ACS Medicinal Chemistry Letters最新文献_第2页

Highly Sensitive Naphthalene-Based Twisted Intramolecular Charge Transfer Molecules for the Detection of In Vitro and In Cellulo Protein Aggregates.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-29 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00363

Joy Debnath, Yuvasree Sekar, Anwesha Bera

引用次数: 0

Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00438

Akram H Abd El-Haleem, Manar Abd El-Karim Kassem, Mohamed R Elnagar, Safinaz E-S Abbas, Ahmed M El Kerdawy, Ahmed K B A W Farouk

{"title":"Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity.","authors":"Akram H Abd El-Haleem, Manar Abd El-Karim Kassem, Mohamed R Elnagar, Safinaz E-S Abbas, Ahmed M El Kerdawy, Ahmed K B A W Farouk","doi":"10.1021/acsmedchemlett.4c00438","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00438","url":null,"abstract":"New derivatives 4a-d, 6, 7a-d, 8a-c, 9, 11a, 11b, 12a-f, 13a-c, and 14 were synthesized and evaluated for their VEGFR-2 inhibition. Compounds 4c, 7b, and 7c showed remarkable enzyme inhibition (IC50 = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC50 = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound 7b displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC50 = 6.66 and 8.51 μM) compared to sorafenib (IC50 = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of 7b in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound 7b revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of 7b showed inhibition of wound closure. Additionally, molecular modeling studies of compounds 4c, 7b, and 7c were carried out.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2150-2157"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845279","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

Structure-Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00510

Jacob P Beard, Sierra L Love, John C Schmitz, Aaron A Hoskins, Kazunori Koide

引用次数: 0

Structure–Activity Relationship Study of Splicing Modulators on Hsh155/SF3B1 through Chemical Synthesis and Yeast Genetics

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 DOI: 10.1021/acsmedchemlett.4c0051010.1021/acsmedchemlett.4c00510

Jacob P. Beard, Sierra L. Love, John C. Schmitz, Aaron A. Hoskins and Kazunori Koide*,

引用次数: 0

Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 DOI: 10.1021/acsmedchemlett.4c0043810.1021/acsmedchemlett.4c00438

Akram H. Abd El-Haleem, Manar Abd El-karim Kassem, Mohamed R. Elnagar, Safinaz E-S. Abbas, Ahmed M. El Kerdawy and Ahmed K. B. A. W. Farouk*,

{"title":"Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity","authors":"Akram H. Abd El-Haleem, Manar Abd El-karim Kassem, Mohamed R. Elnagar, Safinaz E-S. Abbas, Ahmed M. El Kerdawy and Ahmed K. B. A. W. Farouk*, ","doi":"10.1021/acsmedchemlett.4c0043810.1021/acsmedchemlett.4c00438","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00438https://doi.org/10.1021/acsmedchemlett.4c00438","url":null,"abstract":"New derivatives 4a–d, 6, 7a–d, 8a–c, 9, 11a, 11b, 12a–f, 13a–c, and 14 were synthesized and evaluated for their VEGFR-2 inhibition. Compounds 4c, 7b, and 7c showed remarkable enzyme inhibition (IC50 = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC50 = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound 7b displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC50 = 6.66 and 8.51 μM) compared to sorafenib (IC50 = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of 7b in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound 7b revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of 7b showed inhibition of wound closure. Additionally, molecular modeling studies of compounds 4c, 7b, and 7c were carried out.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2150–2157 2150–2157"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843349","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

Psychedelics and Entactogens: Call for Papers

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 DOI: 10.1021/acsmedchemlett.4c0056410.1021/acsmedchemlett.4c00564

Craig W. Lindsley*, Jacob M. Hooker, Kelly Chibale, Christa E. Müller and Squire J. Booker,

引用次数: 0

Design, Synthesis, and Activity Evaluation of C-23-Modified 5-O-Mycaminosyltylonolide Derivatives.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00458

