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Novel carbazole-thiadiazole derivatives as α-amylase and α-glucosidase inhibitors: Design, biological evaluation, and computational insights
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-12 DOI: 10.1016/j.bioorg.2025.108243
İrfan Çapan , Mohammed Hawash , Mohammed T. Qaoud , Nidal Jaradat
Diabetes mellitus remains a global health challenge, demanding innovative therapeutic solutions. Herein, we present the design, synthesis, and pharmacological evaluation of a novel series of carbazole-thiadiazole hybrids targeting key enzymes in carbohydrate metabolism. Among the synthesized compounds, 5l emerged as the most potent inhibitor of α-amylase, with an IC50 value of 0.68 µM—far surpassing the efficacy of the standard drug acarbose (IC50: 5.19 µM). Similarly, 5r exhibited exceptional dual activity against both α-amylase and α-glucosidase, with IC50 values of 1.63 µM and 0.14 µM, respectively, highlighting its dual inhibitory potential. Biological assays demonstrated the compounds’ low cytotoxicity on hepatic stellate (LX-2) cells, affirming their safety for therapeutic use. Molecular docking studies provided mechanistic insights into their binding interactions, revealing strong hydrogen bonding and hydrophobic interactions with key active site residues. Density functional theory (DFT) and electrostatic potential (ESP) analyses further elucidated their electronic properties, offering a deeper understanding of their structure–activity relationships. Pharmacokinetic profiling via the BOILED-Egg model confirmed these derivatives’ excellent oral bioavailability and drug-likeness. Collectively, these findings establish carbazole-thiadiazole hybrids as promising candidates for next-generation antidiabetic therapies, warranting further investigation in preclinical and clinical settings.
{"title":"Novel carbazole-thiadiazole derivatives as α-amylase and α-glucosidase inhibitors: Design, biological evaluation, and computational insights","authors":"İrfan Çapan ,&nbsp;Mohammed Hawash ,&nbsp;Mohammed T. Qaoud ,&nbsp;Nidal Jaradat","doi":"10.1016/j.bioorg.2025.108243","DOIUrl":"10.1016/j.bioorg.2025.108243","url":null,"abstract":"<div><div>Diabetes mellitus remains a global health challenge, demanding innovative therapeutic solutions. Herein, we present the design, synthesis, and pharmacological evaluation of a novel series of carbazole-thiadiazole hybrids targeting key enzymes in carbohydrate metabolism. Among the synthesized compounds, <strong>5l</strong> emerged as the most potent inhibitor of α-amylase, with an IC<sub>50</sub> value of 0.68 µM—far surpassing the efficacy of the standard drug acarbose (IC<sub>50</sub>: 5.19 µM). Similarly, <strong>5r</strong> exhibited exceptional dual activity against both α-amylase and α-glucosidase, with IC<sub>50</sub> values of 1.63 µM and 0.14 µM, respectively, highlighting its dual inhibitory potential. Biological assays demonstrated the compounds’ low cytotoxicity on hepatic stellate (LX-2) cells, affirming their safety for therapeutic use. Molecular docking studies provided mechanistic insights into their binding interactions, revealing strong hydrogen bonding and hydrophobic interactions with key active site residues. Density functional theory (DFT) and electrostatic potential (ESP) analyses further elucidated their electronic properties, offering a deeper understanding of their structure–activity relationships. Pharmacokinetic profiling via the BOILED-Egg model confirmed these derivatives’ excellent oral bioavailability and drug-likeness. Collectively, these findings establish carbazole-thiadiazole hybrids as promising candidates for next-generation antidiabetic therapies, warranting further investigation in preclinical and clinical settings.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108243"},"PeriodicalIF":4.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420080","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}
引用次数: 0
Issue TOC
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-12 DOI: 10.1016/S0045-2068(25)00134-8
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引用次数: 0
Decoding structural determinants of aryl hydrocarbon receptor antagonism by monoterpenoids 解码单萜化合物拮抗芳基烃受体的结构决定因素
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-10 DOI: 10.1016/j.bioorg.2025.108265
Iveta Zůvalová , Barbora Vyhlídalová , Karolína Ondrová , Petr Nádvorník , Jiří Hrubý , Peter Illés , Miroslav Soural , Marek Šebela , Lenka Šindlerová , Lukáš Kubala , Sridhar Mani , Zdeněk Dvořák
Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including CO presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, o-cresol, 3-methyl-S-carvone, EN-2). Whereas 3-methyl-S-carvone and EN-2 were non-competitive AhR pan-antagonists, carvacrol and o-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.
