Bioorganic Chemistry最新文献

{"title":"Structure–activity relationship and antioxidant mechanisms of rabbit-derived peptides with Keap1-binding potential: In vitro, in silico, and in vivo evaluation","authors":"Wanzhou Yang,&nbsp;Zhiyuan Tai,&nbsp;Yuexin Pan,&nbsp;Wenhao Zhang,&nbsp;Jia Ran,&nbsp;Zeyuan Yu,&nbsp;Xiaodong Yu,&nbsp;Qiyi He","doi":"10.1016/j.bioorg.2025.109007","DOIUrl":"10.1016/j.bioorg.2025.109007","url":null,"abstract":"<div><div>Oxidative stress, arising from a dysregulation between the generation of reactive oxygen species (ROS) and antioxidant defense mechanisms, is closely linked to the pathogenesis of numerous chronic diseases. To identify natural peptide-based antioxidants, rabbit meat proteins were enzymatically hydrolyzed using seven proteases. Among them, Hydrolysates produced by papain demonstrated the greatest radical scavenging activity, with DPPH and ABTS inhibition rates of 51.50 % and 61.50 %, respectively. Ultrafiltration and Sephadex G-15 fractionation revealed that the &lt;3 kDa fraction (PH3) and its subfraction F5 possessed the strongest antioxidant activity. LC-MS/MS analysis of F5 identified 163 peptides, of which 56 were predicted to exhibit antioxidant potential using PeptideRanker and AnOxPePred algorithms. Notably, seven novel peptides showed strong binding affinities to Keap1 (binding energy &lt; −8.0 kcal/mol) in molecular docking, suggesting possible modulation of the Keap1–Nrf2 antioxidant pathway. Quantum chemical analysis (HOMO–LUMO orbitals and electrostatic potential mapping) combined with radical scavenging assays demonstrated that electron-donating aromatic residues (Trp, Tyr) played key roles in antioxidant activity via hydrogen atom and electron transfer mechanisms, establishing a molecular-level structure–activity relationship. In vivo validation using an AAPH-induced zebrafish model confirmed the peptides' safety and efficacy, including reduced ROS levels and restored endogenous antioxidant enzyme activities (SOD and CAT). Collectively, these findings provide mechanistic insight into the antioxidant action of rabbit-derived peptides and support their potential application as natural antioxidants for functional food development and oxidative stress-related disease prevention.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109007"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096378","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 novel quinoline-chalcone derivatives as dual inhibitors of tubulin polymerization and P-glycoprotein to overcome cisplatin resistance in cervical cancer","authors":"Tong Yan ,&nbsp;Miao Miao Zhang ,&nbsp;Xin Yi Deng ,&nbsp;Madina Imam,&nbsp;Mourboul Ablise,&nbsp;Wei Yi Zhang","doi":"10.1016/j.bioorg.2025.109006","DOIUrl":"10.1016/j.bioorg.2025.109006","url":null,"abstract":"<div><div>Cervical cancer remains a major cause of cancer death in women, often limited by cisplatin resistance. To overcome multidrug resistance (MDR), we designed and synthesized 23 novel quinoline-chalcone derivatives targeting both P-glycoprotein (P-gp) and the colchicine-binding site (CBS) of tubulin. Among them, compound <strong>6h</strong> exhibited the most potent anti-proliferative activity against both cisplatin-sensitive HeLa cells (IC₅₀ = 6.69 μM) and cisplatin-resistant HeLa/DDP cells (IC₅₀ = 7.21 μM). The potency of compound <strong>6h</strong> was superior than cisplatin (HeLa: 15.54 μM; HeLa/DDP: 94.32 μM) while displaying lower cytotoxicity towards normal cervical cells than cisplatin. Compound <strong>6h</strong> demonstrated lower cisplatin resistance index (RI) in the HeLa/DDP cells than verapamil (RI: 1.27 vs. 2.22). Mechanistic studies demonstrated that compound <strong>6h</strong> inhibited tubulin polymerization and induced G₂/M arrest and apoptosis in both the cell lines. Compound <strong>6h</strong> reversed MDR by inhibiting P-gp efflux function, as evidenced by rhodamine 123 accumulation in HeLa/DDP cells. Molecular docking and dynamics simulations provided structural insights, confirming stable binding of <strong>6h</strong> to the tubulin CBS (ΔG = −12.4 kcal/mol) and the P-gp hydrophobic lumen (ΔG = −10.8 kcal/mol). Zebrafish acute toxicity assay results demonstrated that the safety profile of compound <strong>6h</strong> (0 % mortality at 400 μM) was superior than cisplatin (16.7 % mortality rate at 8 μM). To the best of our knowledge, compound <strong>6h</strong> is the first reported quinoline-chalcone derivative with dual functions: