Bioorganic & Medicinal Chemistry Letters最新文献_第3页

Design, synthesis and antitumor activity of pentacyclic triterpenoid Asiatic acid derivatives as Sp1 inhibitors 五环三萜亚洲酸衍生物Sp1抑制剂的设计、合成及抗肿瘤活性研究。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-08 DOI: 10.1016/j.bmcl.2025.130398

Xue-Hao Lu, Xin-Ru Yu, Liang-Feng Zhang, Yu-Ting Han, Heng Wu, Zan Wang, Yan-Qiu Meng

{"title":"Design, synthesis and antitumor activity of pentacyclic triterpenoid Asiatic acid derivatives as Sp1 inhibitors","authors":"Xue-Hao Lu, Xin-Ru Yu, Liang-Feng Zhang, Yu-Ting Han, Heng Wu, Zan Wang, Yan-Qiu Meng","doi":"10.1016/j.bmcl.2025.130398","DOIUrl":"10.1016/j.bmcl.2025.130398","url":null,"abstract":"<div><div>Asiatic acid (<strong>AA</strong>) was used as the lead compound and 22 inhibitors of specificity protein 1 (Sp1) were designed and synthesized with modification at A ring and C-28 position of <strong>AA</strong>, whose structures were confirmed by HRMS, <sup>1</sup>H NMR and <sup>13</sup>C NMR. The growth inhibitory effects of Asiatic acid derivatives on human breast cancer cells (MCF-7) and cervical cancer cells (Hela) were determined by tetramethyl azole salt (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) colorimetric assay. The results showed that all of these compounds inhibited the proliferation of HeLa and MCF-7 cells, and all the derivatives showed stronger tumor cytotoxicity than <strong>AA</strong>, among which compounds <strong>I</strong><sub><strong>8</strong></sub>, <strong>II</strong><sub><strong>6</strong></sub>, and <strong>III</strong><sub><strong>3</strong></sub> were comparable to the positive control drug cisplatin. Western blot (WB) and Cellular thermal shift assay (CETSA) assay analyses revealed that compound <strong>I</strong><sub><strong>8</strong></sub> could directly bind to Sp1 and dose-dependently reduce Sp1 protein levels, suggesting that compound <strong>I</strong><sub><strong>8</strong></sub> may exert its antitumor effects through binding to Sp1. This provides an experimental basis for the natural pentacyclic triterpenoid Asiatic acid to become a novel anti-tumor new drug candidate.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"130 ","pages":"Article 130398"},"PeriodicalIF":2.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

TRAP1 and its therapeutic potential TRAP1及其治疗潜力。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-05 DOI: 10.1016/j.bmcl.2025.130395

Andrew Gutierrez, Jason Archdeacon, Brian S.J. Blagg

引用次数: 0

Rational design and translational advancement of phospholipid-based nanocarriers for targeted cancer therapy 基于磷脂的靶向肿瘤纳米载体的合理设计与转化研究进展

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-04 DOI: 10.1016/j.bmcl.2025.130396

