933–1939 1933–1939"},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design, Synthesis, and Activity of a Novel Series of Pyridazine-Based ALK5 Inhibitors 基于哒嗪的新型 ALK5 抑制剂系列的设计、合成和活性
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 DOI: 10.1021/acsmedchemlett.4c0037410.1021/acsmedchemlett.4c00374
Daniele Pala, Paolo Ronchi, Donatella Rescigno, Barbara Bertani, Anna Maria Capelli, Sara Guariento, Gessica Marchini, Marco Milioli, Nicola Cesari, Giuseppina Federico, Andrea Grandi, Franco F. Stellari, Sergio Xanxo Fernandez, Alice Pappani, Luca Venturi, Matteo Biagetti, Maurizio Civelli, Teresa Semeraro, Federica Bianchi, Iuni M. L. Trist, Rosaria Remelli, Elisabetta Armani* and Daniela Pizzirani*, 
{"title":"Design, Synthesis, and Activity of a Novel Series of Pyridazine-Based ALK5 Inhibitors","authors":"Daniele Pala,&nbsp;Paolo Ronchi,&nbsp;Donatella Rescigno,&nbsp;Barbara Bertani,&nbsp;Anna Maria Capelli,&nbsp;Sara Guariento,&nbsp;Gessica Marchini,&nbsp;Marco Milioli,&nbsp;Nicola Cesari,&nbsp;Giuseppina Federico,&nbsp;Andrea Grandi,&nbsp;Franco F. Stellari,&nbsp;Sergio Xanxo Fernandez,&nbsp;Alice Pappani,&nbsp;Luca Venturi,&nbsp;Matteo Biagetti,&nbsp;Maurizio Civelli,&nbsp;Teresa Semeraro,&nbsp;Federica Bianchi,&nbsp;Iuni M. L. Trist,&nbsp;Rosaria Remelli,&nbsp;Elisabetta Armani* and Daniela Pizzirani*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0037410.1021/acsmedchemlett.4c00374","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00374https://doi.org/10.1021/acsmedchemlett.4c00374","url":null,"abstract":"<p >ALK5 inhibitors represent an attractive therapeutic approach for the treatment of a variety of pathologies, including cancer and fibrosis. Herein, we report the design and <i>in vitro</i> characterization of a novel series of ALK5 modulators featuring a 4,6-disubstituted pyridazine core. A knowledge-based scaffold-hopping exploration was initially conducted on a restricted set of heteroaromatic cores using available ligand- and structure-based information. The most potent structurally novel hit compound <b>2A</b> was subsequently subjected to a preliminary optimization for the inhaled delivery, applying physicochemical criteria aimed at minimizing systemic exposure to limit the risk of adverse side effects. The resulting inhibitors showed a marked boost in potency against ALK5 and <i>in vitro</i> ADME properties, potentially favoring lung retention. The optimized hits <b>20</b> and <b>23</b> might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1925–1932 1925–1932"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Design, Synthesis, and Activity of a Novel Series of Pyridazine-Based ALK5 Inhibitors. 基于哒嗪的新型 ALK5 抑制剂系列的设计、合成和活性。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00374
Daniele Pala, Paolo Ronchi, Donatella Rescigno, Barbara Bertani, Anna Maria Capelli, Sara Guariento, Gessica Marchini, Marco Milioli, Nicola Cesari, Giuseppina Federico, Andrea Grandi, Franco F Stellari, Sergio Xanxo Fernandez, Alice Pappani, Luca Venturi, Matteo Biagetti, Maurizio Civelli, Teresa Semeraro, Federica Bianchi, Iuni M L Trist, Rosaria Remelli, Elisabetta Armani, Daniela Pizzirani
{"title":"Design, Synthesis, and Activity of a Novel Series of Pyridazine-Based ALK5 Inhibitors.","authors":"Daniele Pala, Paolo Ronchi, Donatella Rescigno, Barbara Bertani, Anna Maria Capelli, Sara Guariento, Gessica Marchini, Marco Milioli, Nicola Cesari, Giuseppina Federico, Andrea Grandi, Franco F Stellari, Sergio Xanxo Fernandez, Alice Pappani, Luca Venturi, Matteo Biagetti, Maurizio Civelli, Teresa Semeraro, Federica Bianchi, Iuni M L Trist, Rosaria Remelli, Elisabetta Armani, Daniela Pizzirani","doi":"10.1021/acsmedchemlett.4c00374","DOIUrl":"10.1021/acsmedchemlett.4c00374","url":null,"abstract":"<p><p>ALK5 inhibitors represent an attractive therapeutic approach for the treatment of a variety of pathologies, including cancer and fibrosis. Herein, we report the design and <i>in vitro</i> characterization of a novel series of ALK5 modulators featuring a 4,6-disubstituted