direct antitumor activity and reversal of P-gp-mediated cisplatin resistance. Our results suggest that compound <strong>6h</strong> is a promising compound and represents a novel strategy for combating drug-resistant cervical cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109006"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096954","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":"Mechanism-guided discovery of chromene-chalcone hybrids targeting PKM2 and microtubules for breast cancer therapy","authors":"Madhurendra Kumar Katiyar ,&nbsp;Shubham Upadhayay ,&nbsp;Dinesh Prasad Jalli ,&nbsp;Vaishnavi Kalmegh ,&nbsp;Gaurav Joshi ,&nbsp;Vibhu Jha ,&nbsp;Muhammad Wahajuddin ,&nbsp;Amit Shard ,&nbsp;Puneet Kumar ,&nbsp;Raj Kumar","doi":"10.1016/j.bioorg.2025.109008","DOIUrl":"10.1016/j.bioorg.2025.109008","url":null,"abstract":"<div><div>This study presents the rational pharmacophore design, synthesis, and biological evaluation of new chromene-chalcone hybrids (CCHs) with dual mechanisms involving pyruvate kinase M2 (PKM2) inhibition and microtubule stabilization for their potential as anticancer agents. The synthetic route involved the formation of a chromene aldehyde <strong>29</strong> via an <em>oxa-Michael addition</em> followed by intramolecular cyclization, which subsequently underwent Claisen Schmidt condensation to afford the final chalcone derivatives. Among the synthesized compounds (<strong>30a-30o</strong>), <strong>30o</strong> emerged as the most promising candidate, exhibiting potent anticancer activity through dual targeting of PKM2 and the microtubule network<strong>.</strong> Compound <strong>30o</strong> demonstrated a significant antiproliferative effect against MCF-7 breast cancer cells, with an IC₅₀ value of 10.2 ± 0.07 μM<strong>,</strong> and showed PKM2 enzymatic inhibition with an IC₅₀ of 0.363 <strong>±</strong> 0.12 μM, as confirmed through enzymatic assays and protein expression. Cell cycle analysis revealed <strong>30o</strong> induced G2/M phase arrest and microtubule-stabilizing activity. Furthermore, molecular modeling studies revealed its binding mode and strong interactions within the PKM2 active site and taxol binding site of tubulin, supporting the experimental findings. ADMET profiling predicted favorable pharmacokinetic and drug-likeness properties, highlighting its potential as a lead compound. Together, these findings underscored compound <strong>30o</strong> as a dual-acting anticancer agent, simultaneously targeting cancer metabolism and cytoskeletal integrity, and offered a promising scaffold for further development in breast cancer therapeutics.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109008"},"PeriodicalIF":4.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155430","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":"Green synthesis approach for flavonoids and protein-rich Plectranthus amboinicus leaf extract-coated ZnO nanoparticles for diverse biological applications","authors":"Rong Li ,&nbsp;Subramanian Palanisamy ,&nbsp;Nan Ma ,&nbsp;Jiuliang Xu","doi":"10.1016/j.bioorg.2025.109004","DOIUrl":"10.1016/j.bioorg.2025.109004","url":null,"abstract":"<div><div>This study demonstrates the eco-friendly fabrication of zinc oxide nanoparticles (ZnO NPs) using a flavonoid- and protein-rich extract from <em>Plectranthus amboinicus</em>, a medicinal herb renowned for its therapeutic properties. UV–vis spectroscopy showed distinct absorbance peaks at 288 nm for the leaf extract and 358 nm for the synthesized ZnO NPs. X-ray diffraction (JCPDF file no. 00–036-1451) verified the presence of the hexagonal wurtzite crystalline phase in the nanoparticles. FTIR analysis revealed that flavonoids and proteins act as bio-reductants and facilitate the electron transfer to the Zn²⁺ ions, thereby converting them to their zero-valent (Zn⁰) state, leading to the formation of ZnO NPs. Scanning electron microscope (SEM) and transmission electron microscope (TEM) analyses revealed spherical ZnO NPs with an average size of 58.24 nm. These nanoparticles exhibited potent antimicrobial effects, successfully inhibiting <em>Shigella flexneri</em> and <em>Enterococcus faecalis</em>, with biofilm inhibition rates surpassing 93 % at a concentration of 100 μg/mL. Antioxidant evaluations indicated a total antioxidant capacity of 75.5 ± 0.24 μg AAE/mg, a reducing power of 65.24 ± 0.73 μg AAE/mg, and 68.30 ± 0.16 % DPPH radicals scavenging activity at 200 μg/mL. Cytotoxic assessments showed the most significant activity at 200 μg/mL. The IC₅₀ values were recorded as 58.53 μg/mL, 40 μg/mL, and 21.69 μg/mL for treatments at 24 h, 48 h, and 72 h. Additionally, the fluorescence staining assay confirms significant apoptotic changes. The findings highlight the multifaceted potential of <em>P. amboinicus</em>-coated ZnO nanoparticles as viable candidates for functional foods and therapies, addressing antimicrobial resistance, oxidative stress, and cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109004"},"PeriodicalIF":4.