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":"https://doi.org/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":"2024-11-16","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":"Esterase-responsive nanoparticles (ERN): A targeted approach for drug/gene delivery exploits","authors":"Ashok Kumar Madikonda ,&nbsp;Amritha Ajayakumar ,&nbsp;Sudeena Nadendla ,&nbsp;Janardhan Banothu ,&nbsp;Venkanna Muripiti","doi":"10.1016/j.bmc.2024.118001","DOIUrl":"10.1016/j.bmc.2024.118001","url":null,"abstract":"<div><div>Nanoparticles are being developed to enhance drug delivery to cancer tumors, leveraging advantages such as the enhanced permeability and retention (EPR) effect. However, traditional nanoparticles often face challenges with low specificity for cancer cells, leading to inefficient delivery and unwanted side effects. Esterase-responsive nanoparticles offer a maximum targeted approach to tumor cells because they release their therapeutic payload at the tumor site under the influence of esterase activity. This review explores the role of esterase-responsive nanoparticles in drug and gene delivery, examines esterase prodrug therapy, and discusses prostate-specific membrane antigen (PSMA) targets esterase-responsive nanoparticles in prostate cancer treatment. Additionally, we reviewed the current research progress and future potential of esterase-responsive nanoparticles in enhancing drug and gene delivery.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118001"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651884","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":"Recent progress on small molecule TLR4 antagonist against triple-negative breast cancer progression and complications","authors":"Darsshen Ramana A.L. Kathirasan ,&nbsp;Siti Nor ’Izzah Binti Normizan ,&nbsp;Nurul Athirah Binti Mohd Salleh ,&nbsp;Khor Poh-Yen","doi":"10.1016/j.bmc.2024.118000","DOIUrl":"10.1016/j.bmc.2024.118000","url":null,"abstract":"<div><div>Toll-like receptor 4 (TLR4) plays a vital role in the innate immune response, but its overactivation has been associated with several diseases, such as aggressive progression of triple-negative breast cancer (TNBC). As a result, inhibiting TLR4 has emerged as a potential therapeutic strategy for this challenging breast cancer subtype. This review summarizes recent advancements in the development of small-molecule TLR4 antagonists to suppress TNBC growth, metastasis, and chemotherapy resistance. We also examine their potential in managing cancer-related complications and propose future directions for their application in TNBC therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118000"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674659","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":"Use of imidazo[1,5-a]quinoline scaffold as the pharmacophore in the design of bivalent ligands of central benzodiazepine receptors","authors":"Marco Paolino ,&nbsp;Mario Saletti ,&nbsp;Jacopo Venditti ,&nbsp;Federica Castriconi ,&nbsp;Germano Giuliani ,&nbsp;Samuele Maramai ,&nbsp;Alessandra Toti ,&nbsp;Carla Ghelardini ,&nbsp;Rosanna Matucci ,&nbsp;Narcy Alcazar Villalobos ,&nbsp;Maurizio Anzini ,&nbsp;Andrea Cappelli","doi":"10.1016/j.bmc.2024.118006","DOIUrl":"10.1016/j.bmc.2024.118006","url":null,"abstract":"<div><div>The imidazo[1,5-<em>a</em>]quinoline scaffold of central benzodiazepine receptor (CBR) ligands was used as the pharmacophore in the design of bivalent ligands bearing spacers showing variable length and different physicochemical features. The newly designed compounds were synthesized along with the corresponding reference monovalent compounds bearing the corresponding spacers terminated with a <em>tert</em>-butoxycarbonyl group. The novel compounds were tested in binding assays with different CBR preparations such as the cerebral cortex from male CD-1 albino mice or the human recombinant α1β3γ2 and α2β3γ2 γ-aminobutyric acid type A receptors (GABA_ARs) stably expressed in mouse L(tk-) cells. The tested compounds showed IC₅₀ values from the sub-micromolar up to the nanomolar range with very similar inhibition constants values for the two isoforms of GABA_ARs. The similarity in the affinity between the bivalent ligands and the corresponding monovalent ones appeared to rule out any bivalent interactions of these ligands with the two isoforms of GABA_ARs. Similarly, both series were able to inhibit the binding of radiolabeled flumazenil to GABA_ARs in cortical membranes of albino CD-1 mice, but most of the tested compounds showed biphasic inhibition curves, suggesting the existence of two well-distinct populations of binding sites. Finally, some CBR ligands selected from the bivalent ligands (i.e. <strong>6a</strong>,<strong>c</strong>) and from the reference monovalent ligands (i.e. <strong>7a</strong>) were then tested <em>in vivo</em> for their potential pharmacological effects, evaluating four classical benzodiazepine actions such as anticonvulsant, anxiolytic, locomotor, and anti-amnesic activities. All the tested compounds showed anticonvulsant and anxiolytic properties with neither muscle relaxant effect nor learning and memory impairments.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118006"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692188","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}