Kateryna Mykhailivna Doroshenko, Oleksander Ivanovich Shefchenko

{"title":"Rational design and translational advancement of phospholipid-based nanocarriers for targeted cancer therapy","authors":"Kateryna Mykhailivna Doroshenko, Oleksander Ivanovich Shefchenko","doi":"10.1016/j.bmcl.2025.130396","DOIUrl":"10.1016/j.bmcl.2025.130396","url":null,"abstract":"<div><div>Phospholipid-derived nanocarriers represent a versatile and chemically customizable class of drug delivery systems that self-assemble into bilayered vesicles due to their intrinsic amphiphilicity. These systems can encapsulate both hydrophilic and hydrophobic drugs through non-covalent interactions and manipulation of lipid phase behavior. This review examines the molecular and supramolecular principles underlying the formation, stability, and functional performance of key phospholipid-based nanocarriers—including liposomes, transferosomes, ethosomes, invasomes, phytosomes, pharmacosomes, and virosomes. We analyze critical structural parameters such as bilayer packing, surface charge, curvature elasticity, and membrane permeability, emphasizing their impact on drug loading efficiency, controlled release, and bioavailability. Advanced multilamellar systems such as vesosomes and spongosomes are also highlighted for their promise in achieving site-specific, sustained drug delivery. Key fabrication methods—including thin-film hydration, ethanol injection, freeze–thaw cycles, and microfluidics—are discussed alongside analytical techniques such as dynamic light scattering (DLS), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and cryo-transmission electron microscopy (cryo-TEM). The review further explores the translational landscape, with a focus on clinically approved liposomal formulations, patent developments, and emerging clinical trials involving stimuli-responsive systems. Persistent challenges such as colloidal stability, tumor penetration, immune system interactions, and scalable manufacturing are critically assessed. Altogether, this review offers a chemistry-focused framework for the rational design and clinical translation of phospholipid nanocarriers in cancer drug delivery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130396"},"PeriodicalIF":2.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

A concise review on MDM2 inhibitors and recent progress in radiopharmaceutical development for imaging MDM2 expression in tumors with PET or SPECT 简要综述了MDM2抑制剂的研究进展，以及利用PET或SPECT对肿瘤中MDM2表达进行成像的放射性药物研究进展。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-04 DOI: 10.1016/j.bmcl.2025.130394

Atchimnaidu Siriki, Graham Ragland, Janardhan Vasireddy, Satish K. Chitneni

{"title":"A concise review on MDM2 inhibitors and recent progress in radiopharmaceutical development for imaging MDM2 expression in tumors with PET or SPECT","authors":"Atchimnaidu Siriki, Graham Ragland, Janardhan Vasireddy, Satish K. Chitneni","doi":"10.1016/j.bmcl.2025.130394","DOIUrl":"10.1016/j.bmcl.2025.130394","url":null,"abstract":"<div><div>Murine double minute 2 (MDM2, also known as human double minute 2 or HDM2) is a negative regulator of the tumor suppressor protein p53 and is overexpressed in many cancers. Over the past two decades, substantial progress has been made in developing inhibitors of the MDM2-p53 interaction, thereby allowing the p53 protein to exert antitumor effects through cell apoptosis and cycle arrest. While there are currently no FDA-approved MDM2 inhibitors available, several small molecule MDM2 inhibitors and a stapled peptide inhibitor of the MDM2-p53 interaction are in clinical development. Availability of these clinical candidates, representing a diverse array of chemical scaffolds that bind to the same p53 binding site on the MDM2 protein with low nanomolar inhibition potency (IC<sub>50</sub>), presents a significant opportunity for developing molecular imaging probes for MDM2 in parallel. This review summarizes the MDM2 inhibitors that have been evaluated in clinical trials, which could serve as starting leads for imaging probe development, and recent progress in developing radiotracers for MDM2 and for evaluating MDM2 expression levels in tumors noninvasively using the highly sensitive, molecular imaging techniques positron emission tomography (PET) or single-photon emission computed tomography (SPECT).</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130394"},"PeriodicalIF":2.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Targeting virulence to disarm the pathogen: Enzyme-activated-substrate inhibition of Anthrax edema factor 靶向毒力解除病原体：酶激活底物抑制炭疽水肿因子。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-09-02 DOI: 10.1016/j.bmcl.2025.130393

Seongjin Kim , Lynne Cregar-Hernandez , Mahtab Moayeri , Stephen H. Leppla , Alan T. Johnson

