Histone deacetylase (HDAC) inhibitors exert anti-tumor effects by modulating epigenetic states, cell cycle progression, and immune responses. This includes reactivating tumor suppressor genes, interfering with DNA damage repair processes, and enhancing anti-tumor immune responses. Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors function by blocking the interaction between PD-1 and its ligand PD-L1, thereby restoring and augmenting T cell-mediated anti-tumor immunity. Studies have demonstrated that HDAC inhibitors can upregulate PD-L1 expression, potentially enhancing the efficacy of immune checkpoint inhibitors and improving therapeutic outcomes by modulating the tumor microenvironment. This review article systematically explores the mechanisms of interaction between HDAC and PD-1/PD-L1 in cancer therapy; recent advances in combination treatment strategies; and the current landscape of dual-target inhibitors from a drug design perspective. It provides a detailed discussion on the challenges and future directions associated with the combined application of HDAC inhibition and cancer immunotherapy, as well as the development of dual-function small molecules.
{"title":"Advances in mechanisms, combined therapeutic strategies and dual-target inhibitors for synergistic antitumor effects of HDAC and PD-1/PD-L1 pathway.","authors":"Zhan-Hui Jin, Jun-Jie Xu, Jin-Ying Liu, Ya-Lan Wang, Hui Liu, Yu-Qing Zhao, Yamei Li, Xiaoting Li, Qing-Kun Shen","doi":"10.1016/j.bioorg.2026.109541","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.109541","url":null,"abstract":"<p><p>Histone deacetylase (HDAC) inhibitors exert anti-tumor effects by modulating epigenetic states, cell cycle progression, and immune responses. This includes reactivating tumor suppressor genes, interfering with DNA damage repair processes, and enhancing anti-tumor immune responses. Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors function by blocking the interaction between PD-1 and its ligand PD-L1, thereby restoring and augmenting T cell-mediated anti-tumor immunity. Studies have demonstrated that HDAC inhibitors can upregulate PD-L1 expression, potentially enhancing the efficacy of immune checkpoint inhibitors and improving therapeutic outcomes by modulating the tumor microenvironment. This review article systematically explores the mechanisms of interaction between HDAC and PD-1/PD-L1 in cancer therapy; recent advances in combination treatment strategies; and the current landscape of dual-target inhibitors from a drug design perspective. It provides a detailed discussion on the challenges and future directions associated with the combined application of HDAC inhibition and cancer immunotherapy, as well as the development of dual-function small molecules.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"109541"},"PeriodicalIF":4.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136925","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}
Alcohol-related disorders contribute significantly to morbidity, mortality, and economic burdens worldwide. Excessive alcohol consumption affects almost all organs, particularly liver, intestine, and kidney, by generating excessive free radicals during metabolism, which disrupts cellular epigenetic homeostasis and contributes to the disease onset. One of the effective therapeutic strategy for alcohol-induced toxicity involves the use of immunosuppressants and corticosteroids, but with numerous side effects. The exploration of cost-effective, low-toxicity natural products for alcohol-associated liver disease is of growing interest. Moreover, the mechanistic relationship between oxidative stress-induced epigenetic dysregulation and ethanol-induced toxicity remains unexplored. Based on the above concepts, we investigated the effect of gallic acid (GA), a phytochemical known for its potent antioxidant activity against ethanol-induced hepatotoxicity. WRL 68 cells were treated with ethanol and GA under two different conditions: acute (24 h) and chronic (14 d). GA (30 μM) protected cells from oxidative stress by maintaining the levels of SOD, CAT, GSH, and TBARS in the ethanol-treated group. Under acute exposure to ethanol, GA significantly downregulated miR_21_5p, miR_17_5p, HAT, and HDM, and upregulated miR_199a_5p, miR_129_5p, miR_26b_5p, HDACs, and HMTs expression. GA preserved DNA integrity and prevented the cells from undergoing apoptosis by suppressing the expression of apoptotic genes (Cas 3, Cas 9, and Bax). During chronic exposure to ethanol, GA restored cellular homeostasis by maintaining the epigenetic balance of the cells and attenuated EMT progression in WRL 68 cells. Based on our findings, we suggest that GA can act as an antioxidant and protect cells from epigenetic dyshomeostasis during ethanol exposure. However, extensive analyses, such as protein expression profiling and ChIP assays, are required to understand the mechanistic insights of GA in maintaining the epigenetic balance of cells under ethanol toxicity.
