Bioorganic Chemistry最新文献

{"title":"Design, and synthesis of 2,4-thiazolidinedione substituted 1,3,5-triazine derivatives as anti-HIV agent via inhibition of reverse transcriptase along with anti-SARS CoV-2, antibacterial and antibiofilm activity","authors":"Saumya Singh ,&nbsp;Kumar Saurabh Srivastava ,&nbsp;Prashant Gahtori ,&nbsp;Ananya Anurag Anand ,&nbsp;Sintu Kumar Samanta ,&nbsp;Mukesh Kumar Kumawat ,&nbsp;Hans Raj Bhat ,&nbsp;Angela Corona ,&nbsp;Enzo Tramontano ,&nbsp;Debashis Mitra ,&nbsp;Udaya Pratap Singh","doi":"10.1016/j.bioorg.2025.108427","DOIUrl":"10.1016/j.bioorg.2025.108427","url":null,"abstract":"<div><div>The present study demonstrated the design and synthesis of novel 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives as putative inhibitors against various infective diseases. The title analogues were synthesized in a multi-step process, and their structures were verified through elemental analysis and a variety of spectral analyses (FT-IR, ¹H NMR, ¹³C NMR, mass). Compounds <strong>12a</strong> was identified as prospective lead compound against HIV-1 based on their high CDdocker interaction energy and stability among the developed derivatives, according to molecular docking and MD simulation experiments with HIV-1 RT. Compound <strong>12a</strong> was found effective against HIV-1 in a cell-based experiment, preventing the virus from replicating in CEM-GFP cells infected with 0.5 MOI of HIV-1 NL4-1. In the RNA-dependent DNA polymerase (RDDP) activity of the HIV-1 RT enzyme using a cell free based RT assay, compound <strong>12a</strong> showed a therapeutic index of 113 and an EC₅₀ of 125.1 nM. All of the compounds inhibited SARS-CoV-2 replication in the VeroE6-GFP cell line to varying degrees; compound <strong>10e</strong>, <strong>12e</strong>, <strong>12a</strong>, <strong>12b</strong>, and <strong>12c</strong>, in particular, showed considerable inhibitory activity. The compounds exhibited stronger antibacterial action against Gram-negative than Gram-positive bacteria in an antimicrobial assay, and a SAR analysis revealed that tri-substituted 1,3,5-triazine derivatives exhibited greater inhibitory activity than di-substituted ones. Additionally, <strong>12d</strong> and <strong>12e</strong> were found to be the most effective inhibitors of <em>P. aeruginosa</em> biofilms when tested against this bacterium. The most active inhibitors, <strong>12a</strong> and <strong>12e</strong>, were also tested for thermodynamic solubility at pH 7.4 via miniaturized shake-flask method. Here, their solubility was found to be significantly influenced by the presence of hydroxyl group and morpholine. In conclusion, our research demonstrated the significant inhibitory activity of 1,2,4-thiazolidinedione substituted 1,3,5-triazine derivatives against HIV, SARS-CoV-2, and bacterial microorganisms.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108427"},"PeriodicalIF":4.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationship study of navarixin analogues as dual CXCR2 and CCR7 antagonists","authors":"Anže Meden ,&nbsp;Sandra Claes ,&nbsp;Tom Van Loy ,&nbsp;Maša Zorman ,&nbsp;Matic Proj ,&nbsp;Dominique Schols ,&nbsp;Stanislav Gobec ,&nbsp;Steven De Jonghe","doi":"10.1016/j.bioorg.2025.108423","DOIUrl":"10.1016/j.bioorg.2025.108423","url":null,"abstract":"<div><div>Despite the promise of the human chemokine receptor 7 (CCR7) as drug target for the treatment of cancer metastasis and autoimmune diseases, there are no potent and selective CCR7 antagonists known in literature. In this work, a 1,2,5-thiadiazole 1,1-dioxide with low μM activity as a CXCR2 and CCR7 antagonist was selected as starting point for a structure-activity relationship study. The replacement of the central thiadiazole dioxide motif with squaramide led to low nanomolar CCR7 antagonism. Additional systematic structural variations afforded various squaramide analogues that displayed potent CCR7 antagonism in a calcium mobilization assay with IC₅₀ values in the low nM range. Unfortunately, the same compounds also displayed potent CXCR2 antagonistic activity and should therefore be considered as dual CCR7/CXCR2 antagonists.