Bioorganic Chemistry最新文献

{"title":"Metabolite profiling in human and mouse liver microsomes of the aminosteroid RM-581, a new orally active anticancer agent","authors":"Donald Poirier ,&nbsp;Martin Jutras ,&nbsp;René Maltais ,&nbsp;Jenny Roy ,&nbsp;Maude Fleury","doi":"10.1016/j.bioorg.2025.108979","DOIUrl":"10.1016/j.bioorg.2025.108979","url":null,"abstract":"<div><div>To progress towards clinical phase studies with orally active aminosteroid RM-581, it was necessary to address its metabolic stability. Analysis by ultra high-pressure liquid chromatography coupled with quadrupole time-of-flight-mass spectrometry (MS) showed the gradual disappearance of RM-581, making it possible to determine a half-life of 14 and 15 min in mouse and human liver microsomes, respectively, and the presence of 6 metabolites in varying proportions (M1 to M6). The MS/MS spectra of metabolites were investigated to assign sub-structures to fragment ions. These analyses made it possible to conclude that the amino acid proline in the C2-side chain of the steroid mestranol core was the main site of metabolism, and the following mass shift relative to the parent compound were observed for each metabolite relative to RM-581: M1(+34), M2(−2), M3(+16), M4(+18), M5(+32) and M6(+16). Suspecting the formation of RM-581 analogs whose pyrrolidine ring of proline has been opened, compound <strong>8</strong> (M4) was synthesized and characterized. Its chromatographic and MS properties made it possible to formally identify the metabolite M4 (M + H⁺ = 665.3684; Rt = 9.11 min) as a primary alcohol derivative. This result also indirectly supports the proposed structures of the other metabolites M6 (aldehyde), M5 (carboxylic acid) and M1 (dihydroxylated quinoline ring). M4 (IC₅₀ = 12–454 μM) was found to be much less potent than RM-581 (IC₅₀ = 0.78–7.55 μM) when tested on 9 human pancreas and leukemia cancer cell lines. M4 (63 %) was also more present in plasma than RM-581 (37 %) when RM-581 was orally administered to rats.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108979"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145060944","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":"Sclareol-based natural nanoparticles with adamantane moieties exert anticancer effects against non-small cell lung carcinoma cells","authors":"Pavle Stojković ,&nbsp;Ema Lupšić ,&nbsp;Nataša Terzić Jovanović ,&nbsp;Ana Stepanović ,&nbsp;Paraskev Nedialkov ,&nbsp;Ana Podolski-Renić ,&nbsp;Milica Pešić ,&nbsp;Igor M. Opsenica","doi":"10.1016/j.bioorg.2025.108967","DOIUrl":"10.1016/j.bioorg.2025.108967","url":null,"abstract":"<div><div>Synthesis of novel derivatives of sclareol bearing an adamantane moiety was achieved aiming to improve cytotoxicity of sclareol. Novel compounds exhibited up to 100 times more pronounced effects compared to the sclareol against non-small cell lung carcinoma cell lines NCI-H460 and its multidrug resistant variant NCI-H460/R. Nine derivatives (<strong>11b</strong>, <strong>11c</strong>, <strong>11i</strong>, <strong>12a</strong>, <strong>12b</strong>, <strong>12c</strong>, <strong>12e</strong>, <strong>12f</strong>, and <strong>12</strong> <strong>g</strong>) caused cell growth inhibition below 50 % at 1 μM concentration in NCI-H460 cells, and four derivatives (<strong>11c</strong>, <strong>11i</strong>, <strong>12b</strong> and <strong>12e</strong>) showed similar activity against NCI-H460/R cells. Notably, compound <strong>12b</strong> exhibited selectivity towards cancer cells, as well as collateral sensitivity being more potent against MDR cells. Sclareol, as well as novel derivatives <strong>12a</strong>, <strong>12b</strong>, <strong>12c</strong>, <strong>12e</strong>, <strong>12f</strong>, and <strong>12</strong> <strong>g</strong> increased accumulation of rhodamine 123 which suggested their potential to modulate P-glycoprotein (P-gp) activity. Compound <strong>12b</strong> emerged as inhibitor of P-gp and <strong>12e</strong> and <strong>12f</strong> as P-gp substrates. Furthermore, <strong>12b</strong>, <strong>12e</strong> and <strong>12f</strong> induced reversal of doxorubicin resistance. Cell death analysis indicated necrosis as a primary type of cell death in NCI-H460 with significant increase in late apoptosis in MDR cells. We discovered for the first time that sclareol can spontaneously form negatively charged nanoparticles by being dissolved in ultrapure water. Adamantyl derivatives <strong>12a-c</strong> and <strong>12e-g</strong> and parental diamine derivatives <strong>8c-f</strong> formed positively charged nanoparticles, implying that they can bind to the negatively charged cellular membrane and penetrate cancer cells. The unique nanoparticle characteristics combined with the significant cytotoxicity of the novel adamantane-sclareol derivatives underscore their potential as promising candidates for advanced anticancer nanotherapeutic applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108967"},"PeriodicalIF":4.