Zhengmin Fan, Ziwei Lin, Hongjin Zhai, Yaquan Cao, Huanhuan Wang, Aichata Maiga, Firas Obald Arhema Frejat, Changzhong Ren, Chun-Li Wu

{"title":"Design, Synthesis, and Activity Evaluation of C-23-Modified 5-O-Mycaminosyltylonolide Derivatives.","authors":"Zhengmin Fan, Ziwei Lin, Hongjin Zhai, Yaquan Cao, Huanhuan Wang, Aichata Maiga, Firas Obald Arhema Frejat, Changzhong Ren, Chun-Li Wu","doi":"10.1021/acsmedchemlett.4c00458","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00458","url":null,"abstract":"The widespread use of tylosin family drugs in clinical practice has led to bacterial resistance and reduced therapeutic efficacy. We designed and synthesized a series of new semisynthetic derivatives of tylosin with 5-O-mycaminosyltylonolide as the mother nucleus, mainly by introducing a variety of amino groups at its C-23 position. Some of the compounds showed high antibacterial activity against Gram-negative and Gram-positive bacteria. These findings indicate that the best compound, c9, possessed significant antibacterial activity (MIC = 0.5 ug/mL), excellent bactericidal efficacy, and a low induction rate of drug resistance against Staphylococcus aureus and Escherichia coli; it also showed good antibacterial activity against drug-resistant bacteria. In addition, compound c9 has a low toxicity in vitro and in vivo. In conclusion, compound c9 could be a potential antimicrobial lead compound that could also contribute to the development of macrolide antibiotics.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2171-2180"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845275","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 Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00471

Patrick Cyr, Lee D Fader, Jason D Burch, Kelly A Pike, Daniel V Sietsema, Marc-Olivier Boily, Stéphane Ciblat, Nicolas Sgarioto, Alexander M Skeldon, Samuel Gaudreault, Philippe Le Gros, Valérie Dumais, Daniel J J McKay, Nathan S Abraham, Ria Seliniotakis, Ramsay E Beveridge

{"title":"Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization.","authors":"Patrick Cyr, Lee D Fader, Jason D Burch, Kelly A Pike, Daniel V Sietsema, Marc-Olivier Boily, Stéphane Ciblat, Nicolas Sgarioto, Alexander M Skeldon, Samuel Gaudreault, Philippe Le Gros, Valérie Dumais, Daniel J J McKay, Nathan S Abraham, Ria Seliniotakis, Ramsay E Beveridge","doi":"10.1021/acsmedchemlett.4c00471","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00471","url":null,"abstract":"Using a high-throughput screening (HTS) approach, a new GTP-site binding pyridine-carboxylate series of cGAS inhibitors was discovered. The biochemical potency of this new pyridine carboxylate series was improved 166-fold from the original hit to double-digit nanomolar levels using structure-based design insights, but the series was found to suffer from low permeability and low bioavailability. A structure-based hybridization of the metal-binding motifs of the pyridine carboxylate series and our previously disclosed tetrahydrocarboline GTP-site ligand 23 identified pyrimidine amide compound 36. Compound 36 is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound 36 displayed a dose-dependent reduction in cGAMP production in a ConA pharmacodynamic mouse model of acute liver injury, demonstrating potential utility as an in vivo tool compound for further investigation of the cGAS pathway.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2201-2209"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845278","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

Design, Synthesis, and Activity Evaluation of C-23-Modified 5-O-Mycaminosyltylonolide Derivatives C-23 改性 5-O-Mycaminosyltylonolide 衍生物的设计、合成和活性评估

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 DOI: 10.1021/acsmedchemlett.4c0045810.1021/acsmedchemlett.4c00458

Zhengmin Fan, Ziwei Lin, Hongjin Zhai, Yaquan Cao*, Huanhuan Wang, Aichata Maiga, Firas Obald Arhema Frejat, Changzhong Ren and Chun-Li Wu*,