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108423"},"PeriodicalIF":4.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143761053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel p-terphenyls with anti-neuroinflammatory activity from fruiting bodies of the Chinese edible mushroom Thelephora ganbajun Zang","authors":"Hang Zhang ,&nbsp;Jingyi Zhang ,&nbsp;Keyin Huang ,&nbsp;Cheng Cai ,&nbsp;Jinyan Jiang ,&nbsp;Zijie Su ,&nbsp;Haixin Gu ,&nbsp;Zidan Duan ,&nbsp;Shijie Shao ,&nbsp;Min Zhou ,&nbsp;Qingfeng Du ,&nbsp;Fei He","doi":"10.1016/j.bioorg.2025.108414","DOIUrl":"10.1016/j.bioorg.2025.108414","url":null,"abstract":"<div><div>The detailed mycochemical exploration of the EtOAc extract of a famous edible mushroom <em>Thelephora ganbajun</em>, resulted in the isolation of six new <em>p</em>-terphenyl derivatives, named theleganbanins A − F (<strong>1</strong>–<strong>6</strong>), together with five known ones, namely atromentin (<strong>7</strong>), fendleryl B (<strong>8</strong>), 2-<em>O</em>-methylatromentin (<strong>9</strong>), vialinin B (<strong>10</strong>), and ganbajunin B (<strong>11</strong>). Their structures were precisely determined through comprehensive spectroscopic analyses, especially 1D and 2D NMR data and HRMS measurement. Single crystal X-ray diffraction and comparison of calculated and experimental ECD spectra were conducted to further confirm the absolute configurations of compounds <strong>1</strong>–<strong>6</strong>. Theleganbanins A (<strong>1</strong>) and B (<strong>2</strong>) featuring a rare <em>α</em>, <em>β</em>-unsaturated<em>-γ</em>-butyrolactone core were proposed to be biosynthesized through aldol condensation for the first time in naturally occurring <em>p</em>-terphenyl derivatives. Theleganbanin C (<strong>3</strong>) was identified as a pair of <em>p</em>-terphenyl enantiomers with a novel 1′, 6′-dyhydro-2′, 5′-pyridinedione ring. Theleganbanin D (<strong>4</strong>) was the first example of <em>p</em>-terphenyl derivatives with a hemiacetal furanone moiety. The anti-neuroinflammatory activities of compounds <strong>1</strong>–<strong>2</strong> and <strong>4</strong>–<strong>10</strong> were screened. As a result, these compounds showed inhibitory activity on the production of pro-inflammatory cytokines TNF-<em>α</em>, IL-6 and IL-1<em>β</em> in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Further investigation showed that compound <strong>2</strong> could inhibit the phosphorylation of JAK2/STAT3 signaling pathway. These finding indicated that <em>p</em>-terphenyl derivatives from edible mushroom <em>Thelephora ganbajun</em> Zang would be promising drug candidates in treatment of neuroinflammatory related diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108414"},"PeriodicalIF":4.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hybride nanoparticles composed of SN38-modified [12]aneN3 and biotinylated lipids for targeted and synergistic lung Cancer therapy","authors":"De-Zhong Xu ,&nbsp;Jing-Bo Yang ,&nbsp;Xi Zhang ,&nbsp;Zhi-Xuan Ren ,&nbsp;Rui Liu ,&nbsp;Quan Tang ,&nbsp;Zhong-Lin Lu ,&nbsp;Yang Liu","doi":"10.1016/j.bioorg.2025.108411","DOIUrl":"10.1016/j.bioorg.2025.108411","url":null,"abstract":"<div><div>The combination of chemo- and gene-therapy for lung cancer therapy has attracted continuous attention due to its high synergistic therapeutic efficiency. Here, three novel esterase-responsive prodrug-based amphiphiles, <strong>SCN1</strong> ∼ <strong>SCN3</strong>, composed of 7-ethyl-10-hydroxycamptothecin (SN38, <strong>S</strong>) and di-(triazole-[12]aneN₃, <strong>N</strong>) moiety through different length of carbon chain (<strong>C</strong>, 5, 7, 11‑carbon alkyl chains, respectively) were