{"title":"Decoding structural determinants of aryl hydrocarbon receptor antagonism by monoterpenoids","authors":"Iveta Zůvalová ,&nbsp;Barbora Vyhlídalová ,&nbsp;Karolína Ondrová ,&nbsp;Petr Nádvorník ,&nbsp;Jiří Hrubý ,&nbsp;Peter Illés ,&nbsp;Miroslav Soural ,&nbsp;Marek Šebela ,&nbsp;Lenka Šindlerová ,&nbsp;Lukáš Kubala ,&nbsp;Sridhar Mani ,&nbsp;Zdeněk Dvořák","doi":"10.1016/j.bioorg.2025.108265","DOIUrl":"10.1016/j.bioorg.2025.108265","url":null,"abstract":"<div><div>Monocyclic monoterpenoids carvones have been recently identified as atypical negative allosteric modulators of aryl hydrocarbon receptor (AhR). In the current work, we performed AhR antagonist activity screening of 100 natural and synthetic monoterpenoids, and their analogues. Using SAR approach, structural determinants of AhR antagonist activity were assigned, including C<img>O presence/position, planarity, and C3/C5-alkylation. Applying pyramidal selection criteria, including absence of residual agonist activity, no cytotoxicity, strong antagonist potency, and pan-antagonism against diverse AhR agonists, we distilled four lead AhR antagonists (carvacrol, <em>o</em>-cresol, 3-methyl-<em>S</em>-carvone, EN-2). Whereas 3-methyl-<em>S</em>-carvone and EN-2 were non-competitive AhR pan-antagonists, carvacrol and <em>o</em>-cresol were ligand-selective AhR antagonists acting by unclear mechanism. We characterized in detail the effects of lead compounds at cellular functions of AhR, including AhR nuclear translocation, AhR dimerization with ARNT, and the expression of AhR-regulated genes. As a proof of concept, effects of monoterpenoids in the murine macrophages were investigated.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108265"},"PeriodicalIF":4.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394553","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}
引用次数: 0
Novel (−)-eigallocatechin-3-gallate-erlotinib conjugates via triazole rings inhibit non-small cell lung cancer cells through EGFR signaling pathway
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-08 DOI: 10.1016/j.bioorg.2025.108263
Cheng-Ting Zi , Yi-Long Wu , Zhen-Hao Liu , Yun Niu , Wen-Juan Yuan , Zi-Wei Yang , Xuan-Jun Wang , Xiu-Li Sun , Liu Yang , Jun Sheng
EGFR is frequently overexpressed in non-small cell lung cancer, and EGFR plays a crucial role in the occurrence and progression of malignant tumors. Currently, drug resistance often develops following treatment with EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib. Therefore, It is essential to investigate new compounds that can effectively target EGFR overexpression. The polyphenols epigallocatechin-3-gallate (EGCG), found in tea, have demonstrated anti-cancer properties. In this study, we linked EGCG and erlotinib through a click reaction using polyglycol to form an EGCG-erlotinib conjugated compounds (EGCG-Erls). We then explored its biological activity through various experiments. The results indicated that the compound 10 exhibited a superior inhibitory effect on NCI-H1975 cells, reduced their cloning and migratory capabilities, promoted cell apoptosis, and inhibited cell cycle progression. Furthermore, it was observed that compound 10 can bind to the EGFR protein and effectively inhibit the expression of phosphorylated EGFR (p-EGFR) and its downstream signaling proteins. Overall, the study suggests that compound 10 may induce apoptosis and inhibit cell proliferation via the EGFR signaling pathway, providing a promising avenue for the development of new EGFR inhibitors.