{"title":"Investigating the epigenetic modulating potential of gallic acid during ethanol-induced toxicity: In silico and in vitro approaches.","authors":"Rubin Nishanth Armstrong, Krithika Narayanan, Maheshvare Natesan, Suresh Senthilkumar, Shalini Rajakumar, Sakthi Sree Karthikeyan, Yamunarani Alagudurai, Devipriya Nagarajan, Rekha Arcot, Naiyf S Alharbi, Muthu Thiruvengadam","doi":"10.1016/j.bioorg.2026.109576","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.109576","url":null,"abstract":"<p><p>Alcohol-related disorders contribute significantly to morbidity, mortality, and economic burdens worldwide. Excessive alcohol consumption affects almost all organs, particularly liver, intestine, and kidney, by generating excessive free radicals during metabolism, which disrupts cellular epigenetic homeostasis and contributes to the disease onset. One of the effective therapeutic strategy for alcohol-induced toxicity involves the use of immunosuppressants and corticosteroids, but with numerous side effects. The exploration of cost-effective, low-toxicity natural products for alcohol-associated liver disease is of growing interest. Moreover, the mechanistic relationship between oxidative stress-induced epigenetic dysregulation and ethanol-induced toxicity remains unexplored. Based on the above concepts, we investigated the effect of gallic acid (GA), a phytochemical known for its potent antioxidant activity against ethanol-induced hepatotoxicity. WRL 68 cells were treated with ethanol and GA under two different conditions: acute (24 h) and chronic (14 d). GA (30 μM) protected cells from oxidative stress by maintaining the levels of SOD, CAT, GSH, and TBARS in the ethanol-treated group. Under acute exposure to ethanol, GA significantly downregulated miR_21_5p, miR_17_5p, HAT, and HDM, and upregulated miR_199a_5p, miR_129_5p, miR_26b_5p, HDACs, and HMTs expression. GA preserved DNA integrity and prevented the cells from undergoing apoptosis by suppressing the expression of apoptotic genes (Cas 3, Cas 9, and Bax). During chronic exposure to ethanol, GA restored cellular homeostasis by maintaining the epigenetic balance of the cells and attenuated EMT progression in WRL 68 cells. Based on our findings, we suggest that GA can act as an antioxidant and protect cells from epigenetic dyshomeostasis during ethanol exposure. However, extensive analyses, such as protein expression profiling and ChIP assays, are required to understand the mechanistic insights of GA in maintaining the epigenetic balance of cells under ethanol toxicity.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"172 ","pages":"109576"},"PeriodicalIF":4.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136939","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}
Pub Date : 2026-01-29DOI: 10.1016/j.bioorg.2026.109559
Álvaro Sarabia-Vallejo , José Clerigué , M. Antonia Martín , Pilar López-Alvarado , Chongzhao Ran , J. Carlos Menéndez
Two curcumin derivatives, structurally related to the CRANAD family of compounds, were investigated for their theranostic properties in Alzheimer's disease. They exhibited fluorescence emission in the NIR region (650–690 nm) with a significant Stokes' shift (70–90 nm). Their affinity for Aβ aggregates, oligomers and monomers allows to detect, differentiate and map in vitro the various amyloid species within and around the plaques by fluorescence microscopy. Fluorescence lifetime microscopy, a robust and sensitive technique allowing to visualize biomolecules with high spatial resolution at nanomolar level, was employed to discriminate the less soluble and more toxic species from the more soluble ones by determination of fluorescence lifetime values at the core and the periphery of the β-amyloid plaques, without the need for the use of antibodies. In vivo brain images show that the fluorescence signals of the sensors are 5–6 times higher for transgenic mice with aberrant proteins than wild type mice after intraperitoneal injection, differentiating plaques of amyloid beta (Aβ) protein in real samples in vivo. These experiments also showed a good blood brain barrier penetration of the sensors, which remain in the brain for 90–120 min, opening up the possibility of their therapeutic use. In vitro studies showed a good activity of both compounds as inhibitors of Aβ aggregation into small soluble oligomers and large insoluble aggregates and also the inhibition of tau protein aggregation, both in a dose-dependent manner. These studies confirm that both compounds have an unprecedented profile that justifies their further study as small-molecule theranostic agents in AD.