designed and synthesized. The amphiphiles displayed excellent self-assembly capabilities and the ability to effectively condense and release siRNA, and <strong>SCN2</strong> showed the most effective in inhibiting proliferation of A549 cells. Furthermore, <strong>SCN2</strong>, siRNA, DOPE (<strong>D</strong>) and DSPE-PEG₂₀₀₀-Biotin (<strong>B</strong>) were co-assembled into hybrid nanoparticles (<strong>SCN2-DB</strong>/siRNA) with an average size of 198 nm, outstanding serum tolerance, high targeting capability, and biocompatibility. Additionally, the release of SN38 (80 %) and siPLK1 (abundant) were observed clearly in the presence of esterase. <em>In vitro</em> experiments verified that <strong>SCN2-DB</strong>/siPLK1 NPs could efficiently suppress the proliferation, migration, and invasion of A549 cells. <em>In vivo</em> experiments demonstrated that <strong>SCN2-DB</strong>/siPLK1 NPs efficiently inhibited tumor growth (90 %) with negligible toxic side effects. The results showed that the combination of SN38 and siPLK1 through esterase-responsive amphiphile provided a strategy for lung cancer therapy that combined chemotherapy, gene therapy, and targeted delivery.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108411"},"PeriodicalIF":4.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New alkanesulfonate-based quinazolinone-acetohydrazide scaffolds: Rational design, synthesis, molecular docking, anticancer properties and potential EGFR and its T790M/L858R mutants inhibitors","authors":"Nagy A. Morsy ,&nbsp;Mohamed A. Omar ,&nbsp;Mohamad M. Ebrahium ,&nbsp;Aladdin M. Srour","doi":"10.1016/j.bioorg.2025.108405","DOIUrl":"10.1016/j.bioorg.2025.108405","url":null,"abstract":"<div><div>Leveraging their potential anticancer properties, two novel series of quinazolinone-based scaffolds, <strong>3a-i</strong> and <strong>7a-i</strong>, have been designed, synthesized, and scanned for their anticancer efficacy across three diverse human cancer cell lines, HepG-2, MCF-7, and HCT-116, alongside a normal cell line (BJ-1). Erlotinib and Doxorubicin served as the reference drugs. Notably, derivatives <strong>3i</strong> and <strong>7f</strong> exhibited the most potent activity against HepG-2, with IC₅₀ values of 1.66 μM and 1.67 μM, respectively, demonstrating about two-fold greater potency than erlotinib and doxorubicin (IC₅₀ = 2.85 μM and 4.25 μM, respectively). Additionally, compound <strong>7i</strong> showed superior efficacy against MCF-7 with an IC₅₀ of 3.25 μM, outperforming erlotinib and doxorubicin (IC₅₀ = 3.56 μM and 5.38 μM, respectively). In the case of colon cancer (HCT-116), compound <strong>7i</strong> also displayed the highest cytotoxic activity compared to erlotinib and doxorubicin (IC₅₀ = 1.20 μM versus 3.05 and 5.70 μM, respectively). Notably, most tested compounds exhibited a favorable safety profile against the normal human cell line (BJ-1). Furthermore, the derivatives demonstrated significant inhibitory properties on the Epidermal Growth Factor Receptor (EGFR) besides its mutations, EGFR^L858R and EGFR^T790M^, compared with Erlotinib, the reference drug. Compound <strong>7f</strong> notably increased Bax and Bcl-2 levels by 1.9 and 1.3 folds, respectively, relative to Erlotinib. Moreover, <strong>7f</strong> induced the apoptotic effect, arrested the cell cycle at the G0/G1 phase, and halted the mitotic cycle in HepG-2 cells. To further validate these findings, docking simulations of the promising derivatives <strong>7i</strong> and <strong>7f</strong> were conducted to assess their anticipated binding affinities with EGFR and its T790M/L858R mutants. Thus, compound <strong>7f</strong> has the potential to be developed into a potent anticancer agent.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108405"},"PeriodicalIF":4.