{"title":"Novel (−)-eigallocatechin-3-gallate-erlotinib conjugates via triazole rings inhibit non-small cell lung cancer cells through EGFR signaling pathway","authors":"Cheng-Ting Zi ,&nbsp;Yi-Long Wu ,&nbsp;Zhen-Hao Liu ,&nbsp;Yun Niu ,&nbsp;Wen-Juan Yuan ,&nbsp;Zi-Wei Yang ,&nbsp;Xuan-Jun Wang ,&nbsp;Xiu-Li Sun ,&nbsp;Liu Yang ,&nbsp;Jun Sheng","doi":"10.1016/j.bioorg.2025.108263","DOIUrl":"10.1016/j.bioorg.2025.108263","url":null,"abstract":"<div><div>EGFR is frequently overexpressed in non-small cell lung cancer, and EGFR plays a crucial role in the occurrence and progression of malignant tumors. Currently, drug resistance often develops following treatment with EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib. Therefore, It is essential to investigate new compounds that can effectively target EGFR overexpression. The polyphenols epigallocatechin-3-gallate (EGCG), found in tea, have demonstrated anti-cancer properties. In this study, we linked EGCG and erlotinib through a click reaction using polyglycol to form an EGCG-erlotinib conjugated compounds (EGCG-Erls). We then explored its biological activity through various experiments. The results indicated that the compound <strong>10</strong> exhibited a superior inhibitory effect on NCI-H1975 cells, reduced their cloning and migratory capabilities, promoted cell apoptosis, and inhibited cell cycle progression. Furthermore, it was observed that compound <strong>10</strong> can bind to the EGFR protein and effectively inhibit the expression of phosphorylated EGFR (p-EGFR) and its downstream signaling proteins. Overall, the study suggests that compound <strong>10</strong> may induce apoptosis and inhibit cell proliferation via the EGFR signaling pathway, providing a promising avenue for the development of new EGFR inhibitors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108263"},"PeriodicalIF":4.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386425","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}
引用次数: 0
7S,15R-Stereoisomer of phenylethylamino derivative of colchicine exhibits potent in-vitro and in-vivo anti-cancer activity against prostate Cancer: Assessing the impact of stereochemistry on biological activity
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-08 DOI: 10.1016/j.bioorg.2025.108262
Chilakala Nagarjuna Reddy , Abhisheik Chowdary Eedara , Sumera Malik , Dilip M. Mondhe , Sandip B. Bharate , Sai Balaji Andugulapati
The non-selective toxicity of colchicine remains a major barrier to its development as an anticancer agent. Here, we report a colchicine derivative, 8l, which exhibits potent and selective antiproliferative activity in prostate cancer cells. The present study investigates the impact of stereochemistry at the C10-substituted chiral amine fragment on the biological activity. Our findings reveal that the stereochemical configuration of 8l (7S,15R diastereomer) is critical for its efficacy, showing 12.5-fold greater antiproliferative activity than its counterpart, the 7S,15S diastereomer 8z. Additionally, 8l demonstrates superior α-tubulin polymerization inhibition compared to 8z, that were further corroborated by docking and simulation studies. Mechanistic insights indicate that 8l increases reactive oxygen species levels by modulating the NRF-2/KEAP-1 axis. In vivo, administration of 8l at doses of 0.3 and 0.6 mg/kg significantly suppresses tumor growth in a PC-3 xenograft mouse model. Collectively, this study highlights the therapeutic potential of 8l as a colchicine-based anticancer agent, effectively attenuating tumor progression through modulation of the NRF-2/KEAP-1 axis.
{"title":"7S,15R-Stereoisomer of phenylethylamino derivative of colchicine exhibits potent in-vitro and in-vivo anti-cancer activity against prostate Cancer: Assessing the impact of stereochemistry on biological activity","authors":"Chilakala Nagarjuna Reddy ,&nbsp;Abhisheik Chowdary Eedara ,&nbsp;Sumera Malik ,&nbsp;Dilip M. Mondhe ,&nbsp;Sandip B. Bharate ,&nbsp;Sai Balaji Andugulapati","doi":"10.1016/j.bioorg.2025.108262","DOIUrl":"10.1016/j.bioorg.2025.108262","url":null,"abstract":"<div><div>The non-selective toxicity of colchicine remains a major barrier to its development as an anticancer agent. Here, we report a colchicine derivative, <strong>8l</strong>, which exhibits potent and selective antiproliferative activity in prostate cancer cells. The present study investigates the impact of stereochemistry at the C10-substituted chiral amine fragment on the biological activity. Our findings reveal that the stereochemical configuration of <strong>8l</strong> (7S,15R diastereomer) is critical for its efficacy, showing 12.5-fold greater antiproliferative activity than its counterpart, the 7S,15S diastereomer <strong>8z</strong>. Additionally, <strong>8l</strong> demonstrates superior α-tubulin polymerization inhibition compared to <strong>8z</strong>, that were further corroborated by docking and simulation studies. Mechanistic insights indicate that <strong>8l</strong> increases reactive oxygen species levels by modulating the NRF-2/KEAP-1 axis. <em>In vivo,</em> administration of <strong>8l</strong> at doses of 0.3 and 0.6 mg/kg significantly suppresses tumor growth in a PC-3 xenograft mouse model. Collectively, this study highlights the therapeutic potential of <strong>8l</strong> as a colchicine-based anticancer agent, effectively attenuating tumor progression through modulation of the NRF-2/KEAP-1 axis.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108262"},"PeriodicalIF":4.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386424","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}
引用次数: 0
Insights into curcumin’s anticancer activity in pancreatic ductal adenocarcinoma: Experimental and computational evidence targeting HRAS, CCND1, EGFR and AKT1
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-08 DOI: 10.1016/j.bioorg.2025.108264
Jun-Feng Cao , Xiao Zhang , Qingjie Xia , Kuan Hang , Jie Men , Jin Tian , Dunshui Liao , Zengliang Xia , Kezhou Li

Purpose

Curcumin, as a natural polyphenolic compound, possesses antitumor, antioxidant properties and anti-inflammatory. Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, and there is a lack of molecular mechanisms and therapeutic options regarding relevant therapeutic agents. Therefore, we investigated the mechanism of curcumin inhibiting pancreatic cancer growth by modulating proliferation of cells and cellular metabolism.

