Bioorganic Chemistry最新文献

{"title":"Self-assembly nanostructured polysulfoniums as antimicrobial potentiator targeted bacterial membrane reversing antimicrobial resistance","authors":"Lu Han ,&nbsp;Yao Deng ,&nbsp;Ying-Xin He ,&nbsp;Si-Ting Li ,&nbsp;Lu-lu Tan ,&nbsp;Zhi-Peng Li ,&nbsp;Xiao-Ping Liao ,&nbsp;Hao Ren ,&nbsp;Chaoqun Zhang ,&nbsp;Jian Sun","doi":"10.1016/j.bioorg.2026.109556","DOIUrl":"10.1016/j.bioorg.2026.109556","url":null,"abstract":"<div><div>Antimicrobial resistance (AMR) poses a critical public health threat, primarily driven by the misuse and overuse of antimicrobials in both veterinary and public healthcare systems. In the face of accelerating AMR and a dwindling antibiotic pipeline, the strategic deployment of adjuvant therapies presents a promising approach to potentiate current antibiotics and combat resistant pathogens. Herein, we designed a series of sulfur-based cationic polymers polysulfoniums to obtain a potential antimicrobial adjuvant tackling AMR infections. These polysulfoniums presented effective activity against Gram-positive and Gram-negative bacteria with minimum inhibition concentrations (MICs) of 2 μg/mL. Furthermore, polysulfoniums can completely eradicate bacteria under both aerobic and anaerobic conditions within 2 h. In-depth mechanistic studies revealed that polysulfoniums exhibited bactericidal activities by disrupting outer membrane and the redox balance. Moreover, polysulfoniums helped antimicrobial to enter the bacterial cytoplasm, and the combination of 1,10-PS+ with antimicrobial agent including gentamicin, florfenicol, and ciprofloxacin were an efficient approach to eliminate the bacteria and restored the antimicrobial effectiveness. Additionally, the combination of 1,10-PS+ and ciprofloxacin exhibited robust bactericidal effects, effectively reducing <em>Salmonella</em> colonization <em>in vivo</em>. Overall, this research shed new light on polysulfoniums as antibacterial potentiator, offering viable strategies to restore antimicrobial sensitivity and enable environmentally sustainable clinical applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109556"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122910","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":"MgO nanoparticles formulated from konjac glucomannan and its therapeutic potential","authors":"Sekar Vijayakumar ,&nbsp;Zaira I. González Sánchez ,&nbsp;Mani Divya ,&nbsp;Esteban F. Durán-Lara ,&nbsp;Kanchanlata Tungare ,&nbsp;Samiksha Garse ,&nbsp;Yonggang Peng ,&nbsp;Ying Yu ,&nbsp;Thandapani Gomathi ,&nbsp;Kumar Netha ,&nbsp;Viswanathan Kalaiselvi ,&nbsp;Palanisamy Yasotha ,&nbsp;Mingchun Li","doi":"10.1016/j.bioorg.2026.109575","DOIUrl":"10.1016/j.bioorg.2026.109575","url":null,"abstract":"<div><div>Konjac glucomannan (KGM) was utilized as a novel, natural capping and stabilizing agent for the green synthesis of magnesium oxide nanoparticles (MgO NPs) with potential biomedical applications. The synthesized KGM-MgO NPs were predominantly spherical with mild aggregation and an average particle size of 13.34 nm, as confirmed by transmission electron microscopy. The biological performance of the nanoparticles was evaluated through antioxidant, hemocompatibility, and cytotoxicity assays, together with <em>in vivo</em> wound healing, in ovo angiogenesis, and phytotoxicity studies. The KGM-MgO NPs exhibited moderate antioxidant activity and remained non-hemolytic up to 100 μg/mL, while inducing a concentration-dependent reduction in viability of A2780 ovarian cancer cells. <em>In vivo</em> wound healing experiments demonstrated that a 1 wt% KGM-MgO NPs formulation significantly enhanced wound contraction (82% by day 14), accompanied by improved collagen deposition and re-epithelialization. No adverse effects on vascular architecture were observed in the chick chorioallantoic membrane model, and no phytotoxic effects were detected in <em>Vigna radiata</em>. These findings establish KGM as an effective biopolymer capping agent for MgO nanoparticles and support their suitability for wound healing and related biomedical applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109575"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098618","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":"Discovery of mangiferin lipophilic amide derivatives as novel fatty acid synthase inhibitors with potent