{"title":"Visualizing and mapping Aβ plaques by curcumin-derived NIR sensors: Multitarget theranostic agents for Alzheimer's disease","authors":"Álvaro Sarabia-Vallejo , José Clerigué , M. Antonia Martín , Pilar López-Alvarado , Chongzhao Ran , J. Carlos Menéndez","doi":"10.1016/j.bioorg.2026.109559","DOIUrl":"10.1016/j.bioorg.2026.109559","url":null,"abstract":"<div><div>Two curcumin derivatives, structurally related to the CRANAD family of compounds, were investigated for their theranostic properties in Alzheimer's disease. They exhibited fluorescence emission in the NIR region (650–690 nm) with a significant Stokes' shift (70–90 nm). Their affinity for Aβ aggregates, oligomers and monomers allows to detect, differentiate and map <em>in vitro</em> the various amyloid species within and around the plaques by fluorescence microscopy. Fluorescence lifetime microscopy, a robust and sensitive technique allowing to visualize biomolecules with high spatial resolution at nanomolar level, was employed to discriminate the less soluble and more toxic species from the more soluble ones by determination of fluorescence lifetime values at the core and the periphery of the β-amyloid plaques, without the need for the use of antibodies. <em>In vivo</em> brain images show that the fluorescence signals of the sensors are 5–6 times higher for transgenic mice with aberrant proteins than wild type mice after intraperitoneal injection, differentiating plaques of amyloid beta (Aβ) protein in real samples <em>in vivo</em>. These experiments also showed a good blood brain barrier penetration of the sensors, which remain in the brain for 90–120 min, opening up the possibility of their therapeutic use. <em>In vitro</em> studies showed a good activity of both compounds as inhibitors of Aβ aggregation into small soluble oligomers and large insoluble aggregates and also the inhibition of tau protein aggregation, both in a dose-dependent manner. These studies confirm that both compounds have an unprecedented profile that justifies their further study as small-molecule theranostic agents in AD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109559"},"PeriodicalIF":4.7,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076911","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}
Pub Date : 2026-01-28DOI: 10.1016/j.bioorg.2026.109574
Xiao-Wei Zhao , Zheng-Biao Zou , Ying-Ying Lin , Ke-Xin Ma , Chun-Lan Xie , Li-Sheng Li , Ying-Ni Pan , Xian-Wen Yang
Two new citrinin analogues (1 and 10) and one new xanthone (17) were isolated from the deep-sea-derived fungus Penicillium sp. 3A00398, along with 55 known compounds. The structures of the new compounds were determined by comprehensive spectroscopic analysis and TD-DFT-based ECD calculations. All isolated compounds were evaluated for their protective effects against RSL3-induced ferroptosis. Penicitrinols Q (1) and B (2), citrinin H1 (4), sclerotinin A (7), 3-hydroxy microxanthone (19), sydowinin A (23), and 2,3,4-trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran (40) exhibited significant effect, with EC₅₀ values below 10 μM. Notably, penicitrinol Q demonstrated the most potent activity, with an EC₅₀ value of 0.48 μM. Further mechanistic investigation revealed that penicitrinol Q exerts the protective role by modulating the expression of the HO-1 gene. This study identifies novel ferroptosis inhibitors and provides new insights into potential therapeutic strategies for ferroptosis-related diseases.