{"title":"Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents","authors":"Yali Kong ,&nbsp;Michael C. Edler ,&nbsp;Ernest Hamel ,&nbsp;Asa R. Britton-Jenkins ,&nbsp;Omar Gillan ,&nbsp;Susan L. Mooberry ,&nbsp;David Mu ,&nbsp;Milton L. Brown","doi":"10.1016/j.bmc.2024.117999","DOIUrl":"10.1016/j.bmc.2024.117999","url":null,"abstract":"<div><div>The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [³H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117999"},"PeriodicalIF":3.3,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637987","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}

{"title":"Exploring the rhodanine universe: Design and synthesis of fluorescent rhodanine-based derivatives as anti-fibrillar and anti-oligomer agents against α-synuclein and 2N4R tau","authors":"Ahmed A. Elbatrawy ,&nbsp;Taiwo A. Ademoye ,&nbsp;Heba Alnakhala ,&nbsp;Arati Tripathi ,&nbsp;Germán Plascencia-Villa ,&nbsp;Xiongwei Zhu ,&nbsp;George Perry ,&nbsp;Ulf Dettmer ,&nbsp;Jessica S. Fortin","doi":"10.1016/j.bmc.2024.117990","DOIUrl":"10.1016/j.bmc.2024.117990","url":null,"abstract":"<div><div>Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that can be responsible for pathological lesions found in the brains of Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD) patients. The early-stage oligomers and protofibrils of tau are believed to be strongly linked to human cognitive impairment while the toxic α-syn oligomers are associated with behavioral motor deficits. Therefore, concurrent targeting of both proteinaceous aggregates and oligomers are very challenging. Herein, rhodanine-based compounds were designed and synthesized to target the fibrils and oligomers of tau and α-syn proteins. In particular, the indole-containing rhodanines <strong>5l</strong> and <strong>5r</strong> displayed significantly high anti-aggregation activity towards α-syn fibrils by reducing of the thioflavin-T (ThT) fluorescence to less than 5 %. Moreover, <strong>5r</strong> showed a remarkable decrease in the fluorescence of thioflavin-S (ThS) when incubated with the non-phosphorylated tau 0N4R and 2N4R, as well as the hyperphosphorylated tau isoform 1N4R. Transmission electron microscopy (TEM) analyses validated the powerful anti-fibrillar activity of <strong>5l</strong> and <strong>5r</strong> towards both protein aggregates. In addition, both <strong>5l</strong> and <strong>5r</strong> highly suppressed 0N4R tau and α-syn oligomer formation using the photo-induced cross-linking of unmodified protein (PICUP) assay. The fluorescence emission intensity of <strong>5l</strong> was quenched to almost half in the presence of both protein fibrils at 510 nm. <strong>5r</strong> showed a similar fluorescence response upon binding to 2N4R fibrils while no quenching effect was observed with α-syn aggregates. <em>Ex vivo</em> disaggregation assay using extracted human A<em>β</em> plaques was employed to confirm the ability of <strong>5l</strong> and <strong>5r</strong> to disaggregate the dense fibrils. Both inhibitors reduced the A<em>β</em> fibrils isolated from AD brains. <strong>5l</strong> and <strong>5r</strong> failed to show activity toward the cell-based α-syn inclusion formation. However, another indolyl derivative <strong>5j</strong> prevented the α-syn inclusion at 5 µM. Collectively, the indolyl-rhodanine scaffold could act as a building block for further structural optimization to obtain dual targeting disease-modifying candidates for AD, LBD, and PD.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117990"},"PeriodicalIF":3.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646094","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}

{"title":"Discovery of the synergy between sulindac and NO expands the application of NSAIDs in cardiac complications","authors":"Wen Zhou ,&nbsp;Ping Jiang ,&nbsp;Chunping Wang ,&nbsp;Shaohua Gou","doi":"10.1016/j.bmc.2024.117991","DOIUrl":"10.1016/j.bmc.2024.117991","url":null,"abstract":"<div><div>Cardiac inflammation, a pathological cornerstone in cardiac dysfunction, triggers diastolic impairment, leading to profound myocardial hypoxia. This hypoxic state serves as a potent stimulus for the amplification of inflammatory mediator release, ultimately limiting the therapeutic potential of monotherapies. To address this challenge, compounds that integrate non-steroidal anti-inflammatory drugs (NSAIDs) with nitric oxide (NO) donors was synthesized. The <em>in vitro</em> screening unveiled the remarkable anti-hypoxic inflammatory injury activity of a sulindac