{"title":"Targeting virulence to disarm the pathogen: Enzyme-activated-substrate inhibition of Anthrax edema factor","authors":"Seongjin Kim , Lynne Cregar-Hernandez , Mahtab Moayeri , Stephen H. Leppla , Alan T. Johnson","doi":"10.1016/j.bmcl.2025.130393","DOIUrl":"10.1016/j.bmcl.2025.130393","url":null,"abstract":"<div><div>Since the discovery by Fleming that a mold could inhibit the growth of bacteria, each new antibiotic developed to treat infections quickly lost its efficacy due to the emergence of resistant strains. As a result, the ongoing threat by antibiotic-resistant pathogens would benefit from new strategies to combat bacterial infections. An ideal drug is one which is efficacious, can limit selective pressure against the pathogen, and potentially augment the currently available antibiotics to restore their efficacy. Targeting virulence factors used by bacteria to establish infections has the potential to meet these goals. Anthrax edema factor (EF), an adenylate cyclase secreted by <em>Bacillus anthracis,</em> which causes anthrax, is an example of this type of virulence factor. Our previous work showed that the activity of EF can be blocked with small molecule covalent inhibitors targeting the catalytic site. The current report extends this work with the discovery of enzyme-activated-substrate inhibitors which display improved drug-like properties and stability.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130393"},"PeriodicalIF":2.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor 发现4-（2-甲氧基苯基）- 1h -吡唑支架的A20是一种有效的选择性ROCK2抑制剂

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-29 DOI: 10.1016/j.bmcl.2025.130391

Junzheng Wang , Bin Peng , Guodong Liang, Yan Zhao, Xin Gao, Yuting Zhao, Lu Ga, Ruijuan Li, Yuheng Ma

引用次数: 0

Design, synthesis and evaluation of clickable photoaffinity probes for nuclear lamins 核层蛋白可点击光亲和探针的设计、合成和评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-28 DOI: 10.1016/j.bmcl.2025.130392

Julia Warren , Jian Wang , Bingbing X. Li , Xiangshu Xiao

{"title":"Design, synthesis and evaluation of clickable photoaffinity probes for nuclear lamins","authors":"Julia Warren , Jian Wang , Bingbing X. Li , Xiangshu Xiao","doi":"10.1016/j.bmcl.2025.130392","DOIUrl":"10.1016/j.bmcl.2025.130392","url":null,"abstract":"<div><div>Nuclear lamins are type V intermediate filament proteins to support the mechanical stability of mammalian cell nucleus. They also participate in various signaling activities in the cells. We recently discovered substituted pyrroloquinazoline <strong>LBL1</strong> as the first small molecule to directly target nuclear lamins despite their poor druggability. Based on <strong>LBL1</strong>, a clickable photoaffinity probe <strong>LBL1-PCF</strong> was designed to identify lamin-interactors in native cells. In this work, we designed and synthesized a series of clickable photoaffinity probes to evaluate the structure-activity relationships for lamin labeling. Appending an azidopropyl group to the pyrroloquinazoline core at <em>N</em>-7 was well-tolerated without affecting the labeling EC<sub>50</sub>. Substitution at <em>N</em>-1 significantly reduced its efficiency for lamin labeling. On the other hand, shifting the azidopropyl group to the benzamide at <em>N</em>-3 of pyrroloquinazoline core abolished its capability for lamin labeling. Our results demonstrate that strategic placement of the clickable group at the pyrroloquinazoline core is of paramount importance for target identification studies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130392"},"PeriodicalIF":2.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis and evaluation of acyl-AMP phosphate isosteres as inhibitors of fungal acetyl CoA synthetase 真菌乙酰辅酶a合成酶抑制剂酰基amp磷酸同异构体的合成及评价。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-28 DOI: 10.1016/j.bmcl.2025.130389

Drashti G. Daraji , Andrew J. Jezewski , Katy M. Alden , Jonah P. Propp , Michael E. Heene , Calvin A. Soldan , Lijun Liu , Kevin P. Battaile , Scott Lovell , Bart L. Staker , Damian J. Krysan , Timothy J. Hagen