pyridazine core. A knowledge-based scaffold-hopping exploration was initially conducted on a restricted set of heteroaromatic cores using available ligand- and structure-based information. The most potent structurally novel hit compound <b>2A</b> was subsequently subjected to a preliminary optimization for the inhaled delivery, applying physicochemical criteria aimed at minimizing systemic exposure to limit the risk of adverse side effects. The resulting inhibitors showed a marked boost in potency against ALK5 and <i>in vitro</i> ADME properties, potentially favoring lung retention. The optimized hits <b>20</b> and <b>23</b> might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1925-1932"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia. 发现IRAK1/4/pan-FLT3激酶抑制剂作为急性髓性白血病的治疗方法。
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00269
Scott B Hoyt, Chris J Finocchio, Elizabeth Croll, Gregory J Tawa, Huixu Li, Li Ma, Kaikai Li, Li Liu, Ranran Li, Xiaohu Zhang, Kelli Wilson, Xin Xu, Pranav Shah, Jordan Williams, Yuhong Fang, Lyndsey C Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F Edmondson, Simone Difilippantonio, LaQuita M Jones, Ashley E Culver-Cochran, Jan S Rosenbaum, Daniel T Starczynowski, Craig J Thomas
{"title":"Discovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.","authors":"Scott B Hoyt, Chris J Finocchio, Elizabeth Croll, Gregory J Tawa, Huixu Li, Li Ma, Kaikai Li, Li Liu, Ranran Li, Xiaohu Zhang, Kelli Wilson, Xin Xu, Pranav Shah, Jordan Williams, Yuhong Fang, Lyndsey C Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F Edmondson, Simone Difilippantonio, LaQuita M Jones, Ashley E Culver-Cochran, Jan S Rosenbaum, Daniel T Starczynowski, Craig J Thomas","doi":"10.1021/acsmedchemlett.4c00269","DOIUrl":"10.1021/acsmedchemlett.4c00269","url":null,"abstract":"<p><p>We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound <b>31</b> which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, <b>31</b> produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1843-1851"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy 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
ACS Medicinal Chemistry Letters Pub Date : 2024-10-23 DOI: 10.1021/acsmedchemlett.4c0039810.1021/acsmedchemlett.4c00398
Anna Lisa Iorio, Elena Lenci, Chiara Marzano, Elisabetta Bucaletti, Bianca Tirinnanzi, Giacomo Casati, Laura Giunti, Caterina Dallari, Caterina Credi, Iacopo Sardi* and Andrea Trabocchi*, 
{"title":"Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy","authors":"Anna Lisa Iorio,&nbsp;Elena Lenci,&nbsp;Chiara Marzano,&nbsp;Elisabetta Bucaletti,&nbsp;Bianca Tirinnanzi,&nbsp;Giacomo Casati,&nbsp;Laura Giunti,&nbsp;Caterina Dallari,&nbsp;Caterina Credi,&nbsp;Iacopo Sardi* and Andrea Trabocchi*,&nbsp;","doi":"10.1021/acsmedchemlett.4c0039810.1021/acsmedchemlett.4c00398","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00398https://doi.org/10.1021/acsmedchemlett.4c00398","url":null,"abstract":"<p >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 <b>7</b> as compared to <b>4</b> and to conventional DOX. These data were confirmed in an <i>in vitro</i> coculture BBB model in which DOX glycoconjugate <b>7</b> 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.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1953–1960 1953–1960"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy. 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
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":"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":"10.1021/acsmedchemlett.4c00398","url":null,"abstract":"<p><p>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 <b>7</b> as compared to <b>4</b> and to conventional DOX. These data were confirmed in an <i>in vitro</i> coculture BBB model in which DOX glycoconjugate <b>7</b> 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.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1953-1960"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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