Bioorganic Chemistry最新文献

{"title":"UPLC-Q-TOF-MS/MS guided isolation of phyllanfranchins A–D, two pairs of undescribed cytotoxic dichapetalin hybrid triterpenoid epimers from Phyllanthus franchetianus","authors":"Ying Xin ,&nbsp;Wang-Hui Niu ,&nbsp;Jia-Huan Shang ,&nbsp;Na Li ,&nbsp;Hong-Tao Zhu ,&nbsp;Xing-Zhi Yang ,&nbsp;Hong-Mei Li ,&nbsp;Xiao-Nian Li ,&nbsp;Ying-Jun Zhang","doi":"10.1016/j.bioorg.2026.109598","DOIUrl":"10.1016/j.bioorg.2026.109598","url":null,"abstract":"<div><div>Four new dichapetalin hybrid triterpenoids, namely phyllanfranchins A–D (<strong>1</strong>–<strong>4</strong>), were obtained from the aerial part of <em>Phyllanthus franchetianus</em> H. L'ev. (Phyllanthaceae), by ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) guided isolation strategy. The linkage of the phenethyl fragment with dammarane C-3 and C-29, along with esterification at C-25 by 4-hydroxyphenylpropanoic acid are unique in this unusual class of natural products. Their structures were elucidated by spectroscopic analysis, NMR calculations and DP4+ probability analyses, computational electronic circular dichroism (ECD) methods, and X-ray crystallography. Notably, compounds <strong>1</strong>–<strong>2</strong> and <strong>4</strong> exhibited potential cytotoxicity against six human cancer (HL-60, K562, A549, HepG2, MDA-MB-231, SW480) (IC₅₀ = 3.38–40 <em>μ</em>M) and one normal BEAS-2B (IC₅₀ = 25.3–40 <em>μ</em>M) cell lines. Among them, compound <strong>1</strong> exhibited potent activity against all six tumor cell lines tested (IC₅₀ = 3.38–5.21 <em>μ</em>M), while demonstrating low cytotoxicity towards normal cells (&gt; 40 <em>μ</em>M). Mechanistic studies revealed that compound <strong>1</strong> induces apoptosis in A549 cells by altering the mitochondrial membrane potential via the Bcl-2/Bax signaling pathway.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109598"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172669","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 and antiprotozoal activity of β-carboline-(piperazinyl)-1,3,5-triazine hybrids","authors":"Caroline Fortuna ,&nbsp;Rodolfo Bento Balbinot ,&nbsp;Débora Laís Gonçalves ,&nbsp;Paula Baréa ,&nbsp;Ana Julia Cecatto ,&nbsp;Debora Cristina Baldoqui ,&nbsp;Celso Vataru Nakamura ,&nbsp;Maria Helena Sarragiotto","doi":"10.1016/j.bioorg.2026.109604","DOIUrl":"10.1016/j.bioorg.2026.109604","url":null,"abstract":"<div><div>Neglected tropical diseases, such as leishmaniasis and Chagas disease cause over 50,000 deaths annually and affect millions worldwide. Current drugs are limited due to their toxicity, prolonged treatment, and drug resistance. The <em>β</em>-carboline scaffold has emerged as a privileged nucleus in the search for novel antiprotozoal derivatives. Our previous studies demonstrated the antileishmanial activity of <em>β</em>-carboline-1,3,5-triazine hybrids containing a <em>N</em>-aminoethyl group as linker connecting the nucleus, as well as the antiprotozoal activity of <em>β</em>-carboline-piperazinyl derivatives. Based on these findings, and in literature reports on the potential of piperazine heterocycle, in this work we synthesized novel <em>β</em>-carboline-(piperazinyl)-1,3,5-triazine hybrids (<strong>4a–g</strong>), and evaluated their activity, and of its precursors (<strong>1a–g</strong>), against <em>Leishmania amazonensis</em> and <em>Trypanosoma cruzi</em>. The <em>β</em>-carboline-3-carboxylic acids <strong>1a-e</strong> were weakly active for <em>L</em>. <em>amazonensis</em> promastigotes, with IC₅₀ values in the range of 55.9 to 159.7 μM. For amastigotes, the compounds exhibited moderate activity, with IC₅₀ values in the range of 18.2 to 62.6 μM. The hybrids <strong>4a</strong>, <strong>4c</strong> and <strong>4d</strong> showed potent activity for <em>L</em>. <em>amazonensis</em> promastigotes, with IC₅₀ values in the range of 8.3 to 9.5 μM, and displayed higher activity and selectivity index (SI in the range of 5.40 to 17.3) than the reference drug miltefosine (IC_50pro = 22.71 μM, SI = 2.4). A moderated activity was observed towards <em>L</em>. <em>amazonensis</em> amastigotes (IC₅₀ in the range of 15.1 to 34.9 μM). The β-carboline carboxylic acids (<strong>1a-g</strong>) and <em>β</em>-carboline-(piperazinyl)-1,3,5-triazines (<strong>4a-g</strong>) showed no significant activity against <em>T. cruzi</em> epimastigotes.