{"title":"Ferroptosis-inhibitory compounds from the deep-sea-derived Penicillium sp.","authors":"Xiao-Wei Zhao , Zheng-Biao Zou , Ying-Ying Lin , Ke-Xin Ma , Chun-Lan Xie , Li-Sheng Li , Ying-Ni Pan , Xian-Wen Yang","doi":"10.1016/j.bioorg.2026.109574","DOIUrl":"10.1016/j.bioorg.2026.109574","url":null,"abstract":"<div><div>Two new citrinin analogues (<strong>1</strong> and <strong>10</strong>) and one new xanthone (<strong>17</strong>) were isolated from the deep-sea-derived fungus <em>Penicillium</em> sp. 3A00398, along with 55 known compounds. The structures of the new compounds were determined by comprehensive spectroscopic analysis and TD-DFT-based ECD calculations. All isolated compounds were evaluated for their protective effects against RSL3-induced ferroptosis. Penicitrinols Q (<strong>1</strong>) and B (<strong>2</strong>), citrinin H1 (<strong>4</strong>), sclerotinin A (<strong>7</strong>), 3-hydroxy microxanthone (<strong>19</strong>), sydowinin A (<strong>23</strong>), and 2,3,4-trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran (<strong>40</strong>) exhibited significant effect, with EC₅₀ values below 10 μM. Notably, penicitrinol Q demonstrated the most potent activity, with an EC₅₀ value of 0.48 μM. Further mechanistic investigation revealed that penicitrinol Q exerts the protective role by modulating the expression of the HO-1 gene. This study identifies novel ferroptosis inhibitors and provides new insights into potential therapeutic strategies for ferroptosis-related diseases.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109574"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076910","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}
Pub Date : 2026-01-28DOI: 10.1016/j.bioorg.2026.109571
Xinyu Zhuang, Han Yang, Fengjiao Zhou, Ruixing Li, Xingyu Zhao, Meijuan Zou, Qing Li
Factor XIa (FXIa) is a promising target for safer anticoagulants. Herein, a series of NBD-based fluorescent probes (FNC2-FNC6) were developed by linking an FXIa inhibitor scaffold to an NBD fluorophore via alkyl chains of varying lengths. Molecular dynamics simulations revealed that shorter linkers, especially a two‑carbon chain, stabilize NBD binding in the FXIa pocket, enhancing fluorescence. Among these probes, FNC2 displayed potent FXIa inhibition (Ki = 14.2 nM) and selectivity over related proteases. It exhibited linear fluorescence increase upon FXIa binding (R2 = 0.9952; LOD = 1.19 μg/mL), enabling accurate quantification in immunoglobulin products (recovery: 94.41%-103.76%; RSD < 2%). FNC2 visualized FXIa in human plasma clots with 2.7-fold higher signal than free NBD, suppressed dose-dependently by asundexian. This structure-guided approach yields selective probes for FXIa detection and thrombus imaging.
{"title":"Development of selective NBD-based fluorescent probes for in vitro detection of factor XIa and Thrombus imaging.","authors":"Xinyu Zhuang, Han Yang, Fengjiao Zhou, Ruixing Li, Xingyu Zhao, Meijuan Zou, Qing Li","doi":"10.1016/j.bioorg.2026.109571","DOIUrl":"https://doi.org/10.1016/j.bioorg.2026.109571","url":null,"abstract":"<p><p>Factor XIa (FXIa) is a promising target for safer anticoagulants. Herein, a series of NBD-based fluorescent probes (FNC2-FNC6) were developed by linking an FXIa inhibitor scaffold to an NBD fluorophore via alkyl chains of varying lengths. Molecular dynamics simulations revealed that shorter linkers, especially a two‑carbon chain, stabilize NBD binding in the FXIa pocket, enhancing fluorescence. Among these probes, FNC2 displayed potent FXIa inhibition (Ki = 14.2 nM) and selectivity over related proteases. It exhibited linear fluorescence increase upon FXIa binding (R<sup>2</sup> = 0.9952; LOD = 1.19 μg/mL), enabling accurate quantification in immunoglobulin products (recovery: 94.41%-103.76%; RSD < 2%). FNC2 visualized FXIa in human plasma clots with 2.7-fold higher signal than free NBD, suppressed dose-dependently by asundexian. This structure-guided approach yields selective probes for FXIa detection and thrombus imaging.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"109571"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099842","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}
Pub Date : 2026-01-28DOI: 10.1016/j.bioorg.2026.109569
Zhongyuan Guo , Huan Liu , Chenxiaoning Meng , Hong Yang , Xinyue Zhang , Xiaoqian Liu , Zhimin Wang
Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive phenotype and limited treatment options. To address this, we employed ligand-based rational drug design coupled with scaffold hybridization to develop a series of novel procaspase-3 activators. From 28 designed compounds, F17 and F21 emerged as lead candidates, exhibiting superior in vitro procaspase-3 activation. Density functional theory calculations confirmed their enhanced zinc-binding affinity, with adsorption energies (Eads) of −14.8332 eV (F17) and −14.8797 eV (F21), compared to −12.7474 eV for PAC-1, along with stronger electrostatic potential minima (−67.20 and −66.99 kcal/mol, respectively). In silico ADMET profiling indicated favorable drug-like properties, including good aqueous solubility, low blood-brain barrier penetration, and moderate intestinal absorption. In TNBC MDA-MB-231 models, both compounds demonstrated potent anti-proliferative activity, with IC50 values of 25.82 μM (F17) and 25.03 μM (F21) after 48 h, outperforming PAC-1 (33.81 μM). They also significantly inhibited cell migration, reducing wound closure to 11.19% (F21) compared with 20.60% in controls, and induced caspase-3-dependent apoptosis. Importantly, in vivo neurotoxicity assessments revealed no significant neuronal damage at doses up to 50 mg/kg, underscoring their improved safety profile over earlier activators. These results establish F21 as a particularly promising preclinical candidate and provide a rational framework for developing target-specific, neurotoxicity-sparing procaspase-3 activators for TNBC therapy.