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143776633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel ALK inhibitors containing DAAP fragments: Rational drug design and anti-tumor activity research","authors":"Ran Wang ,&nbsp;Xiangjing Li ,&nbsp;Li Long,&nbsp;Min Li,&nbsp;Huijing Chen,&nbsp;Han Zhang,&nbsp;Wei Ruan,&nbsp;Hong Zhang,&nbsp;Pengwu Zheng,&nbsp;Shan Xu","doi":"10.1016/j.bioorg.2025.108416","DOIUrl":"10.1016/j.bioorg.2025.108416","url":null,"abstract":"<div><div>Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor subfamily, involved in cellular signaling pathways associated with insulin. While ALK gene remains inactive in normal human tissues, it exhibits high expression specifically in the central nervous system. However, dysregulation of the ALK gene has been implicated in non-small cell lung cancer (NSCLC) development. Although commercially available ALK inhibitors demonstrate favorable clinical efficacy against most Ceritinib-resistant mutants, they exhibit resistance towards G1202R mutants. Therefore, developing novel ALK inhibitors is crucial for addressing drug resistance in patients. We designed and synthesized 48 novel 2,4-diarylpyrimidine-based ALK inhibitors and investigated their antitumor activities. Among them, Ld-10 showed significant inhibitory activity against ALK kinase with an IC₅₀ value of 1135 nM and demonstrated excellent antiproliferative activity against lung cancer cells H2228 with an IC₅₀ value of 1.35 ± 0.13 μM. To further validate the antitumor potential of Ld-10, we conducted a series of in vitro pharmacological experiments. These included a hemolysis assay to confirm its low toxicity profile, an AO assay, a JC-1 staining assay, and a Calcein-AM/PI cell double staining assay for assessing apoptosis induction. Additionally, we performed dose-dependent arrest at G0/G1 phase to evaluate inhibition of cell growth and carried out cell cycle analysis and cloning experiments to provide evidence for significant tumor growth inhibition by compound Ld-10. In vivo pharmacological experiments demonstrated effective tumor growth inhibition without any significant toxic effects on mouse organs caused by Ld-10 administration. Based on these comprehensive findings from our experimental investigations, it can be concluded that Ld-10 holds promising potential as a novel ALK inhibitor.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108416"},"PeriodicalIF":4.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cationic AIEgens with large rigid π-planes: Specific bacterial imaging and treatment of drug-resistant bacterial infections","authors":"Senlin Peng ,&nbsp;Xu Zhou ,&nbsp;Qian Wang ,&nbsp;Lingyi Shen ,&nbsp;Zhi-Yong Wang ,&nbsp;Hong Xu ,&nbsp;Xianjiong Yang ,&nbsp;Carl Redshaw ,&nbsp;Qi-Long Zhang","doi":"10.1016/j.bioorg.2025.108412","DOIUrl":"10.1016/j.bioorg.2025.108412","url":null,"abstract":"<div><div>In this study, four D-π-A type cationic photosensitisers with aggregation-induced emission (AIE) properties were developed based on the electron-donating group triphenylamine and pyrene molecules acting as auxiliary electron donors and main π-bridges, as well as pyridinium salts of different charge numbers acting as electron acceptors: <strong>TPP1</strong>, <strong>MeOTPP1</strong>, <strong>TPP2</strong> and <strong>MeOTPP2</strong>. The introduction of pyrene endowed the AIE photosensitizers with a high solid fluorescence quantum yield and long fluorescence lifetime. All four photosensitizer molecules were able to efficiently generate type I (·OH) and type II (¹O₂) under white light irradiation, achieving efficient inactivation of methicillin-resistant <em>Staphylococcus aureus</em> (<em>MRSA</em>) at low concentrations, and <strong>TPP1</strong> and <strong>TPP2</strong> successfully promoted wound healing in <em>MRSA</em>-infected mice. The introduction of a methoxy group effectively enhanced the intramolecular charge transfer effect, achieved longer wavelength absorption and fluorescence emission redshift, and effectively reduced Δ<em>E_st</em> thereby promoting