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109604"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172670","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":"Hydroxyl radical from iridium(III)-based photosensitizer triggers PANoptosis and ferroptosis for hypoxia-tolerant photodynamic immunotherapy","authors":"Yuting Liu ,&nbsp;Tianyi Kang ,&nbsp;Cuiping Shi ,&nbsp;Fangfang Wei ,&nbsp;Yixiu Zhong ,&nbsp;Xin Hong ,&nbsp;Jianglin Zhang ,&nbsp;Kai Li","doi":"10.1016/j.bioorg.2026.109623","DOIUrl":"10.1016/j.bioorg.2026.109623","url":null,"abstract":"<div><div>Exploring photosensitizers that efficiently generate oxygen-independent hydroxyl radical (•OH) and activate highly immunogenic PANoptosis and ferroptosis shows promise in addressing the limited efficacy of photodynamic immunotherapy (PDI) in the hypoxic and immunosuppressive tumor microenvironment (TME). However, challenges still exist due to the unsatisfactory •OH production efficiency in most organic photosensitizers and the unresolved relationship between •OH and PANoptosis. Here, we designed and synthesized two novel iridium(III) complexes, <strong>Ir1</strong> and <strong>Ir2</strong>. Notably, <strong>Ir1</strong> produced more type I/II reactive oxygen species under light versus <strong>Ir2</strong> and the clinically-used Chlorin e6 (Ce6), including a 25-fold higher •OH yield than both controls. Under extreme intracellular hypoxia, where superoxide anion (O₂^•-) and singlet oxygen (¹O₂) were restricted, <strong>Ir1</strong> maintained normoxia-equivalent •OH production, which endowed it with remarkable phototoxicity (IC₅₀ = 0.98 μM) and effective phototoxic index (PI = 3.05). Mechanistically, the •OH produced by <strong>Ir1</strong> induced PANoptosis by increasing the expression of cleaved Caspase-3, GSDMD-N, and p-MLKL, and activated ferroptosis through the GSH-GPX4-LPO axis. Subsequently, <strong>Ir1</strong> induced immunogenic cell death by enhancing the release of damage-associated molecular patterns under hypoxia, leading to a 1.8-fold increase in dendritic cell maturation. In melanoma-bearing mice, <strong>Ir1</strong> achieved 89% reduction in tumor volume and transformed the immunosuppressed “cold” tumors to the inflamed “hot” phenotypes. This work establishes that the efficient •OH generation from iridium(III)-based photosensitizer can synergistically trigger PANoptosis and ferroptosis. This constitutes a viable approach for achieving effective PDI in hypoxic and immunosuppressive TME.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109623"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146211631","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":"Benzalkonium disinfectants as emerging endocrine disruptors: Inhibition of 11β-Hydroxysteroid dehydrogenase 2 in human and rat models via steric and hydrophobic mechanisms: SPR and docking and enzymatic analysis","authors":"Qingyuan Wang ,&nbsp;Huiqian Zhang ,&nbsp;Feilu Wang ,&nbsp;Yubin Xu ,&nbsp;Zixuan Zheng ,&nbsp;Shaowei Wang ,&nbsp;Ren-shan Ge ,&nbsp;Xiaoheng Li","doi":"10.1016/j.bioorg.2026.109594","DOIUrl":"10.1016/j.bioorg.2026.109594","url":null,"abstract":"<div><div>Quaternary ammonium compounds, including benzalkonium chlorides (BACs), have broad uses as disinfectants, preservatives, and surfactants. The escalating application of QACs as disinfectants post-COVID-19 raises significant public health concerns regarding their potential as endocrine disruptors. To investigate this, a systematic literature review was conducted using PubMed, Web of Science, and Scopus databases for the period 2000–2026, identifying a critical