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096953","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":"Exploring the mechanism of Levistolide A in the treatment of lung cancer cells based on network analysis, molecular docking and experimental validation","authors":"Lei Zhao ,&nbsp;Jingyu Wang ,&nbsp;Yue Han ,&nbsp;Qingkun Wang ,&nbsp;Wenqing Yang ,&nbsp;Yu Zhang ,&nbsp;Zhenhua Lin ,&nbsp;Lianhua Zhu ,&nbsp;Junjie Piao","doi":"10.1016/j.bioorg.2025.109002","DOIUrl":"10.1016/j.bioorg.2025.109002","url":null,"abstract":"<div><div>Levistolide A (LA) is the main active ingredient in the <em>Angelica sinensis</em> (Oliv.) Diels, which has been proved to have therapeutic effects on a variety of tumors, but its role in treating lung cancer remains unreported. In this study, we found that LA can inhibit lung cancer cell lines (A549 and H1299) proliferation and induced apoptosis via CCK-8, plate cloning, EdU labeling, flow cytometry and western blotting assay. Then, network analysis was performed to elucidate the molecular mechanisms of LA in treating lung cancer, we screened and obtained 57 common targets and 14 core targets for LA treatment of lung cancer by PharmMapper, Swiss Target Prediction, GeneCards and OMIM databases. Molecular docking studies demonstrated strong binding of LA to the core targets. KEGG analysis highlighted involvement in “pathways in cancer” and PI3K/AKT signaling. LA increased intracellular ROS levels, which inactivated PI3K/AKT, resulting in apoptosis and growth inhibition via experimental verification. In addition, 740Y<img>P (a PI3K/AKT pathway activator) and NAC (a ROS scavenger) were able to reverse the effects of LA on PI3K/AKT pathway, proliferation and apoptosis in lung cancer cells. In conclusion, these findings highlight the potential of LA as a promising anti-lung cancer agent and provide a foundation for further investigation into its clinical applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109002"},"PeriodicalIF":4.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096375","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":"Transforming ureas into carbamates: From allosteric p38α MAPK ligands to dual BChE/p38α MAPK inhibitors","authors":"Svit Ferjančič Benetik ,&nbsp;Anže Meden ,&nbsp;Damijan Knez ,&nbsp;Peter Mastnak-Sokolov ,&nbsp;Urban Košak ,&nbsp;Selena Horvat ,&nbsp;Anja Pišlar ,&nbsp;Rudolf Andrys ,&nbsp;Kamil Musílek ,&nbsp;Jan Detka ,&nbsp;Kinga Sałat ,&nbsp;Aleš Obreza ,&nbsp;Stanislav Gobec","doi":"10.1016/j.bioorg.2025.108998","DOIUrl":"10.1016/j.bioorg.2025.108998","url":null,"abstract":"<div><div>Given the limited benefits of anticholinergic drugs and the repeated clinical failures of anti-amyloid therapies, the therapeutic focus in Alzheimer's disease (AD) is gradually shifting toward addressing both disease symptoms and its major underlying cause – neuroinflammation. We have developed novel multi-target directed ligands that inhibit butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) to simultaneously target cholinergic deficits and neuroinflammation in AD. Following <em>in silico</em> design, we converted known allosteric pyrazolyl urea p38α MAPK ligands into <em>N</em>,<em>N</em>-disubstituted carbamates that pseudo-irreversibly inhibit hBChE while retaining p38α MAPK inhibitory activity. The lead compound <strong>13a</strong> has favourable central nervous system (CNS) drug-like properties <em>in vitro</em> and shows procognitive effects in an <em>in vivo</em> scopolamine-induced amnesia model. Our series demonstrates that targeted structural modifications of selective kinase inhibitors, based on a comprehensive knowledge of cholinesterase structure and function, enable expansion of the effect to the CNS. This approach offers critical insights to pave the way for the development of novel dual-target agents that modulate both cholinergic and neuroinflammatory pathways in neurodegenerative diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108998"},"PeriodicalIF":4.