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046500","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":"Therapeutic potential, antimicrobial activity against acne-causing bacteria, and modes of action of WKK10 and WRR10, novel cationic antimicrobial peptides","authors":"Santi Phosri ,&nbsp;Sukanya Tastub ,&nbsp;Aekkhaluck Intharuksa ,&nbsp;Tachpon Techarang ,&nbsp;Kanokporn Srisucharitpanit ,&nbsp;Sarah E. Hooper ,&nbsp;Tinnakorn Theansungnoen","doi":"10.1016/j.bioorg.2025.108965","DOIUrl":"10.1016/j.bioorg.2025.108965","url":null,"abstract":"<div><div>Although antimicrobial peptides possess potent antimicrobial activities, the high cost of production, based on amino acid length, has limited their therapeutic and cosmeceutical applications. This study aimed to produce and characterize <em>de novo</em> designed antimicrobial peptides derived from WSKK11 and WSRR11 for efficacy against acne-causing bacteria. Ten designed peptides were evaluated for antimicrobial, hemolytic, and cytotoxic activities, as well as, secondary structures by FTIR and modes of action. Of the ten peptides, WKK10, WWKK11, WRR10, and WRRR11 had antimicrobial activity against <em>Cutibacterium acnes</em> DMST 14916 at the minimum inhibitory concentrations (MICs) of 64, 16, 32, and 32 μg/mL, respectively. The MICs of WKK10, WWKK11, WSRR10, and WRRR11 against <em>Staphylococcus aureus</em> TISTR 746 were 8, 4, 16, and 16 μg/mL, while those against <em>Staphylococcus epidermidis</em> TISTR 518 were 8, 4, 32, and 16 μg/mL, respectively. These peptides were less toxic to human erythrocytes, and WWKK11 and WRRR11 had no toxicity for MRC-5 fibroblasts, with toxicity to RAW 264.7 macrophage (≥50 μg/mL) and HaCaT keratinocyte (≥100 μg/mL). WKK10 and WRR10 were not toxic to RAW 264.7, HaCaT, and MRC-5 cells up to 100 μg/mL. Beta-sheet and alpha-helix structures of the peptides were adopted predominantly in 20 mM Tris-HCl, pH 7.4 and 50% TFE, respectively. The peptides revealed direct activity and perturbation of the cell envelope, observed by scanning electron microscopy. The results indicate that the four novel peptides, particularly WKK10 and WRR10, are promising topical antimicrobial agents for acne treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108965"},"PeriodicalIF":4.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020334","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":"Synthesis, Larvicidal Activity, and In Silico Mechanistic Insights of Novel Polyfunctionalized Pyridine Derivatives Against Culex pipiens L.","authors":"Mohamed G. Abouelenein ,&nbsp;Ahmed A. El-Rashedy ,&nbsp;Doaa R. Abdel- Haleem","doi":"10.1016/j.bioorg.2025.108959","DOIUrl":"10.1016/j.bioorg.2025.108959","url":null,"abstract":"<div><div>A strategically engineered, eco-conscious synthetic platform was developed to access a novel library of eighteen polyfunctionalized pyridine-based heterocycles through high-efficiency multicomponent and annulation strategies, using 2-amino-4-(4-chlorophenyl)-6-(<em>p</em>-tolyl)nicotinonitrile (<strong>M</strong>) as a privileged core. Structural diversity was maximized by integrating potent pharmacophores, including pyrido[2,3-<em>d</em>]pyrimidines, naphthyridines, triazines, and fused pyrrolo/tetrazolo motifs, <em>via</em> both conventional and accelerated (microwave/ultrasound-assisted) routes, affording excellent yields with high structural fidelity as confirmed by IR, ¹H/¹³C NMR, and mass spectrometry. Biological evaluation revealed that all synthesized compounds had excellent larvicidal efficacy against <em>Culex pipiens</em> larvae, especially <strong>15</strong> and <strong>9,</strong> emerging as lead candidates that exhibited exceptional LC₅₀ values of 0.118 and 0.137 μg/mL, respectively. Biochemical assays of the most effective compounds demonstrated pronounced inhibition of key detoxification enzymes, acetylcholinesterase, cytochrome P450 monooxygenase, and carboxylesterase. Advanced <em>in silico</em> analyses, encompassing molecular docking, molecular dynamics (200 ns), MM/GBSA binding free energy, and ADMET predictions, elucidated binding stability, mechanistic pathways, and favorable eco-safety profiles, including low predicted environmental persistence. Collectively, these results position the synthesized derivatives, particularly compound <strong>15</strong>, as a promising generation of larvicidal agents with dual action targets one or more modes of action to reduce the development of resistance.