{"title":"Design, Synthesis, and Activity Evaluation of C-23-Modified 5-O-Mycaminosyltylonolide Derivatives","authors":"Zhengmin Fan, Ziwei Lin, Hongjin Zhai, Yaquan Cao*, Huanhuan Wang, Aichata Maiga, Firas Obald Arhema Frejat, Changzhong Ren and Chun-Li Wu*, ","doi":"10.1021/acsmedchemlett.4c0045810.1021/acsmedchemlett.4c00458","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00458https://doi.org/10.1021/acsmedchemlett.4c00458","url":null,"abstract":"The widespread use of tylosin family drugs in clinical practice has led to bacterial resistance and reduced therapeutic efficacy. We designed and synthesized a series of new semisynthetic derivatives of tylosin with 5-O-mycaminosyltylonolide as the mother nucleus, mainly by introducing a variety of amino groups at its C-23 position. Some of the compounds showed high antibacterial activity against Gram-negative and Gram-positive bacteria. These findings indicate that the best compound, c9, possessed significant antibacterial activity (MIC = 0.5 ug/mL), excellent bactericidal efficacy, and a low induction rate of drug resistance against Staphylococcus aureus and Escherichia coli; it also showed good antibacterial activity against drug-resistant bacteria. In addition, compound c9 has a low toxicity in vitro and in vivo. In conclusion, compound c9 could be a potential antimicrobial lead compound that could also contribute to the development of macrolide antibiotics.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2171–2180 2171–2180"},"PeriodicalIF":3.5,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843350","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

Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-24 DOI: 10.1021/acsmedchemlett.4c0047110.1021/acsmedchemlett.4c00471

Patrick Cyr*, Lee D. Fader, Jason D. Burch, Kelly A. Pike, Daniel V. Sietsema, Marc-Olivier Boily, Stéphane Ciblat, Nicolas Sgarioto, Alexander M. Skeldon, Samuel Gaudreault, Philippe Le Gros, Valérie Dumais, Daniel J. J. McKay, Nathan S. Abraham, Ria Seliniotakis and Ramsay E. Beveridge*,

{"title":"Discovery of Potent and Orally Bioavailable Pyrimidine Amide cGAS Inhibitors via Structure-Guided Hybridization","authors":"Patrick Cyr*, Lee D. Fader, Jason D. Burch, Kelly A. Pike, Daniel V. Sietsema, Marc-Olivier Boily, Stéphane Ciblat, Nicolas Sgarioto, Alexander M. Skeldon, Samuel Gaudreault, Philippe Le Gros, Valérie Dumais, Daniel J. J. McKay, Nathan S. Abraham, Ria Seliniotakis and Ramsay E. Beveridge*, ","doi":"10.1021/acsmedchemlett.4c0047110.1021/acsmedchemlett.4c00471","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00471https://doi.org/10.1021/acsmedchemlett.4c00471","url":null,"abstract":"Using a high-throughput screening (HTS) approach, a new GTP-site binding pyridine-carboxylate series of cGAS inhibitors was discovered. The biochemical potency of this new pyridine carboxylate series was improved 166-fold from the original hit to double-digit nanomolar levels using structure-based design insights, but the series was found to suffer from low permeability and low bioavailability. A structure-based hybridization of the metal-binding motifs of the pyridine carboxylate series and our previously disclosed tetrahydrocarboline GTP-site ligand 23 identified pyrimidine amide compound 36. Compound 36 is potent against both human and mouse cGAS isoforms and has a favorable pharmacokinetic (PK) profile in mice. Additionally, compound 36 displayed a dose-dependent reduction in cGAMP production in a ConA pharmacodynamic mouse model of acute liver injury, demonstrating potential utility as an in vivo tool compound for further investigation of the cGAS pathway.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2201–2209 2201–2209"},"PeriodicalIF":3.5,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843581","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