{"title":"Rational design of novel procaspase-3 activators for the targeted therapy of triple-negative breast cancer","authors":"Zhongyuan Guo , Huan Liu , Chenxiaoning Meng , Hong Yang , Xinyue Zhang , Xiaoqian Liu , Zhimin Wang","doi":"10.1016/j.bioorg.2026.109569","DOIUrl":"10.1016/j.bioorg.2026.109569","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) remains a formidable clinical challenge owing to its aggressive phenotype and limited treatment options. To address this, we employed ligand-based rational drug design coupled with scaffold hybridization to develop a series of novel procaspase-3 activators. From 28 designed compounds, F17 and F21 emerged as lead candidates, exhibiting superior in vitro procaspase-3 activation. Density functional theory calculations confirmed their enhanced zinc-binding affinity, with adsorption energies (Eads) of −14.8332 eV (F17) and −14.8797 eV (F21), compared to −12.7474 eV for PAC-1, along with stronger electrostatic potential minima (−67.20 and −66.99 kcal/mol, respectively). In silico ADMET profiling indicated favorable drug-like properties, including good aqueous solubility, low blood-brain barrier penetration, and moderate intestinal absorption. In TNBC MDA-MB-231 models, both compounds demonstrated potent anti-proliferative activity, with IC<sub>50</sub> values of 25.82 μM (F17) and 25.03 μM (F21) after 48 h, outperforming PAC-1 (33.81 μM). They also significantly inhibited cell migration, reducing wound closure to 11.19% (F21) compared with 20.60% in controls, and induced caspase-3-dependent apoptosis. Importantly, in vivo neurotoxicity assessments revealed no significant neuronal damage at doses up to 50 mg/kg, underscoring their improved safety profile over earlier activators. These results establish F21 as a particularly promising preclinical candidate and provide a rational framework for developing target-specific, neurotoxicity-sparing procaspase-3 activators for TNBC therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109569"},"PeriodicalIF":4.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076912","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}
The C–H functionalization of coumarin benzenoid ring has been underexplored. In this study, we have carried out the Rh(III)-catalyzed C–H olefination on the benzenoid ring of coumarin at C8 and C6 position using O-carbamate directing group. The method is successfully applied to diverse range of coumarins and acrylates. Further, we have evaluated the synthesized compounds for their anti-inflammatory activity against tumor necrosis factor-alpha production in LPS-stimulated RAW264.7 macrophage cell line. Among the synthesized olefinated coumarin compounds, 4ea and 3ag were able to exhibit potent TNF-α expression inhibition, with IC50 values of 6.297 μM and 11.87 μM, respectively. Further, compound 4ea was also found to inhibit the NF-kB expression. In addition, the interaction of the most potent compound 4ea with TNF-α dimer (PDB ID: 2AZ5) was elucidated by molecular docking and molecular simulation studies.
