Bioorganic & Medicinal Chemistry最新文献

{"title":"Charge-neutralized polyethylenimine-lipid nanoparticles for gene transfer to human embryonic stem cells.","authors":"Guoqing Feng, Yang Bai, Pengyu Huang, Yuan Liu, Qingbin Yang, Bowen Li, Qing Yuan, Niansong Qian, Bin Zheng","doi":"10.1016/j.bmc.2024.118008","DOIUrl":"10.1016/j.bmc.2024.118008","url":null,"abstract":"<p><p>Gene delivery is fundamentally crucial for the genetic manipulation of stem cells. Here, we present a straightforward approach to create a library of charge-neutralized polyethylenimine (PEI)-lipid nanoparticles designed for stem cell transfection. These lipid nanoparticles were formulated using small, branched PEI and lipidic anhydrides. Remarkably, over 15% of the lipid nanoparticles demonstrated high transfection efficiency across various cell types, surpassing the efficiency of both Lipofectamine 2000 and FuGENE HD. A structure-activity analysis indicated that the length and ratio of hydrophobic alkyl substitutions were critical parameters for efficient gene delivery. Notably, the transfection efficiency was higher than that of the original cation PEI. Our optimized PEI-lipid system enabled highly effective plasmid DNA delivery and successfully co-transferred two plasmid DNAs into difficult-to-transfect human embryonic stem cells (hESCs), facilitating optogenetic manipulation within these cells.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118008"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783437","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}

{"title":"Potential COX-2 inhibitors modulating NF-κB/MAPK signaling pathways: Design, synthesis and evaluation of anti-inflammatory activity of Pterostilbene-carboxylic acid derivatives with an oxime ether moiety.","authors":"Peng Luo, Taotao Chen, Shaoling Huang, Feng Peng, Yunhou Huang, Weigao Pan","doi":"10.1016/j.bmc.2024.118022","DOIUrl":"10.1016/j.bmc.2024.118022","url":null,"abstract":"<p><p>In this work, a series of novel Pterostilbene-oxime ether-carboxylic acid (POC) derivatives (d1-d10, e1-e10 and 1-13) were designed, synthesized, and characterized by spectroscopic techniques. In order to further determine the absolute configuration of these compounds, one of them, compound d3, was investigated by X-ray single crystal diffraction method. d3 had a triclinic crystal with P-1 space group, and its CHCH and CHN was confirmed as E configuration. A strong hydrogen bond was formed between the hydrogen atom in CHCH moiety and the nitrogen atom in CHN moiety, which was a vital factor in the formation and stability of E configuration in the CHCH and CHN. The safety and anti-inflammatory activities of compounds (d1-d10, e1-e10 and 1-13) in vitro were evaluated. At 20 μM, compounds (d1-d10, e1-e10 and 1-13 were non-toxic and exhibited weak to strong inhibitory effects on the LPS-induced NO release. Among them, five compounds (1, 2, 7, 8 and 9) showed excellent anti-inflammatory effects with IC₅₀ (NO) values ranging from 9.87 to 19.78 μM, as well as strong COX-2 inhibitory abilities with IC₅₀ (COX-2) values ranging from 85.44 to 140.88 nM. Moreover, there was a rough positive correlation between their anti-inflammatory properties and the COX-2 inhibitory abilities. Compounds (1, 2, 7, 8 and 9) smoothly docked with COX-2 protein (PDB ID: 5KIR) to form stable complexes with strong hydrogen bonds, with an affinity range of -8.3 to -9.9 kcal/mol. SAR indicated that the amidation of POC at R₂ position was more favorable for enhancing the compound's biological actives than esterification. In addition, the 4-fluobenzyl substitution at R₂ position of the oxime ether moiety can obviously enhance the activity of above amide derivates. Introducing acyl groups (CO(CH₂)_nCH₃, n = 2, 4 and 6) into NH(CH₂)₃OH group to form ester chain is disadvantageous for activity enhancing, moreover, the longer the carbon chain, the poorer the activity. The strongest COX-2 inhibitor (IC₅₀ (COX-2) = 85.44 ± 3.88 nM), compound 7, exerted as anti-inflammatory activities (IC₅₀ (NO) = 9.87 ± 1.38 μM) by down-regulating the expression of COX-2 and iNOS, and modulating NF-κB/MAPK signaling pathways.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118022"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790512","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}