Methods

Bioinformatics analysis was involved in analyzing the intersecting targets of curcumin and pancreatic ductal adenocarcinoma. The effect of curcumin on proliferation of PANC-1 cells was tested by CCK-8, and total RNA from PANC-1 was also analysed by transcriptome sequencing. Molecular docking was involved in verifying binding stability of curcumin to protein targets. Molecular dynamics simulated and evaluated binding free energy, hydrogen bonds and root mean square fluctuation of the complex.

Results

PPI, GO and KEGG were involved in screening and analysing key interacting protein targets. 40 μg/mL curcumin significantly inhibited the growth and proliferation of PANC-1. Transcriptome sequencing results showed gene expression of Cyclin D1 (CCND1), AKT serine/threonine kinase 1 (AKT1), HRas proto-oncogene (HRAS), epidermal growth factor receptor (EGFR) was significantly down-regulated by curcumin treatment. Result of molecular dynamics and molecular docking inhibited the free binding energies of CCND1/Curcumin, HRAS/Curcumin, AKT1/Curcumin and EGFR/Curcumin were −21.13 ± 3.41 kcal/mol, −21.84 ± 4.38 kcal/mol, −20.61 ± 1.82 kcal/mol and −27.37 ± 1.94 kcal/mol, respectively.

Conclusion

We found curcumin may not only regulate cell cycle progression in PDAC and apoptosis by down-regulating HRAS, thereby inhibiting CCND1 and its downstream signaling pathways, but also inhibit energy metabolism reprogramming, Ras-RAF-MEK-ERK and other downstream signalling pathways by down-regulating EGFR and AKT1, thereby affecting tumor cell metastasis, survival and proliferation.
{"title":"Insights into curcumin’s anticancer activity in pancreatic ductal adenocarcinoma: Experimental and computational evidence targeting HRAS, CCND1, EGFR and AKT1","authors":"Jun-Feng Cao ,&nbsp;Xiao Zhang ,&nbsp;Qingjie Xia ,&nbsp;Kuan Hang ,&nbsp;Jie Men ,&nbsp;Jin Tian ,&nbsp;Dunshui Liao ,&nbsp;Zengliang Xia ,&nbsp;Kezhou Li","doi":"10.1016/j.bioorg.2025.108264","DOIUrl":"10.1016/j.bioorg.2025.108264","url":null,"abstract":"<div><h3>Purpose</h3><div>Curcumin, as a natural polyphenolic compound, possesses antitumor, antioxidant properties and anti-inflammatory. Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, and there is a lack of molecular mechanisms and therapeutic options regarding relevant therapeutic agents. Therefore, we investigated the mechanism of curcumin inhibiting pancreatic cancer growth by modulating proliferation of cells and cellular metabolism.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was involved in analyzing the intersecting targets of curcumin and pancreatic ductal adenocarcinoma. The effect of curcumin on proliferation of PANC-1 cells was tested by CCK-8, and total RNA from PANC-1 was also analysed by transcriptome sequencing. Molecular docking was involved in verifying binding stability of curcumin to protein targets. Molecular dynamics simulated and evaluated binding free energy, hydrogen bonds and root mean square fluctuation of the complex.</div></div><div><h3>Results</h3><div>PPI, GO and KEGG were involved in screening and analysing key interacting protein targets. 40 μg/mL curcumin significantly inhibited the growth and proliferation of PANC-1. Transcriptome sequencing results showed gene expression of Cyclin D1 (CCND1), AKT serine/threonine kinase 1 (AKT1), HRas proto-oncogene (HRAS), epidermal growth factor receptor (EGFR) was significantly down-regulated by curcumin treatment. Result of molecular dynamics and molecular docking inhibited the free binding energies of CCND1/Curcumin, HRAS/Curcumin, AKT1/Curcumin and EGFR/Curcumin were −21.13 ± 3.41 kcal/mol, −21.84 ± 4.38 kcal/mol, −20.61 ± 1.82 kcal/mol and −27.37 ± 1.94 kcal/mol, respectively.</div></div><div><h3>Conclusion</h3><div>We found curcumin may not only regulate cell cycle progression in PDAC and apoptosis by down-regulating HRAS, thereby inhibiting CCND1 and its downstream signaling pathways, but also inhibit energy metabolism reprogramming, Ras-RAF-MEK-ERK and other downstream signalling pathways by down-regulating EGFR and AKT1, thereby affecting tumor cell metastasis, survival and proliferation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108264"},"PeriodicalIF":4.5,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420078","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}