anti-hepatocellular carcinoma activity","authors":"Yin Li ,&nbsp;Liu-Shun Wu ,&nbsp;Meng-Ting Lyu ,&nbsp;Ying Li ,&nbsp;Tong-Sheng Wang ,&nbsp;Feng-Qing Xu ,&nbsp;De-Ling Wu ,&nbsp;Wu-Xi Zhou","doi":"10.1016/j.bioorg.2026.109592","DOIUrl":"10.1016/j.bioorg.2026.109592","url":null,"abstract":"<div><div>Fatty acid synthase (FASN), which is highly expressed in multiple cancers, contributes critically to cancer cell survival, proliferation, and metastasis, rendering it a promising target for therapeutic intervention. To develop novel and efficient FASN inhibitors, a series of lipophilic amide fragments were introduced into the natural inhibitor mangiferin (MGF) to synthesize new MGF derivatives. Among these derivatives, compound <strong>4</strong> demonstrated notable antiproliferative activity against human hepatocellular carcinoma cell lines with high FASN expression. In particular, <strong>4</strong> exhibited the most potent activity against Hep-G2 cells (IC₅₀ = 0.47 ± 0.06 μM), demonstrating 185-fold greater potency than MGF (IC₅₀ = 87.24 ± 2.06 μM). The capability to bind to FASN and inhibit its activity was significantly stronger than that of MGF. Further investigations revealed that <strong>4</strong> was involved in blocking the activation of PI3K/AKT pathway, thereby inducing reactive oxygen species production and promoting cancer cells apoptosis. Moreover, <strong>4</strong> exhibited a high selectivity index toward Hep-G2 cells (SI = 260.00) and inhibited the migration and invasion of Hep-G2 cells. These findings may serve as a valuable reference for the development of novel FASN inhibitors exhibiting potent anti-hepatocellular carcinoma activity.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109592"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117047","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":"Discovery and structure-activity relationship of cannabidiol aminoquinones as anti-Alzheimer's agents via dual modulation of Nrf2/HO-1 and TLR4/NF-κB pathways","authors":"Ziwen Zhang ,&nbsp;Shan Gao ,&nbsp;Jie Zhao ,&nbsp;Xiaodan Liu ,&nbsp;Fangfang Zuo ,&nbsp;Yinxin Wu ,&nbsp;Ling Ai ,&nbsp;Wenjian Tang","doi":"10.1016/j.bioorg.2026.109590","DOIUrl":"10.1016/j.bioorg.2026.109590","url":null,"abstract":"<div><div>Neuroinflammation and oxidative stress are recognized as key drivers of neuronal death and the progression of neurodegenerative diseases. At the same time, they serve as central hubs linking the major pathological hallmarks of Alzheimer's disease (AD), including A<em>β</em> aggregation, tau protein hyperphosphorylation, neurofibrillary tangle formation, and neuronal injury. In this study, we screened natural active molecules of cannabidiol (CBD) and its derivatives, and conducted molecular docking simulations. A class of CBD aminoquinone scaffolds with potential anti-AD activity was identified, and 32 CBD aminoquinone derivatives were synthesized for comprehensive in vitro and in vivo evaluation. Among them, compound <strong>G-12</strong> with <em>p</em>-F-aniline moiety exhibited potent anti-inflammatory activity (IC₅₀ = 1.39 μM), outstanding neuroprotective effects (IC₅₀ = 1.29 μM), and prominent behavioral manifestations. In addition, <strong>G-12</strong> displayed acceptable in vivo pharmacokinetic (PK) properties. The superior performance of <strong>G-12</strong> indicated that through the Nrf2/HO-1 oxidative stress pathway, it affected the TLR4/NF-<em>κ</em>B inflammatory pathway, inhibited neuroinflammation, and thereby influenced A<em>β</em> aggregation, protecting neurons. This strategy that links several major pathological features of AD is effective in combating AD. <strong>G-12</strong> is also a lead compound with the potential to be developed into a multifunctional drug for AD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109590"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123203","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, catalyst-free synthesis, DFT study and anticancer assessment of new 2,9-disubstituted purine-6-carboxamides","authors":"Joydeep Chatterjee ,&nbsp;Shivkanya M. Bhujbal ,&nbsp;Gaurav Joshi ,&nbsp;Uttam Kumar Mishra ,&nbsp;Ashoke Sharon ,&nbsp;Muskan ,&nbsp;Shivam Singh ,&nbsp;Muhammad Wahajuddin ,&nbsp;Prasad V. Bharatam ,&nbsp;Rajdeep Dalal ,&nbsp;Raj Kumar","doi":"10.1016/j.bioorg.2026.109529","DOIUrl":"10.1016/j.bioorg.2026.109529","url":null,"abstract":"<div><div>A