gap regarding BAC's effects on glucocorticoid metabolism. The current study therefore aims to explore the suppressive effects of nine BACs on human and rat 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), a steroidogenic enzyme for glucocorticoid inactivation, in human and rat microsomes (placental and renal sources) using HPLC-MS/MS technique and Surface Plasmon Resonance (SPR) assays. BACsblocked 11β-HSD2 depending on alkyl group, with C10⁺ derivatives exhibiting marked activity for human and C12⁺ derivatives for rat enzyme. C16 BAC emerged as the strongest suppressor (IC₅₀ = 4.22 μM against human enzyme; 24.74 μM against rat homolog). SPR assay showed that C16 BAC had a high affinity binding with <em>KD</em> of 1.95 μM while C18 had moderate affinity with <em>KD</em> of 19.5 μM against human 11β-HSD2. Mechanistic studies identified BACs as mixed/noncompetitive inhibitors of 11β-HSD2 in both species. In intact human BeWo cells, C10-C18 BACs effectively suppressed cortisol metabolism at 1–100 μM. Pearson correlation analysis linked inhibitory potency to structural features (LogP, molecular weight, alkyl carbon count, heavy atoms, flex, Fsp³, volume, Sterimol L) for both enzymes. A 3D-QSAR highlighted apolar interactions are critical. Molecular docking further elucidated binding mechanisms, showing that BACs occupy the NAD⁺-binding site via van der Waals, H-bonds, apolar contacts, and charges. Collectively, this study reveals a novel mechanism by which BACs disrupt glucocorticoid metabolism through inhibiting 11β-HSD2. The findings underscore BACs as potent environmental endocrine disruptors, warranting urgent re-evaluation of their safety guidelines<em>.</em></div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109594"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172666","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":"PET imaging of XPO1 engagement with [18F]selinexor: A pharmacodynamic theranostic strategy for multiple myeloma","authors":"Xinlin Zhong ,&nbsp;Lizhen Wang ,&nbsp;Junjie Yan ,&nbsp;Chen Su ,&nbsp;Xinyu Wang ,&nbsp;Donghui Pan ,&nbsp;Yuping Xu ,&nbsp;Chongyang Chen ,&nbsp;Min Yang","doi":"10.1016/j.bioorg.2026.109625","DOIUrl":"10.1016/j.bioorg.2026.109625","url":null,"abstract":"<div><div>Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in multiple myeloma (MM), represents a validated therapeutic target. However, noninvasive imaging approaches capable of assessing XPO1 engagement and pharmacodynamic modulation during therapy remain limited. Here, we present the radiosynthesis and preclinical evaluation of [¹⁸F]selinexor, an XPO1-targeted positron emission tomography (PET) radiotracer derived from the clinically used drug selinexor <em>via</em> an ¹⁸F/¹⁹F isotope exchange method. This labeling approach preserves the parent drug's molecular structure and pharmacological characteristics, enabling <em>in vivo</em> tracking of selinexor. [¹⁸F]Selinexor was synthesized with a radiochemical yield of 23.9 ± 4.1% and molar activity of 0.41 ± 0.08 GBq/μmol. The tracer exhibited favorable stability, XPO1-specific binding, and tumor retention. PET imaging and pharmacokinetic analysis demonstrated rapid systemic distribution followed by slow elimination, closely consistent with known pharmacokinetics of selinexor. Predominant hepatobiliary clearance and prolonged blood retention supported optimal tumor uptake at delayed imaging time points, with tracer uptake peaking at 3 h post-injection in MM.1S (2.92 ± 0.30% ID/g) and NCI-H929 (2.50 ± 0.18% ID/g) xenografts. Uptake was markedly reduced upon blocking, confirming the tracer's <em>in vivo</em> specificity. During therapeutic intervention, repeated selinexor administration effectively suppressed tumor growth and was accompanied by a progressive reduction in tumor uptake from 3.03 ± 0.25% ID/g (day 0) to 0.93 ± 0.13% ID/g (day 15). Notably, this reduction in uptake occurred independently of changes in tumor volume and correlated with decreased XPO1 expression by