引用次数: 0
Dihydro-β-agarofuran sesquiterpenoids from the root bark of Tripterygium wilfordii and their anti-neuroinflammatory activities
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-07 DOI: 10.1016/j.bioorg.2025.108236
Hai-Yue Zhao , Zhao-Chun Zhan , Hui-Lin Ou , Tian-Yuan Wu , Hui-Hui Zhu , Qiang Lin , Yao-Lan Li , Jing-Hao Wang , Guang-Xiong Zhou , Qing Tang , Yu-Bo Zhang , Guo-Cai Wang
A phytochemical study of Tripterygium wilfordii root bark was conducted 25 novel dihydro-β-agarofuran sesquiterpenoids (125) and 20 known analogues (2645). Structural analysis elucidated by comprehensive spectroscopic analysis, including X-ray crystallography and electronic circular dichroism (ECD). Anti-neuroinflammatory assessments in BV-2 cells revealed certain compounds effectively suppressed tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). A preliminary structure–activity relationships analysis explored the relationship between compound structure and their inflammatory mediator inhibition. Notably, compound 7 modulated nuclear factor-κB (NF-κB) signaling by inhibiting IκBα and p65 phosphorylation. These findings offer novel perspectives on the bioactivity and anti-neuroinflammatory mechanisms of Tripterygium wilfordii derivatives.
{"title":"Dihydro-β-agarofuran sesquiterpenoids from the root bark of Tripterygium wilfordii and their anti-neuroinflammatory activities","authors":"Hai-Yue Zhao ,&nbsp;Zhao-Chun Zhan ,&nbsp;Hui-Lin Ou ,&nbsp;Tian-Yuan Wu ,&nbsp;Hui-Hui Zhu ,&nbsp;Qiang Lin ,&nbsp;Yao-Lan Li ,&nbsp;Jing-Hao Wang ,&nbsp;Guang-Xiong Zhou ,&nbsp;Qing Tang ,&nbsp;Yu-Bo Zhang ,&nbsp;Guo-Cai Wang","doi":"10.1016/j.bioorg.2025.108236","DOIUrl":"10.1016/j.bioorg.2025.108236","url":null,"abstract":"<div><div>A phytochemical study of <em>Tripterygium wilfordii</em> root bark was conducted 25 novel dihydro-<em>β</em>-agarofuran sesquiterpenoids (<strong>1</strong>–<strong>25</strong>) and 20 known analogues (<strong>26</strong>–<strong>45</strong>). Structural analysis elucidated by comprehensive spectroscopic analysis, including X-ray crystallography and electronic circular dichroism (ECD). Anti-neuroinflammatory assessments in BV-2 cells revealed certain compounds effectively suppressed tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). A preliminary structure–activity relationships analysis explored the relationship between compound structure and their inflammatory mediator inhibition. Notably, compound <strong>7</strong> modulated nuclear factor-κB (NF-κB) signaling by inhibiting IκBα and p65 phosphorylation. These findings offer novel perspectives on the bioactivity and anti-neuroinflammatory mechanisms of <em>Tripterygium wilfordii</em> derivatives.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108236"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394552","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}
引用次数: 0
Chroman-Schiff base derivatives as potential Anti-Tubercular Agents: In silico studies, Synthesis, and Biological evaluation
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-07 DOI: 10.1016/j.bioorg.2025.108249
Samar Mujeeb , Kuldeep Singh , Martha K. Al-Zrkani , Dhurgham Al-Fahad , Syed Misbahul Hasan , Marwah Al Shouber , Fuzail Ahmad , Husian Njem Hameed , Danish Iqbal , Mehnaz Kamal