green, catalyst-free synthesis of seventeen new 2,9-disubstituted purine-6-carboxamides (<strong>5</strong> and <strong>6</strong>) designed as EGFR inhibitors in high yields (85–93%) was accomplished. DFT analysis revealed the formation of an energetically favorable oxazolidine transition state with a lower activation barrier compared to alternative pathways, supporting the experimentally observed selectivity. In vitro anticancer activity against A549 lung cancer cells demonstrated dose-dependent growth inhibition, with IC₅₀ values ranging from 4.35 to 22.1 μM, and compound <strong>6E</strong> emerged as the most potent derivative. It exhibited superior activity compared to the reference drug erlotinib, with a cellular IC₅₀ of 4.35 μM vs 11.83 μM and an EGFR enzymatic IC₅₀ of 105.96 nM vs 218.47 nM, indicating approximately 2-fold enhanced potency. Flow cytometric analysis demonstrated that compound <strong>6E</strong> significantly reduced p-PI3K levels, comparably to erlotinib, indicating effective suppression of EGFR–AKT downstream signaling at the cellular level. Mechanistic investigations demonstrated that <strong>6E</strong> increased ROS generation, induced mitochondrial depolarisation, and promoted apoptotic cell death. Further, molecular docking and MD simulations of the <strong>6E</strong>-EGFR complex highlighted key amino acid interactions, corroborating the observed in vitro EGFR inhibition.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109529"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146123180","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 thiadiazole derivatives: synthesis, in silico, in vitro and in vivo evaluation of analgesic and anti-inflammatory activities","authors":"Hazal Eken ,&nbsp;Derya Osmaniye ,&nbsp;Berkant Kurban ,&nbsp;Cansu Yıldız ,&nbsp;Rana Arslan","doi":"10.1016/j.bioorg.2026.109565","DOIUrl":"10.1016/j.bioorg.2026.109565","url":null,"abstract":"<div><div>Pain and inflammation are closely linked pathophysiological processes contributing to numerous diseases. However, current pharmacological treatments are limited by adverse effects and incomplete efficacy, underscoring the need for safer alternatives. Thiadiazole derivatives have emerged as promising candidates due to their broad biological activities and cyclooxygenase-2 (COX-2) inhibitory potential. In this study, six novel thiadiazole derivatives (<strong>4a–4f</strong>) were synthesized and initially evaluated by molecular docking. Based on docking scores comparable to celecoxib, three compounds (<strong>4d</strong>, <strong>4e</strong>, <strong>4</strong> <strong>f</strong>) were selected for <em>in vivo</em> pharmacological testing.</div><div>Central analgesic activity was assessed using the hot-plate and tail-immersion tests, peripheral analgesic effects were evaluated by the acetic acid-induced writhing test, and anti-inflammatory properties were investigated in the carrageenan-induced paw edema model. Compounds <strong>4d</strong>, <strong>4e</strong>, and <strong>4</strong> <strong>f</strong> significantly prolonged reaction times in thermal nociception assays and attenuated writhing responses, indicating both central and peripheral analgesic activity. In the paw edema model, all three derivatives effectively reduced inflammation.</div><div>Molecular docking analyses further confirmed stable COX-2 binding interactions, supporting their selective inhibitory potential. Collectively, these findings suggest that the newly synthesized thiadiazole derivatives hold potential as analgesic and anti-inflammatory drug candidates and needs to be evaluated through comprehensive preclinical and clinical studies in future.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109565"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098617","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 of EEF1A1 as a therapeutic target in TNBC: Anticancer action of a novel Penicillide-derived inhibitor through ribosomal protein regulation","authors":"Jing Yu ,&nbsp;Ru-Yi Chen ,&nbsp;Yan-Jun Liu ,&nbsp;Fang-Jian Feng ,&nbsp;Yu-Jia Li ,&nbsp;Yan-Jie Hu ,&nbsp;Guan-Jun Yang ,&nbsp;Jiong Chen ,&nbsp;Li-Jian Ding","doi":"10.1016/j.bioorg.2026.109602","DOIUrl":"10.1016/j.bioorg.2026.109602","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is one of the most prevalent and aggressive subtypes of breast cancer worldwide, contributing significantly to cancer-related mortality in women. Due to the absence of effective targeted therapies, there is an urgent need to identify novel molecular targets and bioactive compounds for TNBC treatment. Eukaryotic elongation factor 1A1 (EEF1A1), a key regulator of protein synthesis through its role in peptide chain elongation, has emerged as a potential therapeutic candidate; however, its functional role in TNBC remains poorly understood.