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118490","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":"Selection and identification of a novel DNA aptamer for recognizing colorectal cancer stem cells","authors":"Wanming Li ,&nbsp;Tao Bing ,&nbsp;Qun Wang ,&nbsp;Yanxi Li ,&nbsp;Shihan Sun ,&nbsp;Xin Li ,&nbsp;Yinuo Ma ,&nbsp;Rui Wang ,&nbsp;Wei Ba ,&nbsp;Xinyan Li ,&nbsp;Dihua Shangguan ,&nbsp;Jin Fang","doi":"10.1016/j.bioorg.2025.108989","DOIUrl":"10.1016/j.bioorg.2025.108989","url":null,"abstract":"<div><div>Metastasis is one of the main causes of cancer-related deaths. Cancer stem cells (CSCs) have the ability to initiate metastasis; however, there is a lack of effective biomarkers to characterize CSC. In this study, subtractive cell-SELEX was performed using colorectal cancer (CRC) HCT116 cells with high stemness characteristics and CL187 cells with low stemness characteristics as the target and negative cells, respectively, for stemness-specific aptamers selection. Two aptamers were obtained, among which aptamer L33 had good specificity for CRC cells with stemness characteristics. Besides, aptamer L33 had excellent affinity with a Kd of 16.6 ± 2.1 nM and good temperature stability. Subsequently, we obtained two cell subpopulations by L33-based cell sorting and confirmed that the L33-positive cell subpopulation had higher expression of stemness-associated markers, stronger tumor sphere-forming capacity, chemotherapy drug tolerance, migration and invasion ability, and in vivo tumorigenicity. After confirming that aptamer L33 is closely associated with tumor stemness, we used L33 as a stem circulating tumor cell (CTC) capture probe and found a higher detection rate of L33-positive CTCs in the peripheral blood of patients with metastatic CRC, suggesting that CTC capture analysis based on L33 has a stronger ability to predict metastasis. Therefore, aptamer L33 developed in this study may provide a potential target for the diagnosis of metastatic CRC and CSC based therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108989"},"PeriodicalIF":4.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096374","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 biological screening of some diaryl acetamide derivatives as potential cytotoxic agents on HL-60(TB) cell line","authors":"Mohammed K. Abdelhameid ,&nbsp;Mohammed A. Hara ,&nbsp;Mohamed Ramadan ,&nbsp;Ehab S. Taher ,&nbsp;Mostafa A.Ramadan ,&nbsp;Khaled O. Mohamed ,&nbsp;Ahmed T. Negmeldin","doi":"10.1016/j.bioorg.2025.108999","DOIUrl":"10.1016/j.bioorg.2025.108999","url":null,"abstract":"<div><div>In this study, novel diaryl acetamide derivatives were designed and evaluated as potential cytotoxic agents against the leukemic cells HL-60 (TB) with tyrosine kinase FMS-3(FLT-3) enzyme inhibitory activity. The designed molecules were synthesized and investigated for the FLT-3 enzyme inhibition. Compounds <strong>5a</strong>, <strong>15b</strong>, and <strong>16b</strong> showed significant inhibitory activity against the FLT-3 enzyme. Assessment of cytotoxicity on HL-60 cells revealed that compound <strong>15b</strong> exhibited superior activity than Quizartinib (AC220). Additionally, compounds <strong>5a</strong> and <strong>15b</strong> effectively arrested the cell cycle at the G₁ phase upon testing on HL-60 cells, suggesting potential abilities in blocking HL-60 cells' proliferation. The annexin-V stain assay demonstrated that compounds <strong>5a</strong>, <strong>15b</strong>, and <strong>16b</strong> induced apoptosis in HL-60 cells. Furthermore, the ELISA assay showed that the blocking of cell cycle proliferation of HL-60 cells was mediated <em>via</em> the induction of cell cycle regulatory proteins p53 and p21. Meanwhile, the observed apoptosis induction was mediated by increasing apoptotic mediators, Bax/Bcl-2 ratio, and up-regulating caspase-3. Molecular docking studies revealed the binding affinities and interactions of the newly synthesized compounds, along with the reference compound Quizartinib, with the FLT-3 enzyme binding site.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108999"},"PeriodicalIF":4.