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108959"},"PeriodicalIF":4.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020337","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":"A facile method for the preparation of 7,8-dihydro-4H-chromene-4,5(6H)-diones as non-aromatic cycle A analogs of isoflavones and their evaluation as antiproliferative agents","authors":"Dmitry B. Rubinov ,&nbsp;Veronica G. Zinovich ,&nbsp;Alexander M. Scherbakov ,&nbsp;Tatyana V. Chukarina ,&nbsp;Danila V. Sorokin ,&nbsp;Sviatlana E. Ohurtsova ,&nbsp;Elena V. Shafranovskaya ,&nbsp;Valeryia V. Laptsevich ,&nbsp;Alexandra L. Mikhaylova ,&nbsp;Fedor B. Bogdanov ,&nbsp;Alexander V. Baranovsky ,&nbsp;Raman M. Puzanau ,&nbsp;Yury G. Pakhadnia ,&nbsp;Fedor A. Lakhvich ,&nbsp;Yuri A. Piven","doi":"10.1016/j.bioorg.2025.108960","DOIUrl":"10.1016/j.bioorg.2025.108960","url":null,"abstract":"<div><div>In this article, we describe a facile method for the synthesis of a novel class of compounds – 3-aryl-7,8-dihydro-4<em>H</em>-chromene-4,5(6<em>H</em>)-diones. The target compounds were prepared from easily accessible 2-(2-arylacetyl)cyclohexane-1,3-diones using a low-cost dimethylformamide-dimethyl sulfate adduct in the presence of triethylamine. The obtained compounds, which can be considered non-aromatic cycle A analogs of isoflavones, demonstrated moderate antiproliferative activity in the micromolar IC₅₀ range and modest selectivity toward HER2-positive cancer cells. A molecular modeling study suggested that their possible mechanism of action may involve HER2 inhibition. Additionally, by introducing a 3-chloro-4-((3-fluorobenzyl)oxy)phenyl group into the structure of the reported compounds, we designed and synthesized compound <strong>4o</strong> as a potential selective HER2 inhibitor. Two compounds, <strong>4b</strong> and <strong>4o</strong>, which had different predicted binding modes to HER2, were tested <em>in vitro</em> for kinase activity inhibition against eight tyrosine kinases. At a concentration of 1 μM, compound <strong>4b</strong> inhibited HER2 and HER4 by 74 % and 69 %, respectively. At the same concentration, compound <strong>4o</strong> significantly inhibited only HER2 by 84 %. However, immunoblotting in A431 cells treated with <strong>4b</strong> or <strong>4o</strong> unexpectedly showed a reduction in total HER2 expression rather than in phosphorylated HER2 (p-HER2). Furthermore, both compounds reduced cyclin D1 level and stimulated PARP cleavage.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108960"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046019","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":"Preparation, characterization, and antioxidant activity of bovine bone peptide-calcium chelate against oxidative stress-induced injury in Caco-2 cells","authors":"Aqing Jian ,&nbsp;Baide Mu ,&nbsp;Kun Li ,&nbsp;Qingyi Deng ,&nbsp;Juan Wang ,&nbsp;Chunxiang Piao ,&nbsp;Tingyu Li ,&nbsp;Mingxun Cui ,&nbsp;Guanhao Li ,&nbsp;Hongmei Li","doi":"10.1016/j.bioorg.2025.108958","DOIUrl":"10.1016/j.bioorg.2025.108958","url":null,"abstract":"<div><div>In this study, bovine peptide‑calcium chelates (BBP-Ca) were prepared via enzymatic hydrolysis to generate peptides and fermentation to obtain soluble calcium ions, which were then chelated together. The structural characteristics of BBP-Ca were comprehensively analyzed using FTIR, SEM, and UV spectroscopy. Additionally, its antioxidant capacity was evaluated by examining its protective effects against oxidative stress-induced damage in Caco-2 cells. The effect of BBP-Ca on the H₂O₂-induced model demonstrated its ability to inhibit ROS generation, reduce MDA levels, and enhance the activities of SOD, CAT, and GSH-Px. Furthermore, BBP-Ca was found to upregulate the mRNA expression of the nuclear factor erythroid-2-related factor 2 (Nrf2), which in turn increased the expression of the antioxidant enzymes heme oxygenase-1 (HO − 1) and NAD(<em>P</em>)H quinone oxidoreductase 1 (NQO1), while also downregulating the expression of Kelch-like ECH-associated protein 1 (Keap1). These findings suggest that BBP-Ca can mitigate H₂O₂-induced oxidative damage in Caco-2 cells via the Nrf2 signaling pathway. This study promoted the progress in the field of food-source mineral supplements by directly preparing peptide‑calcium chelates from bovine bones, avoiding synthetic additives.