immunohistochemistry. Conversely, doxorubicin reduced tumor size without affecting uptake, indicating preserved XPO1-associated signal. Together, these findings demonstrate that [¹⁸F]selinexor PET functions as a noninvasive imaging tool for evaluating the <em>in vivo</em> pharmacokinetics and pharmacodynamic behavior of selinexor, and capturing treatment-induced alterations in XPO1 engagement, although further structural optimization will be required prior to potential translation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109625"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172667","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":"An unprecedented potent inhibitor of MV4-11 cells: investigations into the mechanism of action beyond FLT3 inhibition","authors":"Xiuqi Wang ,&nbsp;Rosa Anna DeFilippis ,&nbsp;Huimin Geng ,&nbsp;Neil P. Shah ,&nbsp;Hong-yu Li","doi":"10.1016/j.bioorg.2026.109601","DOIUrl":"10.1016/j.bioorg.2026.109601","url":null,"abstract":"<div><div>Activating mutations in FLT3 occur in 30% of acute myeloid leukemia (AML) cases. The AML patient-derived MV4–11 cell line contains a genetic alteration in FLT3 (“FLT3-ITD”), causing constitutive FLT3 activation. From screening, we identified compound 1 with unprecedently high anti-MV4–11 effects, with IC₅₀ = 0.0021 ± 0.0003 nM. From the dose response curve, the effects of compound 1 are gradual and may have biphasic characteristics. Further studies identified compound 1 as a type-I FLT3 inhibitor with comparable potency to quizartinib and gilteritinib; however, compound 1 is much more potent against MV4–11 cells, indicating that it may have a second molecular mechanism of action independent of FLT3 inhibition. Interestingly, compound 1's high potency is uniquely toward MV4–11 cells, and distinct from other cell lines either with or without FLT3 mutations. Preliminary efforts to unravel this mechanism were undertaken. The results of apoptosis assay and cell cycle analysis showed that the effects of compound 1 on MV4–11 may be biphasic, with an immediate cell cycle stabilizing effect at low picomolar concentrations, and a stronger effect to arrest cell cycle and induce apoptosis at low nanomolar concentrations. However, kinase selectivity profiling demonstrates that other than FLT3, compound 1 lacks strong binding affinities with other kinases. Therefore, the high inhibitory potency of compound 1 on MV4–11 cells appear unlikely to be due to synergism of co-inhibition of FLT3 and any other kinases. Altogether, compound 1 may serve as a promising lead compound for further optimization and research on a potentially new molecular antiproliferative mechanism.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109601"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146147271","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 novel ULK1 inhibitors by virtual screening, synthesis, in vitro assay and molecular dynamics simulations","authors":"Yifan Yang ,&nbsp;Huijie Han ,&nbsp;Jingjing Li ,&nbsp;Chaochun Wei ,&nbsp;Xiaokun Zhang ,&nbsp;Qidi Zhong ,&nbsp;Hong Yan ,&nbsp;Juan Wang","doi":"10.1016/j.bioorg.2026.109628","DOIUrl":"10.1016/j.bioorg.2026.109628","url":null,"abstract":"<div><div>The serine/threonine kinase UNC-51-like autophagy-activating kinase 1 (ULK1) has emerged as a promising target for cancer treatment. This study utilized an integrative approach combining computational and experimental methods to discover novel ULK1 inhibitors. Through molecular fingerprint similarity and shape-based screenings of the ChEMBL database, along with fragment growth modifications of <strong>DCC-3116</strong>, three datasets comprising a total of 1.5 million compounds were generated. A multi-level molecular docking workflow shortlisted 1520 compounds, from which 9 promising candidates (<strong>SX1-SX3</strong>, <strong>D1-D5</strong>, and <strong>CL130</strong>) were identified based on their strong binding modes, favorable binding free energies, and desirable ADMET properties. These