{"title":"Design, Synthesis and Biological Evaluation of 2-Phenyl Indole Analogues of OXi8006 as Colchicine Site Inhibitors of Tubulin Polymerization and Vascular Disrupting Agents.","authors":"Rebecca Vairin, Caleb Tamminga, Zhe Shi, Christian Borchardt, Jayaram Jambulapati, Ruoli Bai, Hashini Wanniarachchi, Lorena Bueno, Ernest Hamel, Ralph P Mason, Mary Lynn Trawick, Kevin G Pinney","doi":"10.1016/j.bmc.2024.117981","DOIUrl":"10.1016/j.bmc.2024.117981","url":null,"abstract":"<p><p>Inhibitors of tubulin polymerization represent a promising therapeutic approach for the treatment of solid tumors. Molecules that bind to the colchicine site are of interest as they can function with a dual mechanism of action as both potent antiproliferative agents and tumor-selective vascular disrupting agents (VDAs). One such example is a 2-aryl-3-aroyl-indole molecule (OXi8006) from our laboratory that demonstrates potent inhibition of tubulin polymerization and strong antiproliferative activity (cytotoxicity) against a variety of human cancer cell lines. A water-soluble prodrug OXi8007, synthesized from OXi8006, demonstrates in vivo disruption of tumor-associated microvessels in several tumor types (mouse models). The molecular framework of OXi8006 inspired a series of fourteen new 2-aryl-3-aroyl-indole analogues that incorporated various functional group modifications on both the indole core and the aroyl ring. Electron withdrawing and donating groups at the mono-substituted 3' position and the di-substituted 3',5' positions were all accommodated while maintaining inhibition of tubulin polymerization (IC₅₀ < 5 μM), with several analogues demonstrating activity comparable to OXi8006 and the benchmark natural product combretastatin A-4 (CA4). Preliminary structure-activity relationship (SAR) studies were further enhanced by molecular docking to predict possible colchicine site interactions. Two analogues (KGP366 and KGP369) previously synthesized in our laboratory were re-synthesized using a somewhat modified route to increase synthetic efficiency and were subsequently converted to their corresponding water-soluble phosphate prodrug salts to evaluate their efficacy as VDAs. Administration of the prodrug salt (KGP415) of KGP369 caused significant reduction in bioluminescence signal from an orthotopic kidney tumor (RENCA-luc) in BALB/c mice, indicative of VDA activity. Collectively, these new functionalized indole-based analogues have extended SAR knowledge related to the colchicine binding site, and the most biologically active analogues hold promise for continued development as pre-clinical candidates for cancer therapy.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"117981"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816628","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}

{"title":"Synthetic glycol-split heparin tri- and tetrasaccharides provide new insights into structural peculiarities for antiheparanase activity.","authors":"Minghong Ni, Michela Parafioriti, Emiliano Esposito, Margherita Danzi, Ornela Cano, Laura Muzi, Yasmin Kayal, Vito Ferro, Israel Vlodavsky, Stefano Elli, Annamaria Naggi, Maurice Petitou, Marco Guerrini","doi":"10.1016/j.bmc.2024.118052","DOIUrl":"10.1016/j.bmc.2024.118052","url":null,"abstract":"<p><p>Heparanase is the only known endo-β-glucuronidase able to cleave heparan sulfate, participating in degradation and remodelling of the extracellular matrix. Heparanase upregulation promotes tumor growth and metastasis, therefore, its inhibition is a target for anticancer therapies. Heparan sulfate mimetics bearing glycol-split (gs) units are one of the most promising class of heparanase inhibitors. Herein we describe a total synthesis of two trisaccharides (MeO-GlcNS6S-IdoA/GlcA-GlcNS6S-OMe) differing in epimeric uronic acid residues and one tetrasaccharide (MeO-IdoA-GlcNS6S-IdoA-GlcNS6S-OMe), together with their corresponding glycol-split versions, prepared by periodate oxidation and further modified either via reduction or Pinnick oxidation to obtain gs or tricarboxylated saccharides. An intermediate imine was observed during periodate oxidation, which causes formation of byproducts. Evaluation of the heparanase inhibitory activity showed that the glycol-split trisaccharides were more potent than their intact uronic acid congeners. The binding interactions of the glycol-split trisaccharides with heparanase were investigated by a combined STD NMR and molecular docking approach, with good agreement obtained between the STD NMR experimental data, docking calculations and the in vitro activity results, helping to rationalize the observed inhibition data.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118052"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913157","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}