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108958"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020335","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":"High-throughput screening identifies a dual-activity inhibitor of OXCT1 for hepatocellular carcinoma therapy","authors":"Rui Liu ,&nbsp;Yuchen Sun ,&nbsp;Shengqi Shen ,&nbsp;Tingting Li ,&nbsp;Nanchi Xiong ,&nbsp;Wenhao Ma ,&nbsp;Zilong Zhou ,&nbsp;Haiying Liu ,&nbsp;Yiyang Chu ,&nbsp;Mingming Wang ,&nbsp;Xue Ai ,&nbsp;Ling Ye ,&nbsp;Huafeng Zhang","doi":"10.1016/j.bioorg.2025.108964","DOIUrl":"10.1016/j.bioorg.2025.108964","url":null,"abstract":"<div><div>3-Oxoacid CoA-transferase 1 (OXCT1) plays a crucial role in hepatocellular carcinoma (HCC) progression through its ketolytic and succinyltransferase activities. Despite its potential as a therapeutic target, no small molecules have been developed to inhibit the dual enzymatic activities of OXCT1 specifically. In this study, our structural analysis revealed that the active sites for both enzymatic functions of OXCT1 are located in the same pocket. Targeting this pocket inhibits the binding of OXCT1 to its substrates and blocks both of its enzymatic activities. Thus, we developed two high-throughput screening systems to assess the effects of small molecules on OXCT1's distinct enzymatic activities. By combining these experimental approaches with virtual screening, we identified a compound, D574–0246 (iOXCT1), which effectively inhibits both enzymatic activities. <em>In vitro</em> and <em>in vivo</em> validation demonstrated that iOXCT1 suppresses HCC growth <em>via</em> OXCT1 inhibition. Collectively, our results establish OXCT1 as a promising therapeutic target and identify iOXCT1 as a novel dual-activity inhibitor, providing a foundation for developing OXCT1-targeted therapies against HCC.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108964"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145011061","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":"Biogenic gold nanoparticles synthesized from Caulerpa sertularioides: A green approach for antioxidant, antibacterial and anticancer applications","authors":"Vibitha Sri Sivakumar ,&nbsp;Subramanian Palanisamy ,&nbsp;Periyannan Rajasekar ,&nbsp;Jeneeta Solomon ,&nbsp;Thirunageswaran Pandi ,&nbsp;Vinosha Manoharan ,&nbsp;Anjali Ravichandran ,&nbsp;Sonaimuthu Mohandoss ,&nbsp;Thangapandi Marudhupandi ,&nbsp;SangGuanYou ,&nbsp;Narayanasamy Marimuthu Prabhu","doi":"10.1016/j.bioorg.2025.108963","DOIUrl":"10.1016/j.bioorg.2025.108963","url":null,"abstract":"<div><div>This research used an aqueous extract from <em>Caulerpa sertularioides</em> to convert gold ions, demonstrating the eco-friendliness, low toxicity, and cost-effectiveness of green nanoparticle synthesis. The formation of <em>C. sertularioides</em>-mediated gold nanoparticle (Cs-AuNPs) was authenticated by the UV–visible absorption peak at 538 nm. FT-IR identified functional groups responsible for reducing gold ions to Cs-AuNPs. XRD and electron microscopy (FESEM and HR-TEM) confirmed the face-centered cubic (fcc) structure and spherical shape, averaging 26.3 nm in size. The synthesized Cs-AuNPs were evaluated for antioxidant, antibacterial, and cytotoxic properties. Cs-AuNPs demonstrated a dose-dependent antioxidant activity. The antibacterial assay on <em>Photobacterium damselae</em> showed a concentration-dependent effect, with the highest activity of 21 mm at 100 μg/mL. The MTT experiment showed significant cytotoxic activity against HT-29 cells, with an IC₅₀ of 15.44 μg/mL. Additionally, Cs-AuNPs exhibited no toxicity toward zebrafish embryos. These results suggest that <em>C. sertularioides</em> may serve as a sustainable source for producing AuNPs, which hold promise for biomedical applications as antibacterial and anticancer agents.