{"title":"Synthesis and evaluation of acyl-AMP phosphate isosteres as inhibitors of fungal acetyl CoA synthetase","authors":"Drashti G. Daraji , Andrew J. Jezewski , Katy M. Alden , Jonah P. Propp , Michael E. Heene , Calvin A. Soldan , Lijun Liu , Kevin P. Battaile , Scott Lovell , Bart L. Staker , Damian J. Krysan , Timothy J. Hagen","doi":"10.1016/j.bmcl.2025.130389","DOIUrl":"10.1016/j.bmcl.2025.130389","url":null,"abstract":"<div><div>Acetyl-CoA synthetase (ACS) is a member of the adenylate-forming enzymes superfamily. This enzyme plays a crucial role in cellular metabolism. While ACS enzymes are non-essential in mammals, they are essential in some fungal species and parasites that are pathogenic to humans. Hence, inhibition of the ACS enzyme is an emerging target for the development of novel anti-infectives. Alkyl AMP esters and acyl sulfamoyl adenosine (Acyl-AMS) are potent inhibitors of fungal ACS enzymes by mimicingthe acyl-AMP enzyme intermediate. Molecular docking studies were performed to facilitate the design of analogs and to explore their potential ligand-binding interactions with the ACS enzyme. A series of acyl-AMP isosteres were synthesized and screened for inhibitory activity against fungal ACS enzymes. Notably, Compound <strong>14</strong> was successfully crystallized with the <em>Cryptococcus neoformans</em> ACS1 enzyme, providing valuable structural insight for future inhibitor design.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130389"},"PeriodicalIF":2.2,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Tunable spontaneous release of a carboxylic acid via a β-eliminative cleavable linker 羧酸通过β-消除可切割连接体的可调节自发释放。

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-27 DOI: 10.1016/j.bmcl.2025.130390

Brenno Masina , Nicola R.F. Knowles , Ronald T. Raines

引用次数: 0

Biochemical investigations into the incorporation of 8-oxo-2′-deoxyguanosine-5′-triphosphate with two A-family polymerases 8-氧-2 ' -脱氧鸟苷-5 ' -三磷酸与两种a家族聚合酶结合的生化研究

IF 2.2 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-26 DOI: 10.1016/j.bmcl.2025.130385

Michelle L. Hamm, Katherine Alexander, Mary W.N. Burns, Joseph S. Capalbo, Lily B. Kaufman, Georges A. Leconte

{"title":"Biochemical investigations into the incorporation of 8-oxo-2′-deoxyguanosine-5′-triphosphate with two A-family polymerases","authors":"Michelle L. Hamm, Katherine Alexander, Mary W.N. Burns, Joseph S. Capalbo, Lily B. Kaufman, Georges A. Leconte","doi":"10.1016/j.bmcl.2025.130385","DOIUrl":"10.1016/j.bmcl.2025.130385","url":null,"abstract":"<div><div>8-Oxo-2′-deoxyguanosine-5′-triphosphate (OdGTP) is a promutagenic oxidatively damaged nucleotide that can base pair to both 2′-deoxycytidine (dC) and 2′-deoxyadenosine (dA) and may play a role in antibiotic initiated bacterial cell death. We evaluated the insertion of OdGTP, dGTP, and eight related analogs opposite dC and dA with two A-family bacterial replicative polymerases, nuclease deficient Polymerase I from <em>E. coli</em> (KF-exo) and <em>Geobacillus Stearothermophilus</em> (BF). Results from these studies demonstrate that KF-exo is much less likely than BF to incorporate OdGTP opposite either dC or dA as compared to incorporation of dGTP opposite dC. Our work also highlights similarities and differences in the active sites that can occur between two polymerases within the same family. For example, the C2-amine of OdGTP appears to have little impact during incorporation opposite dA with either enzyme. However, when inserting opposite dC, the C2-amine can form a stabilizing hydrogen bond to the template dC, and increase activity, especially when large atoms are present at the C8-position. KF-exo is more sensitive than BF to large substituents at the C8-position during incorporation opposite dC, while BF, but not KF-exo, likely forms a minor groove hydrogen bond to the C8‑oxygen during incorporation opposite dA. Overall, these findings provide mechanistic insights into how oxidative stress can contribute to genomic instability through polymerase-mediated misincorporation events.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"129 ","pages":"Article 130385"},"PeriodicalIF":2.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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