ROS (Reactive Oxygen Species) generation. However, after the introduction of the methoxy group, the CAC (Critical Aggregate Concentration) of <strong>MeOTPP1</strong> and <strong>MeOTPP2</strong> became smaller and the hydrophobicity was enhanced, which affected the interaction with bacteria. In fact, the photodynamic antimicrobial activity and imaging ability against bacteria were reduced. <strong>TPP2</strong> achieves efficient killing of <em>MRSA</em> and <em>MDR E.coli</em> (Multidrug-resistant <em>Escherichia coli</em>) by disrupting the bacterial cell membrane due to its high photosensitization efficiency, two positive charges and very high CAC value. Under light (40 mW·cm⁻²), only 1 μM of <strong>TPP2</strong> inactivated 87 % of <em>MRSA</em>, followed by <strong>TPP1</strong>, which inactivated 59 %, while <strong>MeOTPP1</strong> and <strong>MeOTPP2</strong> showed no significant antibacterial activity at this concentration. At a concentration of 10 μM, <strong>TPP2</strong> deactivated more than 95 % of <em>MDR E.coli</em>, <strong>TPP1</strong> deactivated about 41 %, and <strong>MeOTPP1</strong> and <strong>MeOTPP2</strong> had no antimicrobial activity against <em>MDR E.coli</em> at this concentration. In addition, <strong>TPP1</strong>, <strong>MeOTPP1</strong> and <strong>TPP2</strong> were able to rapidly identify <em>MRSA</em> and <em>MDR E.coli</em> under the irradiation of 365 nm UV light, which provides a visual method for the rapid identification of <em>MRSA</em> and <em>MDR E.coli</em>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108412"},"PeriodicalIF":4.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances of dual inhibitors based on ALK for the treatment of cancer","authors":"Jin-Feng Chen ,&nbsp;Shu-Jin Guo ,&nbsp;Bin He ,&nbsp;Wei Zheng ,&nbsp;Wen-Jie Jiang ,&nbsp;Zhuo Yuan ,&nbsp;Yu Xiang ,&nbsp;Cheng Peng ,&nbsp;Wei Xiong ,&nbsp;Jian-You Shi","doi":"10.1016/j.bioorg.2025.108417","DOIUrl":"10.1016/j.bioorg.2025.108417","url":null,"abstract":"<div><div>Anaplastic lymphoma kinase (ALK), which encodes a highly conserved receptor tyrosine kinase (RTK), is important for the development and progression of many tumors, especially non-small cell lung cancer (NSCLC). Currently, third-generation ALK inhibitors are used to treat ALK-mutant NSCLC, but the rapid emergence of resistance during treatment greatly limits their efficacy in clinic. In comparison to single-target inhibitors, ALK dual inhibitors offer the benefits of reducing the emergence of drug resistance, improving treatment efficacy, and optimizing pharmacokinetic features due to the synergistic function of ALK and other associated targets involved in tumor progression. Therefore, we outline the development of ALK dual inhibitors, highlight their design approaches and structure-activity relationship (SAR), and offer insights into new challenges and potential future directions in this area.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108417"},"PeriodicalIF":4.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 in vitro evaluation of non-steroidal anti-inflammatory prodrugs for osteoarthritis","authors":"Iuliia Voitovich ,&nbsp;Nancy Ty ,&nbsp;Marion Couderc ,&nbsp;Emmanuel Moreau ,&nbsp;Caroline Peyrode ,&nbsp;Valérie Weber","doi":"10.1016/j.bioorg.2025.108410","DOIUrl":"10.1016/j.bioorg.2025.108410","url":null,"abstract":"<div><div>Osteoarthritis (OA), a degenerative joint disease characterized by chronic pain and stiffness, is the most common cause of disability in older adults. To date, OA lacks curative treatment and medical care is limited to symptom relief particularly through the use of oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, gastrointestinal and cardiovascular adverse effects and only limited benefits in long-term relief of pain are still associated. Moreover, efficiency is in part impeded by rapid clearance of the drugs and by the special physiological environment