derivative, despite its suboptimal COX-2 inhibition when comparing with other NSAIDs derivatives. This revelation propelled us to delve deeper into the intricate synergistic relationship between sulindac and NO. Employing two-way ANOVA and high-throughput screening technique, we incontrovertibly confirmed their synergism. Further, the underlying mechanism was unmasked through the detection of signal molecule release levels and western blot analysis. In a definitive step, we evaluated the therapeutic effects of sulindac and its derivatives <em>in vivo</em>, leveraging a rat model that recapitulates cardiac inflammation coupled with hypoxia. Our findings herald a promising drug candidate and establish a foundation for the expanded utilization of NSAIDs in the intricate landscape of cardiovascular diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117991"},"PeriodicalIF":3.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613397","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":"Exploring structure-directed immunogenic cytotoxicity of arginine-rich peptides for cytolysis-induced immunotherapy of cancer","authors":"Liu Huang ,&nbsp;Ang Li ,&nbsp;Han-jie Liu ,&nbsp;Shuang-shuang Ji ,&nbsp;Hao Fei","doi":"10.1016/j.bmc.2024.117984","DOIUrl":"10.1016/j.bmc.2024.117984","url":null,"abstract":"<div><div>The same cells can die with varied immunological consequences. For the purpose of cancer therapy, stronger immunogenic death of cancer cells is considered favorable. Membrane disruptive peptides are cytotoxic agents with tunable structures capable of not just killing heterogeneous cancer cells, but also inducing immunogenic death. However, the chemo-structural principles that underlie their immunogenic cytotoxicity remain elusive. Here we investigated a series of arginine-rich amphipathic peptides with representative structures on the relationship between the mode of cell death and the immunogenic potency. Among several hydrophobic motif-appended cyclic octaarginine peptides, FC-14 was found to induce cell stress and necroptotic death, unlike apoptotic peptide RL2 and membrane-dissolving peptide RL1. Their differing abilities to release immunogenic death markers correlated well with their potential to activate innate immunity and protective vaccinal effect in a prophylactic model, with FC-14 being the most potent. FC-14 can be <u>p</u>re-<u>op</u>sonized with <u>a</u>lbumin into <u>n</u>anoparticles (PopAN-FC-14) using PopAN technology to improve its pharmacokinetic properties for intravenous injection. In a syngeneic mouse model of subcutaneous breast cancer, PopAN-FC-14 showed superior therapeutic effect and safety profile than the albumin formulated nanomedicine Nab-paclitaxel (Nab-PTX). Boost injections of PopAN-FC-14 significantly enhanced tumor-specific cellular and humoral immunities, acting similarly as <em>in-situ</em> cancer vaccine. Overall, this work demonstrates a novel focus on the immunogenic cytotoxicity of peptides and a practical approach for effective systemic therapy of cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117984"},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680366","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":"https://doi.org/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":"2024-11-07","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":"Sulfonamide-derivatized galactosides selectively target an unexplored binding site in the galectin-9N-terminal domain","authors":"Mukul Mahanti ,&nbsp;Sofi Gummesson ,&nbsp;Anders Sundin ,&nbsp;Hakon Leffler ,&nbsp;Fredrik Zetterberg ,&nbsp;Ulf J Nilsson","doi":"10.1016/j.bmc.2024.117989","DOIUrl":"10.1016/j.bmc.2024.117989","url":null,"abstract":"<div><div>Four directional and positional variants of sulfonamide-derivatized galactopyranosides were synthesized and evaluated against human galectin-1, -3, -4C (C-terminal), -7, -8N (N-terminal), -8C (C-terminal), -9N (N-terminal), and -9C (C-terminal), which revealed that one of the sulfonamide positions and directionalities (methyl 3-{4-[2-(phenylsulfonylamino)-phenyl]-triazolyl}-3-deoxy-α-<span>d</span>-galactopyranosides) bound with 6–15 fold higher affinity than the corresponding phenyltriazole (lacking the phenylsulfonamide moiety) for galectin-9N. Molecular dynamic simulations suggested that inhibitor adopted a conformation that is complementary to the galectin-9N binding site and where the sulfonamide moiety protrudes into an unexplored and non-conserved binding site perpendicular to and below the A–B subsite to interact with a His61 N<img>H proton. This resulted in the discovery of galectin-9N inhibitors with unprecedented selectivity over other galectins, thus constituting valuable tools for studies of the biological functions of galectin-9.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117989"},"PeriodicalIF":3.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643590","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}