{"title":"Benzenoid ring C–H olefination of Coumarins under Rh(III)-catalysis: Synthesis, anti-inflammatory evaluation and in silico studies","authors":"Amardeep Singh , Manjeet Chopra , Archit Mukherjee , Akshay Kamble , Alok Jain , Hemant Kumar , Satyasheel Sharma","doi":"10.1016/j.bioorg.2026.109553","DOIUrl":"10.1016/j.bioorg.2026.109553","url":null,"abstract":"<div><div>The C–H functionalization of coumarin benzenoid ring has been underexplored. In this study, we have carried out the Rh(III)-catalyzed C–H olefination on the benzenoid ring of coumarin at C8 and C6 position using <em>O</em>-carbamate directing group. The method is successfully applied to diverse range of coumarins and acrylates. Further, we have evaluated the synthesized compounds for their anti-inflammatory activity against tumor necrosis factor-alpha production in LPS-stimulated RAW264.7 macrophage cell line. Among the synthesized olefinated coumarin compounds, <strong>4ea</strong> and <strong>3ag</strong> were able to exhibit potent TNF-α expression inhibition, with IC<sub>50</sub> values of 6.297 μM and 11.87 μM, respectively. Further, compound <strong>4ea</strong> was also found to inhibit the NF-kB expression. In addition, the interaction of the most potent compound <strong>4ea</strong> with TNF-α dimer (PDB ID: <span><span>2AZ5</span><svg><path></path></svg></span>) was elucidated by molecular docking and molecular simulation studies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109553"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076852","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}
Pub Date : 2026-01-27DOI: 10.1016/j.bioorg.2026.109539
Venkatramanan Kumar , Mariya Tom , R.M. Santhosini , Reeshma Begam , S. Jayashree , S.M. Jaimohan
Protein misfolding and aggregation are central pathological processes underlying amyloidosis, a group of disorders characterized by the deposition of insoluble amyloid fibrils. These toxic aggregates form due to conformational destabilization and exposure of hydrophobic protein regions, leading to aberrant interactions that disrupt normal cellular functions. Amyloid fibrillation is a key pathological event in both neurodegenerative and systemic disorders. In metabolic and systemic amyloidosis, such as lysozyme derived and insulin derived amyloidosis, peripheral fibril deposition leads to progressive organ dysfunction, while cerebral amyloid accumulation is associated with neurodegenerative diseases like Alzheimer’s. To inhibit protein aggregation and destabilize preformed fibrils, a wide range of amyloid inhibitors has been explored. While naturally derived molecules offer some anti-amyloid activity, their limitations have driven growing interest in synthetic and semi-synthetic organic molecules, repurposed drugs, organic dyes, and short peptides. These agents offer enhanced chemical versatility, improved biocompatibility, and the ability to modulate multiple stages of amyloid aggregation. This review provides an overview of the molecular mechanisms of protein misfolding and recent advances in the molecular design, structure–activity relationships, and evaluation of synthetic and semi-synthetic amyloid inhibitors. Using lysozyme and insulin as model systems, we highlight emerging strategies for anti-amyloidogenic intervention.
{"title":"Recent advances in small molecules for amyloid fibril inhibition: chemical strategies and molecular mechanistic insights from lysozyme and insulin models","authors":"Venkatramanan Kumar , Mariya Tom , R.M. Santhosini , Reeshma Begam , S. Jayashree , S.M. Jaimohan","doi":"10.1016/j.bioorg.2026.109539","DOIUrl":"10.1016/j.bioorg.2026.109539","url":null,"abstract":"<div><div>Protein misfolding and aggregation are central pathological processes underlying amyloidosis, a group of disorders characterized by the deposition of insoluble amyloid fibrils. These toxic aggregates form due to conformational destabilization and exposure of hydrophobic protein regions, leading to aberrant interactions that disrupt normal cellular functions. Amyloid fibrillation is a key pathological event in both neurodegenerative and systemic disorders. In metabolic and systemic amyloidosis, such as lysozyme derived and insulin derived amyloidosis, peripheral fibril deposition leads to progressive organ dysfunction, while cerebral amyloid accumulation is associated with neurodegenerative diseases like Alzheimer’s. To inhibit protein aggregation and destabilize preformed fibrils, a wide range of amyloid inhibitors has been explored. While naturally derived molecules offer some anti-amyloid activity, their limitations have driven growing interest in synthetic and semi-synthetic organic molecules, repurposed drugs, organic dyes, and short peptides. These agents offer enhanced chemical versatility, improved biocompatibility, and the ability to modulate multiple stages of amyloid aggregation. This review provides an overview of the molecular mechanisms of protein misfolding and recent advances in the molecular design, structure–activity relationships, and evaluation of synthetic and semi-synthetic amyloid inhibitors. Using lysozyme and insulin as model systems, we highlight emerging strategies for anti-amyloidogenic intervention.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109539"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076752","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}
