ACS Medicinal Chemistry Letters最新文献_第7页

A Retinoid X Receptor Ligand-Based Borocaptate Conjugate with Enhanced Intracellular Boron Retention for Boron Neutron Capture Therapy 基于类视黄醇X受体配体的硼螯合物与增强细胞内硼保留用于硼中子捕获治疗

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-06-27 DOI: 10.1021/acsmedchemlett.6c00053

Atsushi Mashimo, Yuta Takamura, Ryuya Ohtani, Maho Takamura-Takioku, Michiko Fujihara, Mayu Kawasaki, Shogo Nakano, Mayuri Inoue, Natsuko Kondo, Yoshinori Sakurai, Hiroki Kakuta

{"title":"A Retinoid X Receptor Ligand-Based Borocaptate Conjugate with Enhanced Intracellular Boron Retention for Boron Neutron Capture Therapy","authors":"Atsushi Mashimo, Yuta Takamura, Ryuya Ohtani, Maho Takamura-Takioku, Michiko Fujihara, Mayu Kawasaki, Shogo Nakano, Mayuri Inoue, Natsuko Kondo, Yoshinori Sakurai, Hiroki Kakuta","doi":"10.1021/acsmedchemlett.6c00053","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00053","url":null,"abstract":"Boron neutron capture therapy requires sustained intracellular 10B accumulation, yet the clinical standard, L-boronophenylalanine(BPA, 1), rapidly effluxes from cells. We explored anintracellular retention strategy by converting borocaptate (BSH, 2) into a nuclear receptor ligand-based conjugate to improveintracellular retention of boron delivery agents. Retinoid X receptor(RXR) ligand scaffolds were selected as a proof-of-concept platformbecause RXRs are broadly expressed and predominantly nuclear. Thelead conjugate CBTF-BSH (3), designed from fluorescentRXR antagonist 5, showed greater intracellular boronretention than 1, consistent with reduced washout. Despitelower total intracellular boron accumulation than 1, 3 decreased colony formation of MCF7 human breast cancer cellsafter neutron irradiation without detectable RXR degradation. Theseresults support RXR ligand-based conjugate design as a proof-of-conceptstrategy for improving intracellular boron retention and neutron-inducedcytotoxicity, although tumor-selective delivery and the precise retentionmechanism require further optimization.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1744–1750"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729555","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

Novel N-Oxide Derivatives for Treating HIV Infection or AIDS or AIDS Related Complex 新型n -氧化物衍生物用于治疗HIV感染或艾滋病或艾滋病相关复合物

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-04 DOI: 10.1021/acsmedchemlett.6c00343

Ram W. Sabnis

引用次数: 0

Structure–Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors 结构-活性关系研究导致有效和选择性盐诱导激酶抑制剂的鉴定

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-01 DOI: 10.1021/acsmedchemlett.6c00199

Daniel T. Webb, Katherine L. Jones, Gerald Keil, Matthew Holt, Nicholas Richards, Yvonne Walker, Andrea Taylor, Maryam Ahmadi, Lampros Milanos, Natsuko Macabuag, Eilidh Bush, Matthew Gill, Rebecca Penrose, David M. Lindsay, William J. Kerr, William Esmieu

{"title":"Structure–Activity Relationship Studies Resulting in the Identification of Potent and Selective Salt-Inducible Kinase Inhibitors","authors":"Daniel T. Webb, Katherine L. Jones, Gerald Keil, Matthew Holt, Nicholas Richards, Yvonne Walker, Andrea Taylor, Maryam Ahmadi, Lampros Milanos, Natsuko Macabuag, Eilidh Bush, Matthew Gill, Rebecca Penrose, David M. Lindsay, William J. Kerr, William Esmieu","doi":"10.1021/acsmedchemlett.6c00199","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00199","url":null,"abstract":"Salt-inducible kinases(SIK1/2/3) belong to the AMPKfamily ofserine/threonine kinases, and SIK inhibition has been identified asa promising strategy for therapeutic intervention in oncology andimmunology. Herein, we describe the use of parallel chemistry approachesto facilitate the development of novel SIK inhibitors. From theseefforts, potent pan-SIK inhibitors were identified, as well as compoundswhich demonstrated biased isoform selectivity toward SIK3, and possessedattractive in vitro ADME properties. To validatethe most promising compounds as high-quality chemical tools, cellulartarget engagement was assessed using NanoBRET assays, and selectivitywas investigated across the wider kinome. Finally, the pharmacologicaleffects of several compounds were studied using cellular models ofacute myeloid leukemia, resulting in the identification of potentantiproliferative agents. The compounds reported represent high-qualitychemical tools of potential value for target validation studies andcould serve as effective starting points for a lead optimization campaign.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1795–1805"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729409","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

In This Issue, Volume 17, Issue 8 本刊第17卷第8期

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 DOI: 10.1021/acsmedchemlett.6c00405

Rui Xiong

引用次数: 0

A Rationally Engineered Norfloxacin–Phenoxazine Hybrid as a Dual-Function Anticancer Agent: DNA Intercalation Synergizes with Topoisomerase II Inhibition against Murine Breast Tumor 合理设计的诺氟沙星-苯恶嗪双功能抗癌剂：DNA嵌入与拓扑异构酶II协同抑制小鼠乳腺肿瘤

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-04 DOI: 10.1021/acsmedchemlett.6c00021