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108963"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027338","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 and synthesis of multitarget triazinoindole derivatives with potent antiproliferative activity: Targeting EGFR, SIRT1, MDM2, Hsp90, PI3K, p53, and caspase-9","authors":"Waleed A. Badawi ,&nbsp;Eman S. Ezz-ElDien ,&nbsp;Mohamed A. El-Atawy ,&nbsp;Alaa Z. Omar ,&nbsp;Ezzat A. Hamed ,&nbsp;Hoda A. Ahmed ,&nbsp;Mariusz Jaremko ,&nbsp;Abdul-Hamid Emwas ,&nbsp;Tarek M. Okda ,&nbsp;Mahmoud Z. El-Readi ,&nbsp;Mohammed Elhag","doi":"10.1016/j.bioorg.2025.108943","DOIUrl":"10.1016/j.bioorg.2025.108943","url":null,"abstract":"<div><div>Driven by the urgent need for novel anticancer agents capable of overcoming limitations associated with conventional therapies, a new series of Benzyl-5<em>H</em>-[1,2,4]triazino[5,6-<em>b</em>]indoles derivatives bearing flexible pyrazole or pyrazoline moieties were designed, synthesized, and evaluated for antiproliferative efficacy. Most of the synthesized compounds demonstrated notable cytotoxicity compared to the reference compound inauhzin (INZ). Specifically, compounds <strong>4</strong>, <strong>10</strong>, <strong>11</strong>, and <strong>12</strong> exhibited potent activity against A549 lung cancer cells, with IC₅₀ values of 7.39 μM, 3.17 μM, 0.82 μM, and 5.38 μM, respectively, outperforming INZ (IC₅₀ <strong>=</strong> 8.97 μM). Against Caco-2 colorectal cancer cells, compounds <strong>4</strong>, <strong>5</strong>, and <strong>10</strong> displayed IC₅₀ values of 2.35 μM, 3.28 μM, and 2.63 μM, respectively, compared to INZ (IC₅₀ <strong>=</strong> 3.64 μM).</div><div>To elucidate the potential mechanisms underlying the anticancer activity of the most active compounds, a comprehensive set of assays was conducted, including cell cycle analysis, apoptosis evaluation, and quantification of key molecular targets such as EGFR, SIRT1, MDM2, Hsp90, PI3K, p53, and caspase-9. These biomarkers are intricately interconnected within cellular signaling pathways, whereby inhibition of EGFR and PI3K suppresses proliferative signaling, downregulation of SIRT1 and MDM2 leads to p53 activation, and subsequent induction of caspase-9-mediated apoptosis and cell cycle arrest. Notably, most of the tested compounds demonstrated promising results in modulating these targets, which supports their potential as effective anticancer agents. Additionally, selected compounds showed excellent binding to the target sites when docked into the active domains of EGFR, Hsp90, PI3K, SIRT1, and MDM2.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108943"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027340","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":"A novel arylnaphthalene lignan analogue targets CYP51 to inhibit Cryptococcus neoformans growth","authors":"Chaowei Zhang ,&nbsp;Meirong Zhao ,&nbsp;Dongyu Huang ,&nbsp;Yubin Lei ,&nbsp;Jie Ma ,&nbsp;Xiaojian Li ,&nbsp;Yan Wu ,&nbsp;Zhendan He ,&nbsp;Yifu Guan ,&nbsp;Hedong Bian ,&nbsp;Xun Song","doi":"10.1016/j.bioorg.2025.108900","DOIUrl":"10.1016/j.bioorg.2025.108900","url":null,"abstract":"<div><div>JR20, a novel arylnaphthalene lignan derivative, exhibits potent antifungal activity against <em>Cryptococcus neoformans</em> (IC₅₀ = 2.82 μg/mL) through dual mechanisms targeting CYP51 and mitochondrial function. Mechanistic studies combining molecular docking, transcriptomics, and biochemical assays confirmed JR20's specific binding to CYP51, significantly reducing ergosterol biosynthesis and causing membrane disruption (evidenced by SEM/TEM showing cell wall collapse and plasmolysis). Flow cytometry revealed fungal necrosis induction, while mitochondrial dysfunction was demonstrated through membrane potential loss, ROS accumulation, and ATP synthesis impairment. <em>In vivo</em> studies using a murine deep infection model demonstrated JR20's therapeutic efficacy, showing both anti-infective and anti-inflammatory properties. As a lignan derivative, JR20 represents a promising antifungal candidate addressing drug resistance through its unique dual-action mechanism, highlighting the potential of natural product research for developing novel antifungals against resistant pathogens.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108900"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027339","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}