Tuberculosis (TB) continues to pose a significant public health challenge worldwide. Hydrazide-containing compounds have demonstrated considerable potential as anti- tubercular agents. In this study, we designed, synthesized, and evaluated a series of chroman- Schiff base derivatives, integrating a chroman scaffold with substituted phenyl moieties, as potential therapeutic candidates against TB. In silico studies were conducted to assess the binding interactions of the synthesized derivatives, specifically their R- and S-isomers, with the tuberculosis target protein InhA (PDB ID: 1ZID). Molecular docking revealed that two R-isomer derivatives, SM-5A and SM-6A, exhibited superior binding affinities (−10.6 kcal/mol) compared to the reference ligand INH-NADH (−10.3 kcal/mol) and the natural substrate NADH (−7.5 kcal/mol). Molecular dynamics simulations confirmed the long-term stability of these compound-protein complexes over a 100 ns trajectory, further substantiating their potential as stable inhibitors. The structures of the synthesized derivatives were validated using spectroscopic techniques, including FTIR, 13C NMR, 1H NMR, and HR-MS. Biological evaluation via in vitro anti-tubercular assays against Mycobacterium tuberculosis H37Rv (using the Microplate Alamar Blue Assay) demonstrated that several RRR-isomers displayed notable activity. Among them, SM-2 and SM-5 showed the most potent effects, with minimum inhibitory concentrations (MIC) of 32 µg/mL, comparable to standard anti-tubercular drugs such as isoniazid, ethambutol, and rifampicin. These findings highlight the chroman-schiff base scaffold as a promising foundation for the development of novel anti-tubercular agents. The integration of computational and experimental approaches in this study underscores the potential of these derivatives for further optimization and development into effective anti-tubercular therapeutics.
{"title":"Chroman-Schiff base derivatives as potential Anti-Tubercular Agents: In silico studies, Synthesis, and Biological evaluation","authors":"Samar Mujeeb ,&nbsp;Kuldeep Singh ,&nbsp;Martha K. Al-Zrkani ,&nbsp;Dhurgham Al-Fahad ,&nbsp;Syed Misbahul Hasan ,&nbsp;Marwah Al Shouber ,&nbsp;Fuzail Ahmad ,&nbsp;Husian Njem Hameed ,&nbsp;Danish Iqbal ,&nbsp;Mehnaz Kamal","doi":"10.1016/j.bioorg.2025.108249","DOIUrl":"10.1016/j.bioorg.2025.108249","url":null,"abstract":"<div><div>Tuberculosis (TB) continues to pose a significant public health challenge worldwide. Hydrazide-containing compounds have demonstrated considerable potential as anti- tubercular agents. In this study, we designed, synthesized, and evaluated a series of chroman- Schiff base derivatives, integrating a chroman scaffold with substituted phenyl moieties, as potential therapeutic candidates against TB. <em>In silico</em> studies were conducted to assess the binding interactions of the synthesized derivatives, specifically their R- and S-isomers, with the tuberculosis target protein InhA (PDB ID: 1ZID). Molecular docking revealed that two R-isomer derivatives, <strong>SM-5A</strong> and <strong>SM-6A</strong>, exhibited superior binding affinities (−10.6 kcal/mol) compared to the reference ligand INH-NADH (−10.3 kcal/mol) and the natural substrate NADH (−7.5 kcal/mol). Molecular dynamics simulations confirmed the long-term stability of these compound-protein complexes over a 100 ns trajectory, further substantiating their potential as stable inhibitors. The structures of the synthesized derivatives were validated using spectroscopic techniques, including FTIR, <sup>13</sup>C NMR, <sup>1</sup>H NMR, and HR-MS. Biological evaluation via <em>in vitro</em> anti-tubercular assays against Mycobacterium tuberculosis <em>H<sub>37</sub>Rv</em> (using the Microplate Alamar Blue Assay) demonstrated that several RRR-isomers displayed notable activity. Among them, <strong>SM-2</strong> and <strong>SM-5</strong> showed the most potent effects, with minimum inhibitory concentrations (MIC) of 32 µg/mL, comparable to standard anti-tubercular drugs such as isoniazid, ethambutol, and rifampicin. These findings highlight the chroman-schiff base scaffold as a promising foundation for the development of novel anti-tubercular agents. The integration of computational and experimental approaches in this study underscores the potential of these derivatives for further optimization and development into effective anti-tubercular therapeutics.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108249"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420081","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}