Rubi Roy, Tasnim Ria, Koyel Das, Vikram Patial, Gourab Das, Ugir Hossain Sk

{"title":"A Rationally Engineered Norfloxacin–Phenoxazine Hybrid as a Dual-Function Anticancer Agent: DNA Intercalation Synergizes with Topoisomerase II Inhibition against Murine Breast Tumor","authors":"Rubi Roy, Tasnim Ria, Koyel Das, Vikram Patial, Gourab Das, Ugir Hossain Sk","doi":"10.1021/acsmedchemlett.6c00021","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00021","url":null,"abstract":"Breastcancer therapy is compromised by acquired resistanceandsystemic toxicity, necessitating new therapeutic strategies. Herein,a series of hybrid molecules were synthesized by conjugating nononcogenicFDA-approved norfloxacin with DNA-targeting phenoxazine/phenothiazinethrough alkyl, amide, and triazole linkers. Photophysical studiesdemonstrated DNA intercalation, while molecular docking revealed stableinteractions with topoisomerase II. The hybrids showed selective cytotoxicityagainst breast cancer cells, with compound 4 displayingsuperior potency (IC50 = 3.55 ± 0.28 μM in MCF-7),surpassing the parent drugs and tamoxifen. Cellular studies demonstratedG0/G1 arrest, apoptosis, and DNA damage, as evidenced by γH2AXfoci formation. Enzyme-based topoisomerase II inhibition, togetherwith cellular TARDIS assays analysis, indicated stabilization of topoII–DNA cleavage complexes. In vivo, compounds 4 and 10 produced significant tumor regressionwithout detectable hepatic or renal toxicity. Immunofluorescence analysisconfirmed elevated cleaved caspase-3, γH2AX, favoring DNA damage-mediatedapoptosis. These findings highlight the emergence of norfloxacin-basedhybrids as promising anticancer agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1678–1690"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729499","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

Bicyclo[1.1.1]pentane as a Phenyl Isosteric Replacement 双环[1.1.1]戊烷作为苯基等构替代物

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-11 DOI: 10.1021/acsmedchemlett.6c00246

Anastasia Saar, David C. Kombo, Sukanthini Thurairatnam, Michael Kothe, Gregory Merriman, Artem V. Tsymbal, John L. Kane, Jr., Matthew J. LaMarche, Paraskevi Gkeka, Yi Li

{"title":"Bicyclo[1.1.1]pentane as a Phenyl Isosteric Replacement","authors":"Anastasia Saar, David C. Kombo, Sukanthini Thurairatnam, Michael Kothe, Gregory Merriman, Artem V. Tsymbal, John L. Kane, Jr., Matthew J. LaMarche, Paraskevi Gkeka, Yi Li","doi":"10.1021/acsmedchemlett.6c00246","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00246","url":null,"abstract":"In medicinal chemistry, phenyl rings are often replacedwith bioisosteresto optimize druglike properties. Bicyclo[1.1.1]pentane (BCP) is awidely used sp3-rich phenyl bioisostere offering improvedmetabolic stability and reduced lipophilicity. Herein, we report aretrospective analysis of BCP deployment in 24 internal drug discoveryprojects across target classes. Analysis of matched molecular pairsfrom the 7 structure-enabled projects with primary assay data revealedthat 46% retained activity, 17% showed minimal loss (1- to 3-fold),13% showed partial loss (3- to 10-fold), and 24% showed significantloss (>10-fold) relative to the phenyl analog with terminal BCPreplacementsoutperforming scaffold replacements. BCP analogs showed improved lipophilicefficiency (mean ΔLipE = 0.88), particularly when the phenylring did not engage in π-mediated contacts. These findings demonstratethat successful bioisosteric replacement requires evaluating spatialaccessibility and electrostatic character above and below the phenylplane, structural role (terminal versus scaffold), and specific protein–ligandinteractions, rather than geometric equivalence alone.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1835–1843"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729567","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

Novel Benzofuran Derivatives as SARM1 Inhibitors for Treating Axonal Degeneration 新型苯并呋喃衍生物作为SARM1抑制剂治疗轴突变性

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-16 DOI: 10.1021/acsmedchemlett.6c00377

Ram W. Sabnis, Anika R. Sabnis

引用次数: 0

Novel Heterocyclic Compounds for Treating HIV Infection 治疗HIV感染的新型杂环化合物

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-03 DOI: 10.1021/acsmedchemlett.6c00371

Ram W. Sabnis

引用次数: 0

Targeted Degradation of KAT6A: Expanding the Therapeutic Frontier of Epigenetic Drug Discovery 靶向降解KAT6A：扩展表观遗传药物发现的治疗前沿

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-12 DOI: 10.1021/acsmedchemlett.6c00361

Anna C. Renner, Robert B. Kargbo

引用次数: 0

Synthesis of Enantiospecific Androgen Receptor Antagonists of Enzalutamide-Resistant Human Prostate Cancer Cells 恩杂鲁胺耐药人前列腺癌细胞对映特异性雄激素受体拮抗剂的合成

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-06-25 DOI: 10.1021/acsmedchemlett.6c00085

Chao Liu, Yuanye Sun, Pyone Myat Thwe, Glenn A. Harter, Sujatha Chilakala, Jonathan E. Katz, Ethan Canfield, Grzegorz Zapotoczny, Bethany Haliday, Elizabeth Elton, Boris A. Kashemirov, Katherin Patsch, David B. Agus, Charles E. McKenna

引用次数: 0