candidate compounds were synthesized and demonstrated nanomolar inhibitory activity in the ULK1 ADP-Glo kinase assay. Notably, <strong>D1</strong>-<strong>D3</strong> exhibited significantly higher inhibitory potency compared to the reference <strong>SBI-0206965</strong> (<em>IC</em>_<em>50</em> = 38.19 nM), with <em>IC</em>_<em>50</em> values of 14.91 nM, 0.74 nM, and 1.06 nM, respectively. The anti-proliferation assay of <strong>D1</strong> was conducted on HeLa cells, yielding an <em>IC</em>_<em>50</em> value of 0.83 μM. Molecular dynamics simulations further confirmed the stability of these compounds within the ULK1 binding pocket, while principal component analysis and dynamic cross-correlation matrix analyses revealed distinct conformational and binding behaviors. Binding free energy calculations indicated that the interactions between the candidate compounds and ULK1 were either stronger or comparable to those of <strong>SBI-0206965</strong>. Overall, these results suggest that <strong>SX1</strong>-<strong>SX3</strong>, and <strong>D1-D5</strong> were promising ULK1 inhibitors, providing a solid foundation for further development as potential anticancer drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109628"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172538","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 evaluation of Bis-3,4-dimethoxybenzene-based fibrate derivatives guided by structural simplification and Bioisosterism principle as potential hypolipidemic and hepatoprotective agents","authors":"Ling Ding ,&nbsp;Yuyu An ,&nbsp;Wenjing Li ,&nbsp;Huizi Shangguan ,&nbsp;Haoyu Tu ,&nbsp;Xinya Xu ,&nbsp;Yongheng Shi ,&nbsp;Jiping Liu ,&nbsp;Yundong Xie","doi":"10.1016/j.bioorg.2026.109626","DOIUrl":"10.1016/j.bioorg.2026.109626","url":null,"abstract":"<div><div>Using Phillygenin as the lead compound, a series of fibrate derivatives featuring a bis-3,4-dimethoxyphenyl skeleton were designed and synthesized based on bioelectronic isosterism and structural simplification principles. Preliminary screening using a Triton WR-1339-induced acute hyperlipidemia mouse model revealed that compound T2 significantly reduced triglyceride (TG) and total cholesterol (TC) levels. Further investigation in a high-fat diet-induced chronic hyperlipidemia animal model revealed that T2 not only significantly reduced TG, TC, and low-density lipoprotein cholesterol (LDL-C) levels but also elevated high-density lipoprotein cholesterol (HDL<img>C) levels. Moreover, T2 effectively improved liver injury by significantly reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Histopathological analysis indicated that T2 mitigated hepatic lipid deposition and alleviated liver tissue damage. T2 significantly upregulated the protein expression level of PPAR-α, a key nuclear receptor regulating lipid metabolism in the liver. Simultaneously, T2 exhibits pronounced antioxidant and anti-inflammatory activities. Molecular docking simulations reveal strong binding affinity between T2 and the PPAR-α protein binding site. Collectively, T2 emerges as a potential candidate compound with dual lipid-lowering and hepatoprotective effects, warranting further investigation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109626"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146172668","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":"Triazole-substituted pyrazole–pyrimidine hybrids as anticancer agents: synthesis, cytotoxicity, apoptosis mechanisms, and JAB1-targeted structure-based design","authors":"Fatma Albayrak Halac ,&nbsp;Zeynep Tugay Tulumcu ,&nbsp;Büsra Nur Aydın Kandemir ,&nbsp;Ramazan Altundas ,&nbsp;Kader Sahin ,&nbsp;Ayse Büsranur Celik ,&nbsp;Serdar Durdağı ,&nbsp;Elif Damla Arısan ,&nbsp;Levent Gülüm ,&nbsp;Yusuf Tutar ,&nbsp;Irem Kulu","doi":"10.1016/j.bioorg.2026.109633","DOIUrl":"10.1016/j.bioorg.2026.109633","url":null,"abstract":"<div><div>In this study, twelve new triazole substituted pyrazole-pyrimidine hybrid compounds were synthesized