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084667","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 new Thieno[2,3-d]pyrimidine-based derivatives as anti-breast cancer: Biological evaluation, PIM-1 kinase inhibition, and in silico studies","authors":"Menna Tallah M. Sayed ,&nbsp;Zeinab Mahmoud ,&nbsp;Makarem M. Said ,&nbsp;Amr M. Abdou ,&nbsp;Rasha A. Hassan","doi":"10.1016/j.bioorg.2025.109003","DOIUrl":"10.1016/j.bioorg.2025.109003","url":null,"abstract":"<div><div>This study primarily aimed to develop and evaluate new thieno[2,3-<em>d</em>]pyrimidine derivatives with potential anticancer properties through a comprehensive process of design and synthesis. Using a variety of spectroscopic methods, the chemicals produced were thoroughly analyzed. The cytotoxic effects of the derivatives on the MCF-7 breast cancer cell line were examined. Compound <strong>15</strong> demonstrated the strongest anticancer activity, with IC₅₀ value of 34.49 ± 1.32 μM, compared to doxorubicin (IC₅₀ = 34.20 ± 0.28 μM). The most potent derivatives were assessed for their ability to suppress PIM-1 kinase activity. PIM-1 inhibitory activity of compounds <strong>8</strong>, <strong>12</strong>, <strong>15</strong>, and <strong>17</strong> was evaluated compared to staurosporine. The results showed potent to moderate activity with IC₅₀ values of 0.771 ± 0.028, 1.332 ± 0.049, 0.212 ± 0.008, and 2.66 ± 0.099 μM, respectively, and IC₅₀ = 0.47 ± 0.017 μM for staurosporine. Moreover, a scratch wound healing assay revealed that compound <strong>15</strong> significantly impeded cell migration. Additionally, compound <strong>15</strong> displayed a marked increase in Bax expression by 2.35-fold and caspase-3 levels by 1.12-fold in MCF-7 breast cancer cell line. On the other hand, it caused a downregulation of Bcl-2 level by 0.31-fold. Additionally, the binding relationships produced between compound <strong>15</strong> and the PIM-1 kinase active site were investigated using molecular docking experiments, providing insights into their inhibitory potential. Finally, to further assess the stability of the compound <strong>15-</strong>PIM-1 kinase complex and validate the docking results, molecular dynamics (MD) simulations were performed.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 109003"},"PeriodicalIF":4.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090765","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":"Identification and mechanism of hepatoprotective saponins and endogenous metabolites in the sweet variant of Gynostemma pentaphyllum","authors":"Hanghang Wang ,&nbsp;Chen Chen ,&nbsp;Mingzhen Xue ,&nbsp;Yu Zhang ,&nbsp;Keming Chen ,&nbsp;Bingjie Sun ,&nbsp;Peipei Wang ,&nbsp;Xinyi Tong ,&nbsp;Xiong Yu ,&nbsp;Han Li ,&nbsp;Jia Li ,&nbsp;Lihong Hu ,&nbsp;Yi Zang ,&nbsp;Linguo Zhao ,&nbsp;Xiachang Wang ,&nbsp;Yinan Zhang","doi":"10.1016/j.bioorg.2025.108996","DOIUrl":"10.1016/j.bioorg.2025.108996","url":null,"abstract":"<div><div><em>Gynostemma pentaphyllum (</em>Thunb.<em>) Makino</em> has been traditionally utilized as medicinal herb and function food in traditional Chinese medicine for treating chronic hepatic disorders. Sweet variants of <em>G. pentaphyllum</em> collected from different regions of China are cultivated as the primary resources for the preparation of curative products. We and other groups identified a series of dammarane-type triterpenoids enriched in the plant, such as gypenosides LVI and XLVI, as the bioactive components responsible for the hepatoprotective effect. However, their therapeutic potential may be constrained by low oral bioavailability and complex metabolic pathways. This study applied an in vitro analysis of gut microbiome-based metabolism to determine the major pathway of the gypenosides. Structure-activity relationships, pharmacokinetic studies, and pharmacodynamic results revealed that the removal of the C-3 saccharide chain is not only the main metabolic pathway in the intestinal tract but also generates the active hepatoprotective ingredient with higher bioavailability and potency than the proteotype. Notably, the investigation of underlying the mechanism demonstrated that the compounds inhibited the activation of hepatic stellate cells via the AMPK/P300/Smad3 signaling pathway. Collectively, these findings demonstrate that in vivo metabolism is critical for unlocking the therapeutic potential of orally administered sweet variant <em>G. pentaphyllum</em>, as this metabolic process releases active ingredients that overcome the bioavailability limitations of the parent gypenoside.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"Article 108996"},"PeriodicalIF":4.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084606","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}