引用次数: 0
A novel PET tracer for noninvasive imaging the checkpoints expression of innate and adaptive immunity in tumors by simultaneously targeting CD24 and PD-L1 一种新型 PET 示踪剂,通过同时靶向 CD24 和 PD-L1 对肿瘤中先天性免疫和适应性免疫的检查点表达进行无创成像
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-07 DOI: 10.1016/j.bioorg.2025.108260
Yijin Zou , Tianshi Que , Penghui Sun , Jiahao Xie , Dazhi Shi , Hubing Wu , Jian-Er Tan
The success of tumor immunotherapy depends on the innate and adaptive immune responses, with CD24 and PD-L1 being key targets. DBP1 peptide is a novel bispecific D-peptide, targeting both CD24 and PD-L1 simultaneously. In this study, by radiolabeling DBP1 peptide, we developed a novel PET modality to noninvasively evaluate CD24 and PD-L1 expressions in tumors. To enhance the solubility of DBP1, a hydrophilic lysine was added into C-terminal residue of the peptide, which was then modified with a chelator NOTA to produce the radiotracer precursor NOTA-DBP1k. NOTA-DBP1k showed high affinity for CD24 (KD = 10.70 ± 0.70 nM) and PD-L1 (KD = 5.40 ± 0.61 nM). [68Ga]Ga-NOTA-DBP1k was synthesized with a high radiochemical yield (71 ± 3.0 %) and exhibited high hydrophilicity and stability. [68Ga]Ga-NOTA-DBP1k showed higher uptake in high CD24/PD-L1 expressed MCF-7 cells than that in low CD24/PD-L1 expressed U-87MG cells in vitro. In vivo, [68Ga]Ga-NOTA-DBP1k showed high uptake in MCF-7 tumors and had favorable tumor-to-background ratios by microPET imaging. On the contrary, low uptake was found in U-87MG tumors, which was significantly lower than that in MCF-7 tumors (0.42 ± 0.02 %ID/g vs. 1.01 ± 0.06 %ID/g, p < 0.05). The biodistribution study was consistent with the findings of microPET imaging results. These results demonstrated that [68Ga]Ga-NOTA-DBP1k can noninvasively image the CD24 and PD-L1 checkpoint expression of innate and adaptive immunity in tumors and may be helpful for guiding the CD24/PD-L1 dual-checkpoints blockage immunotherapy.
{"title":"A novel PET tracer for noninvasive imaging the checkpoints expression of innate and adaptive immunity in tumors by simultaneously targeting CD24 and PD-L1","authors":"Yijin Zou ,&nbsp;Tianshi Que ,&nbsp;Penghui Sun ,&nbsp;Jiahao Xie ,&nbsp;Dazhi Shi ,&nbsp;Hubing Wu ,&nbsp;Jian-Er Tan","doi":"10.1016/j.bioorg.2025.108260","DOIUrl":"10.1016/j.bioorg.2025.108260","url":null,"abstract":"<div><div>The success of tumor immunotherapy depends on the innate and adaptive immune responses, with CD24 and PD-L1 being key targets. <sup>D</sup>BP1 peptide is a novel bispecific D-peptide, targeting both CD24 and PD-L1 simultaneously. In this study, by radiolabeling <sup>D</sup>BP1 peptide, we developed a novel PET modality to noninvasively evaluate CD24 and PD-L1 expressions in tumors. To enhance the solubility of <sup>D</sup>BP1, a hydrophilic lysine was added into C-terminal residue of the peptide, which was then modified with a chelator NOTA to produce the radiotracer precursor NOTA-<sup>D</sup>BP1k. NOTA-<sup>D</sup>BP1k showed high affinity for CD24 (<em>K</em><sub>D</sub> = 10.70 ± 0.70 nM) and PD-L1 (<em>K</em><sub>D</sub> = 5.40 ± 0.61 nM). [<sup>68</sup>Ga]Ga-NOTA-<sup>D</sup>BP1k was synthesized with a high radiochemical yield (71 ± 3.0 %) and exhibited high hydrophilicity and stability. [<sup>68</sup>Ga]Ga-NOTA-<sup>D</sup>BP1k showed higher uptake in high CD24/PD-L1 expressed MCF-7 cells than that in low CD24/PD-L1 expressed U-87MG cells <em>in vitro</em>. <em>In vivo</em>, [<sup>68</sup>Ga]Ga-NOTA-<sup>D</sup>BP1k showed high uptake in MCF-7 tumors and had favorable