of the joint impeding deep penetration of drugs. Hence, to overcome those limitations and improve patient outcome, developing new therapeutic approaches based on anti-inflammatory prodrugs with prolonged drug residence time within the joints appears as a promising strategy in OA. We report herein the development of NSAID prodrugs, derived from diclofenac and naproxen, bearing a positively charged quaternary ammonium (QA) to target the negative-fixed charge density in cartilage by the mean of electrostatic interactions. Our charge-based targeted approach aims to extend the residence time of NSAID within the cartilaginous tissues, leading to a potential decrease of side effects and improved efficiency of locally released drugs. Syntheses of various amide and esters prodrugs of diclofenac and naproxen bearing a QA function were performed, including some hypoxia-activated prodrugs. Since most diclofenac derivatives suffered from high instability preventing any further development, we focused on the naproxen derivatives that were relatively stable in PBS buffer over a 24-h period even if three different degradation patterns were observed in murine plasma. A preliminary screening of their <em>in vitro</em> anti-inflammatory efficacy highlighted a correlation between the PGE-2 inhibition and these cleavage patterns. These results support further <em>in vitro</em> and <em>in vivo</em> evaluations of four of these derivatives in OA models.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"160 ","pages":"Article 108410"},"PeriodicalIF":4.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143823654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-Cancer Potential of Dehydrozingerone's Phenoxy-Acetamide Derivatives: Discovery of a Potent Lead with Dual Anti-Proliferative and Anti-Metastatic Activities","authors":"Chetan Kumar ,&nbsp;Anshurekha Dash ,&nbsp;Rohit Singh ,&nbsp;Tanzeeba Amin ,&nbsp;Salil Suresh ,&nbsp;Anindya Goswami ,&nbsp;Ravindra S. Phatake","doi":"10.1016/j.bioorg.2025.108413","DOIUrl":"10.1016/j.bioorg.2025.108413","url":null,"abstract":"<div><div>Herein, we report the design and synthesis of twenty-eight novel phenoxy-acetamide derivatives of dehydrozingerone (DHZ), aimed at exploring their potential as anticancer agents. The newly synthesized compounds were characterized using NMR, mass spectrometry, and HPLC. The in vitro anticancer activity was evaluated against MCF-7, HCT-116, and A549 cancer cell lines, where compounds <strong>2</strong>, <strong>4</strong>, <strong>9</strong>, <strong>14</strong>, <strong>26</strong>, and <strong>27</strong> exhibited the highest potency, with IC₅₀ values ranging from 3.52 to 9.93 <em>μ</em>M. These promising molecules were further tested against PC3 and Panc1 cell lines, demonstrating strong anticancer effects. Selectivity index analysis revealed that compound <strong>14</strong> demonstrated the highest selectivity for PC3, while compound <strong>2</strong> consistently exhibited notable selectivity across multiple cancer cell lines, highlighting their potential for targeted therapy. Clonogenic assays confirmed that compound <strong>2</strong> significantly reduced the long-term proliferative capacity of HCT-116 and MCF-7 cells in a dose-dependent manner. Mechanistic studies revealed that compound <strong>2</strong> induced cell cycle arrest by modulating Cyclin D1, leading to altered BAX/Bcl-2 and PARP levels, caspase cascade activation, and apoptotic cell death. Additionally, compound <strong>2</strong> regulated epithelial-mesenchymal transition (EMT), as evidenced by downregulation of Snail and upregulation of E-cadherin and occludin in a dose-dependent manner. Furthermore, molecular docking and ADMET predictions support compound <strong>2</strong> as a promising lead for anticancer drug discovery.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108413"},"PeriodicalIF":4.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}