{"title":"Synthesis and in vitro evaluation of novel compounds and discovery of a promising iodine-125 radioligand for purinergic P2X7 receptor (P2X7R).","authors":"Lin Qiu, Jinzhi Wang, Manju Tewari, Derek T Rensing, Terrance M Egan, Joel S Perlmutter, Zhude Tu","doi":"10.1016/j.bmc.2024.118054","DOIUrl":"10.1016/j.bmc.2024.118054","url":null,"abstract":"<p><p>The purinergic P2X ligand-gated ion channel 7 receptor (P2X7R) plays a critical role in various inflammatory processes and other diseases. Fast determination of compounds P2X7R binding potency and discovery of a promise PET radiotracer for imaging P2X7R require a P2X7R suitable radioligand for radioactive competitive binding assay. Herein, we designed and synthesized thirteen new P2X7R ligands and determined the in vitro binding potency. The fluorescence screening assay identified the iodide compound 1c with high potency and specificity toward P2X7R with an IC₅₀ of 0.25 ± 0.05 nM. Therefore, 1c was ¹²⁵I-labeled to afford [¹²⁵I]1c with a good radiochemical yield (44 ± 12 %, n = 3) and high radiochemical purity (>95 %). Radioligand saturation binding assay showed that [¹²⁵I]1c specifically bound to human P2X7R with high affinity (K_d = 1.68 nM and B_max = 94 fmol/mg). A radioactive high throughput binding assay using [¹²⁵I]1c for our new compounds demonstrated that the imidazole compounds 1b, 1c, and 1d exhibited high inhibition for >70 %, while the analogues of GSK314181A exhibited low inhibition for <35 %. In addition, our radioligand competitive binding assays using [¹²⁵I]1c demonstrated that 1b, 1c, and 1d have high potency with IC₅₀ values of 7.91 ± 0.22, 7.06 ± 1.68, and 7.16 ± 0.41 nM toward P2X7R, respectively.Together, compounds 1b, 1c, and 1d are highly potent for P2X7R, and [¹²⁵I]1c has great potential to be a radioligand for screening P2X7R binding potency of the new compounds and investigating the P2X7R expression in animal models of human disease.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118054"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908824","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}

{"title":"Discovery of novel xanthohumol C derivatives regulating XRCC2 transcription and expression for the treatment of colorectal cancer.","authors":"Qianqian Zhu, Mengying Wang, Yan Wang, Bin Li, Jiahao Zheng, Yina Hu, Changgui Shi, Dalong Wang, Di Cao, Zhiguo Liu, Xiaohui Zheng, Kun Wang","doi":"10.1016/j.bmc.2024.118048","DOIUrl":"10.1016/j.bmc.2024.118048","url":null,"abstract":"<p><p>X-ray repair cross-complementing 2 (XRCC2), a critical protein in homologous recombination (HR), plays a significant role in the occurrence, progression, and drug resistance of colorectal cancer (CRC). In this study, a series of xanthohumol C derivatives were synthesized, and their anticancer activity was evaluated. The results revealed that A33 demonstrated the potent anticancer activity and effectively inhibited the proliferation of CRC cells in vitro. Mechanistic investigations revealed that A33 suppressed the transcription and expression of XRCC2, resulting in cell cycle delay and the accumulation of DNA damage, ultimately leading to cell proliferation inhibition. Furthermore, A33 displayed high safety, favorable bioavailability (F = 37.51 %), and potent tumor growth inhibition in vivo, which highlighting its potential as a candidate for the development of novel anti-CRC therapies.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118048"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890848","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}

{"title":"An overview of GPX4-targeting TPDs for cancer therapy.","authors":"Xiaojuan Yang, Liqiang Wu, Shaohong Xu","doi":"10.1016/j.bmc.2024.118046","DOIUrl":"10.1016/j.bmc.2024.118046","url":null,"abstract":"<p><p>Ferroptosis is a newly identified form of regulated, non-apoptotic cell death caused by iron-dependent phospholipid peroxidation. Glutathione peroxidase 4 (GPX4) inactivation-induced ferroptosis is an efficient antitumor treatment. Currently, several GPX4 inhibitors have been identified. However, these inhibitors exhibit low selectivity and poor pharmacokinetic properties that preclude their clinical use. Targeted protein degradation (TPD) is an efficient strategy for discovering drugs and has unique advantages over target protein inhibition. Given GPX4's antitumor effects and the potential of TPD, researchers have explored GPX4-targeting TPDs, which outperform conventional inhibitors in several aspects, such as increased selectivity, strong anti-proliferative effects, overcoming drug resistance, and enhancing drug-like properties. In this review, we comprehensively summarize the progress in GPX4-targeting TPDs. In addition, we reviewed the changes and challenges related to the development of GPX4-targeting TPDs for cancer therapy.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118046"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851736","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}