through click reaction and evaluated for their cytotoxic activity against pancreatic, breast, and gastric cancer cell lines. Among the tested compounds, 4e demonstrated the most potent cytotoxic activity, with IC₅₀ values below 10 μM across all evaluated cancer cell lines: Breast cancer cell lines MCF-7 (5.6 ± 1.01 μM), MDA-MB-231 (8.18 ± 1.26 μM), and gastric cancer cell line HGC-27 (5.68 ± 0.45 μM). Furthermore, RT-qPCR analysis revealed that 4e significantly modulated the expression of apoptosis-related genes, notably inducing a marked downregulation of BIRC3, implicating the activation of the mitochondria-mediated intrinsic apoptotic pathway. Flow cytometry confirmed apoptosis induction. Furthermore, computational metabolomic pathway analysis indicated that <strong>4e</strong> altered glucose metabolism, notably affecting genes and metabolites associated with glycolysis and fatty acid biosynthesis. These results highlight compound <strong>4e</strong> as a promising anticancer candidate with dual action on apoptotic signaling and metabolic pathways. Given the potent biological activity of <strong>4e</strong>, further optimization was pursued through a structure-based drug design strategy targeting the oncogenic regulator JAB1, 4e was designed as a scaffold for targeting JAB1. A virtual library of analogues was generated, and all derivatives were docked against the JAB1 crystal structure (PDB ID: 5JOG). Several compounds showed higher docking scores than the co-crystallized ligand (<strong>CSN5i-3</strong>), suggesting enhanced binding affinity. In parallel, binary QSAR models were developed using the MetaCore/MetaDrug platform to predict anticancer activity. Based on the combined docking and QSAR analyses, several promising analogues were identified and proposed for synthesis and subsequent biological evaluation in future studies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109633"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218059","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 serine-derived Phosphinic peptides as potent MMP-13 inhibitors","authors":"Andreas Mores ,&nbsp;Moaz M. Abdou ,&nbsp;Yuxin Xie ,&nbsp;Ruba Kellow ,&nbsp;Rehab H. Abd El-Aleam ,&nbsp;Palmer Sivoko Imbenzi ,&nbsp;Faez Iqbal Khan ,&nbsp;Magdalini Matziari","doi":"10.1016/j.bioorg.2026.109572","DOIUrl":"10.1016/j.bioorg.2026.109572","url":null,"abstract":"<div><div>A streamlined synthetic route was developed to diversify serine-derived phosphinic peptides at the P1 position into dehydroalanine and thio-substituted (cysteine-like) analogues designed to engage the elongated S1 pocket of MMP-13. Three inhibitors (<strong>9</strong>, <strong>10a</strong>, and <strong>10b</strong>) were synthesized and evaluated against MMP-13. Compounds <strong>9</strong> and <strong>10a</strong> showed high-nanomolar inhibition (K_i = 50 nM and 40 nM, respectively), while the naphthyl analogue <strong>10b</strong> was less active (K_i = 100 nM). Compound <strong>10a</strong> was the most potent within this series, although the reference inhibitor <strong>RXP03</strong> remains more potent (K_i = 16 nM). Molecular docking reproduced the crystallographic pose of a co-crystallized ligand (RMSD = 1.24 Å) and indicated binding features consistent with phosphinate–Zn²⁺ coordination, hydrogen-bonding, and hydrophobic contacts in the S1 pocket. Molecular dynamics simulations further supported stable protein–ligand complexes and provided comparative interaction/stability trends among the three inhibitors. SwissADME predictions indicated high polarity and multiple drug-likeness violations, suggesting limited oral absorption and motivating future optimization (<em>e.g.,</em> prodrug/delivery strategies). Selectivity against other MMPs was not assessed in this study.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"173 ","pages":"Article 109572"},"PeriodicalIF":4.7,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146147291","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}