</div><div>In this study, we isolated a series of Penicillide-like compounds from the mycelium of <em>Penicillium</em> sp. NBU2256, designated as compounds <strong>1</strong>–<strong>5</strong>. Using CCK-8 cytotoxicity assays, compound <strong>2</strong> was identified as the most potent inhibitor of TNBC cell viability. Subsequent mechanistic investigations revealed that compound <strong>2</strong> induced apoptosis, triggered cell cycle arrest, and modulated cancer stem cell properties. To elucidate its molecular target, we employed drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA), which identified EEF1A1 as a direct binding partner of compound <strong>2</strong>. Network pharmacology analysis further predicted RPL27A and RPLP0 as downstream effectors of EEF1A1 signaling. Functional validation using actinomycin D and cycloheximide treatments demonstrated that compound <strong>2</strong> suppresses RPL27A and RPLP0 expression at the translational level, thereby inhibiting tumor cell invasion and migration and exerting robust antitumor effects.</div><div>Collectively, these findings provide novel insights into the anticancer mechanisms of EEF1A1-targeting agents and highlight EEF1A1 as a promising therapeutic target for the treatment of TNBC.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109602"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155587","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":"Multimerization approach to improve a cell surface plectin binding cancer stem cell targeted peptoid drug‑lead","authors":"Charles Owusu Ansah ,&nbsp;D. Gomika Udugamasooriya","doi":"10.1016/j.bioorg.2026.109578","DOIUrl":"10.1016/j.bioorg.2026.109578","url":null,"abstract":"<div><div>Cancer stem cells (CSCs) or tumor-initiating cells represent a drug-resistant subpopulation with self-renewal and metastatic capacity. There are no CSC-specific drugs that have been developed so far. Plectin is a cytoskeletal protein that uniquely translocates to the outer cell membrane (surface translocated plectin - STP) in CSCs and contributes to proliferation, migration, invasion, and metastasis. We previously identified an STP targeted peptoid-PCS2, and the dimeric version PCS2D1.2, which selectively binds to non-small cell lung cancer (NSCLC) derived CSCs, displayed both in vitro and in vivo anti-cancer activity. The current study reports the identification of the minimum pharmacophore and the optimization of PCS2D1.2 to obtain an improved version of trimeric peptoid PCS2T3.9. Various multimerization strategies with linker optimization and truncation of non-important residues resulted in PCS2T3.9, which demonstrated 21-fold improvement of the cytotoxic activity against high STP expressing H358 non-small cell lung cancer (NSCLC) cells, while showing minimum effects on low STP expressing H460 cells. PCS2T3.9 had no cytotoxic activity on normal bronchial epithelial HBEC-3KT cells. Furthermore, PCS2T3.9 effectively suppressed colony formation and cell migration—hallmarks of CSC phenotype—specifically in H358 cells but not in H460 cells. These findings strongly correlate high STP expression with cancer stemness characteristics and confirm the selective targeting of PCS2T3.9 on CSCs, producing anti-cancer activity. The highly specific and selective cytotoxic effects of PCS2T3.9 on STP-enriched CSCs offer a significant therapeutic advantage by potentially minimizing off-target effects on normal tissues, establishing this peptoid as a promising candidate for CSC-specific NSCLC therapy development.