{"title":"Discovery of 2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (ASP0965): A potent, orally active and brain-penetrable NLRP3 inflammasome inhibitor with a novel scaffold for the treatment of α-synucleinopathy.","authors":"Yusuke Inagaki, Takashi Kamikubo, Ikumi Kuriwaki, Junko Watanabe, Susumu Yamaki, Maiko Iida, Kyoko Tomita, Kenichi Kakefuda, Jun Kurokawa, Tetsuo Kiso, Kengo Saba, Takanori Koike","doi":"10.1016/j.bmc.2024.118042","DOIUrl":"10.1016/j.bmc.2024.118042","url":null,"abstract":"<p><p>NLRP3 inflammasome inhibitor is a highly attractive drug target for the treatment of various inflammatory diseases. Here, we report the discovery of pyridazine derivatives as a new class of scaffold for NLRP3 inflammasome inhibitors. We optimized HTS hit 2a to improve both in vitro IL-1β inhibitory activity and the mean photo effect (MPE) value in the in vitro 3T3 neutral red uptake (NRU) phototoxicity test. As a result, we identified compound 5e (ASP0965) with brain penetrability and showing efficacy in the brain on oral administration in the rat pharmacodynamics (PD) model and the mouse α-synuclein injection model. These findings suggest that compound 5e is a promising clinical candidate for α-synucleinopathy therapeutics.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118042"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913460","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}

{"title":"Design, synthesis and biological evaluation of new SIRT3 activators for the treatment of triple-negative breast cancer.","authors":"Guichan Huang, Hailing Wang, Xi Zhao, Chen Wang, Jin Zhang, Dahong Yao, Chenyang Li","doi":"10.1016/j.bmc.2024.118040","DOIUrl":"10.1016/j.bmc.2024.118040","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) represents a highly malignant subtype of breast cancer with limited therapeutic options. In this study, we designed and synthesized a series of 1,4-DHP derivatives by structure-based strategy, 43 was documented to be a potent SIRT3 activator and exhibited profound anti-proliferative activity in BT-549 and MDA-MB-231 cells with low toxicity over normal cells. Additionally, 43 displayed the ability of direct binding to SIRT3 with a K_d value of 51.51 μM in BLI assay, and the potential bonding mode was elucidated through molecular docking. 43 could inhibit the proliferation, migration, and glycolysis, induced mitochondrial membrane potential decreased and apoptosis in BT-549 and MDA-MB-231 cells. Collectively, these results demonstrate that 43 is a potent SIRT3 activator with the potential to anti-TNBC through signaling pathways regulated by SIRT3.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118040"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821538","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}

{"title":"Selective photo crosslinking to methylarginine readers by sulfonium peptides.","authors":"Ting Luo, Feng Feng, Kun Zou, Yumo Zhao, Yingxiao Gao, Mingxuan Wu","doi":"10.1016/j.bmc.2024.118015","DOIUrl":"10.1016/j.bmc.2024.118015","url":null,"abstract":"<p><p>Arginine methylation is an important posttranslational modification that regulates epigenetics and pre-mRNA splicing. Similar to lysine methylation, reader proteins that bind site-specific modified proteins are key mediators for arginine methylation functions. Some arginine methylation has been shown significant functions from phenotype, but the molecular mechanisms remain elusive, probably due to lack of identification of the readers. Current methods rely on methylarginine peptide tools for pull-down or binding assays, but affinities to readers are usually tens to hundreds micromolar. As a consequence, development of chemical probes that crosslink specific readers is much in demand. We recently reported a methyllysine reader-selective crosslinking strategy by sulfonium peptides. NleS⁺me2 (norleucine-ε-dimethylsulfonium) imitate dimethyllysine and crosslink tryptophan or tyrosine inside binding pocket of readers. Arginine methylation readers contain aromatic cages for methylarginine binding, that is the similar binding mechanism for methyllysine. Therefore, we developed sulfonium probes that mimic methylarginine and crosslink tryptophan or tyrosine inside reader binding pockets. Because the single electron transfer from aromatic residue to sulfonium is binding-dependent, the conjugation showed high selectivity. Therefore, such sulfonium probes could be applied broadly for methylarginine readers investigations.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118015"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790514","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}