Pub Date : 2026-01-27DOI: 10.1016/j.bioorg.2026.109567
Diego Dal Ben, Catia Lambertucci, Michela Buccioni, Beatrice Francucci, Andrea Spinaci, Rosaria Volpini, Gabriella Marucci
The G protein-coupled receptor GPR17 is expressed by neuronal cells in various brain areas, where it modulates oligodendrocytes maturation and differentiation and myelination process. The altered expression and activity of this receptor are associated with neurodegenerative processes like myelinating disorders, brain ischemia, and multiple sclerosis. Hence, the development of pharmacological tools able to modulate GPR17 activity may represent a potential key strategy to treat CNS disorders. In this work, we developed adenine nucleotides consisting in 5′-triphosphate derivatives, their α,β- or β,γ-modified triphosphate analogues, and 3′,5′-bisphosphate derivatives, with the adenine core presenting further modifications given by the presence of substituents at the 2- and/or N6-position. Results of biological evaluation at HEK293 L9–2 cells transiently transfected with human GPR17 demonstrated that the novel compounds are endowed with nanomolar or picomolar potency and various profiles of efficacy. GPR17 selectivity of these molecules was also demonstrated by evaluating them at HEK293 L9–2 cells transiently transfected with human purinergic P2Y12, P2Y13, and P2Y14 receptors.
{"title":"Adenine nucleotides as potent and selective GPR17 modulators","authors":"Diego Dal Ben, Catia Lambertucci, Michela Buccioni, Beatrice Francucci, Andrea Spinaci, Rosaria Volpini, Gabriella Marucci","doi":"10.1016/j.bioorg.2026.109567","DOIUrl":"10.1016/j.bioorg.2026.109567","url":null,"abstract":"<div><div>The G protein-coupled receptor GPR17 is expressed by neuronal cells in various brain areas, where it modulates oligodendrocytes maturation and differentiation and myelination process. The altered expression and activity of this receptor are associated with neurodegenerative processes like myelinating disorders, brain ischemia, and multiple sclerosis. Hence, the development of pharmacological tools able to modulate GPR17 activity may represent a potential key strategy to treat CNS disorders. In this work, we developed adenine nucleotides consisting in 5′-triphosphate derivatives, their α,β- or β,γ-modified triphosphate analogues, and 3′,5′-bisphosphate derivatives, with the adenine core presenting further modifications given by the presence of substituents at the 2- and/or <em>N</em><sup>6</sup>-position. Results of biological evaluation at HEK293 L9–2 cells transiently transfected with human GPR17 demonstrated that the novel compounds are endowed with nanomolar or picomolar potency and various profiles of efficacy. GPR17 selectivity of these molecules was also demonstrated by evaluating them at HEK293 L9–2 cells transiently transfected with human purinergic P2Y<sub>12</sub>, P2Y<sub>13</sub>, and P2Y<sub>14</sub> receptors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109567"},"PeriodicalIF":4.7,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076747","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}
Pub Date : 2026-01-27DOI: 10.1016/j.bioorg.2026.109565
Hazal Eken , Derya Osmaniye , Berkant Kurban , Cansu Yıldız , Rana Arslan
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 (4a–4f) were synthesized and initially evaluated by molecular docking. Based on docking scores comparable to celecoxib, three compounds (4d, 4e, 4f) were selected for in vivo pharmacological testing.
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 4d, 4e, and 4f 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.
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.
{"title":"Novel thiadiazole derivatives: synthesis, in silico, in vitro and in vivo evaluation of analgesic and anti-inflammatory activities","authors":"Hazal Eken , Derya Osmaniye , Berkant Kurban , Cansu Yıldız , 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":"2026-01-27","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}
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