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109578"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122928","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":"Antimicrobial peptides RI8 and RW8 target bacterial membranes and genomic DNA to overcome drug resistance","authors":"Ziwei Gao ,&nbsp;Meng-Yue Zhang ,&nbsp;Yan-Liang Cheng ,&nbsp;Yi-Fan Shi ,&nbsp;Xiao-Le Shan ,&nbsp;Zi-Xuan Zhang ,&nbsp;Yu-Ling Han ,&nbsp;Shuang Li","doi":"10.1016/j.bioorg.2026.109599","DOIUrl":"10.1016/j.bioorg.2026.109599","url":null,"abstract":"<div><div>The global rise of multidrug-resistant (MDR) pathogens invalidates conventional antibiotics, while natural antimicrobial peptides (AMPs) lack proteolytic stability and precise targeting. This study reports a protease-resistant symmetric (RRYY)₂P(YYRR)₂ scaffold (Y = isoleucine/tryptophan) with alternating cationic-hydrophobic repeats, a central proline hinge, and palindromic topology for dual bacterial membrane-genomic DNA targeting. Two derived peptides, RI8 and RW8, were characterized: RI8 showed broad-spectrum activity against MDR pathogens (MIC: 2–16 μg/mL), high therapeutic index (39.4), negligible hemolysis (&lt;1% at 128 μg/mL), and retained efficacy in physiological salts/serum. RW8 exhibited robust protease resistance (1–2× MIC vs trypsin/chymotrypsin, 0.5× MIC vs 8 mg/mL pepsin for 8 h) and <em>Staphylococcus aureus</em> biofilm inhibition (71.4% at 2× MIC) via downregulating <em>ica</em>D/<em>ica</em>B/<em>sar</em>A. Mechanistically, both peptides disrupted bacterial membranes and bound genomic DNA; molecular dynamics simulations confirmed membrane insertion via helix-to-coil transition. In murine models, RI8/RW8 accelerated MDR-infected wound healing and reduced bacterial burdens by 2–5 logs; for <em>S. aureus</em> pneumonia, they outperformed levofloxacin (3–5 vs 2 logs bacterial load reduction) and restored immune function (improved thymus index, reduced pro-inflammatory cytokines). This work establishes a symmetric peptide scaffold as a versatile AMP platform, with RI8 showing promise for systemic MDR infections and RW8 for localized biofilm-associated infections. Overall, these findings highlight a rational design strategy that may help address key translational limitations of conventional antibiotics.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109599"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130465","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":"Modulating the cytotoxic activity of Titanocene complexes through aliphatic chain modification to optimize albumin affinity","authors":"Alicia Maldonado Medina ,&nbsp;Virginia Pérez-Garrido ,&nbsp;Irene Sevilla Carrillo ,&nbsp;Ana María Rodríguez ,&nbsp;Isabel Martinez-Argudo ,&nbsp;Rosario Serrano ,&nbsp;Juan Ángel Organero ,&nbsp;Raul Calero ,&nbsp;María José Ruiz ,&nbsp;Boiko Cohen","doi":"10.1016/j.bioorg.2026.109607","DOIUrl":"10.1016/j.bioorg.2026.109607","url":null,"abstract":"<div><div>Titanocene complexes are promising antineoplastic agents limited by poor aqueous stability. This study introduces a series of cytotoxic prodrugs designed to overcome inherent drawbacks of titanocene and its derivatives. We demonstrate that by attaching long aliphatic chains and a tridentate dipic-type ligand, we can improve their solubility and stability, while adjusting their affinity for albumin. The presence of the long aliphatic chain and the reduced polarity of the titanocene headgroup favor self-assembly in PBS with an apparent aggregation onset near ∼10⁻⁵ M (onset concentration, OC). However, when albumin protein is present in solution the self-assembly process is strongly affected due to formation of protein-complex adducts and the OC increases almost 10-fold for the derivative with 14 carbon atoms chain and even higher for the 18 carbon atoms ones. Molecular docking studies indicate that the primary interaction site in BSA is IB, away from the classical fatty acid or drug interaction sites. UV–visible absorption and NMR spectroscopies demonstrate that the formed adducts are dynamic and undergo additional conformation changes. Finally, as proof-of-concept, we demonstrate the structure-activity relationship between cytotoxicity and the length of the aliphatic chain. An increase in the length of the aliphatic chain leads to enhanced cellular internalization of titanium, which correlates with greater cytotoxic activity. These results provide the basis for the development of stable and cytotoxic titanocene-based prodrugs with improved albumin protein affinity.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"Article 109607"},"PeriodicalIF":4.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130463","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}