tumor-to-background ratios by microPET imaging. On the contrary, low uptake was found in U-87MG tumors, which was significantly lower than that in MCF-7 tumors (0.42 ± 0.02 %ID/g vs. 1.01 ± 0.06 %ID/g, <em>p</em> &lt; 0.05). The biodistribution study was consistent with the findings of microPET imaging results. These results demonstrated that [<sup>68</sup>Ga]Ga-NOTA-<sup>D</sup>BP1k can noninvasively image the CD24 and PD-L1 checkpoint expression of innate and adaptive immunity in tumors and may be helpful for guiding the CD24/PD-L1 dual-checkpoints blockage immunotherapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108260"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394546","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}
引用次数: 0
Dimethylallylated stilbenoids by chemo-selective prenyltransferases and their α-glucosidase inhibitory effects
IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-07 DOI: 10.1016/j.bioorg.2025.108261
Min Yang , Jun Jin , Jiale Yi , Xia Yu , Chun-Mao Yuan , Kang Zhou
Prenylated stilbenoids are known for their unique health benefits and have been found to exhibit strong α-glucosidase inhibitory activities. In this study, the dimethylallylation of eight stilbenoids was investigated, which was catalyzed by engineered enzymes of the fungal prenyltransferase AnaPT. These reactions of stilbenoids catalyzed by AnaPT_F265D and AnaPT_F265G are chemo-selective and 17 products are all C-dimethylallylated stilbenoids, including twelve mono- and five di-dimethylallylated stilbenoids, significantly expanding the structure diversity of naturally occurring dimethylallylated stilbenoids. 10 Compounds were reported for the first time in this study. The molecular docking of 1D1 with AnaPT was also conducted, which revealed that N115 was likely a key residue. Our results showed that the catalytic efficiencies of AnaPT_F265D_N115K and AnaPT_F265D_N115A were higher than the other mutants obtained. Eight compounds (1D1, 2D1, 3D23D4, 6D1, 6D4, and 8D1) exhibited inhibitory effects on α-glucosidase with IC50 values ranging from 5.43 ± 0.16 to 42.61 ± 0.17 μM. Among them, compound 8D1 with IC50 value of 5.43 ± 0.16 μM showed about 40 times stronger than the positive control, acarbose with an IC50 of 217.07 ± 1.92 μM in α-glucosidase inhibitory assays. These fundings not only enrich the structure diversity of dimethylallylated stilbenoids but also lay the foundation for the discovery of potential candidate compounds for the treatment of diabetes and anti-obesity drugs.
{"title":"Dimethylallylated stilbenoids by chemo-selective prenyltransferases and their α-glucosidase inhibitory effects","authors":"Min Yang ,&nbsp;Jun Jin ,&nbsp;Jiale Yi ,&nbsp;Xia Yu ,&nbsp;Chun-Mao Yuan ,&nbsp;Kang Zhou","doi":"10.1016/j.bioorg.2025.108261","DOIUrl":"10.1016/j.bioorg.2025.108261","url":null,"abstract":"<div><div>Prenylated stilbenoids are known for their unique health benefits and have been found to exhibit strong α-glucosidase inhibitory activities. In this study, the dimethylallylation of eight stilbenoids was investigated, which was catalyzed by engineered enzymes of the fungal prenyltransferase AnaPT. These reactions of stilbenoids catalyzed by AnaPT_F265D and AnaPT_F265G are chemo-selective and 17 products are all <em>C</em>-dimethylallylated stilbenoids, including twelve mono- and five di-dimethylallylated stilbenoids, significantly expanding the structure diversity of naturally occurring dimethylallylated stilbenoids. 10 Compounds were reported for the first time in this study. The molecular docking of <strong>1D1</strong> with AnaPT was also conducted, which revealed that N115 was likely a key residue. Our results showed that the catalytic efficiencies of AnaPT_F265D_N115K and AnaPT_F265D_N115A were higher than the other mutants obtained. Eight compounds (<strong>1D1</strong>, <strong>2D1</strong>, <strong>3D2</strong>–<strong>3D4</strong>, <strong>6D1</strong>, <strong>6D4</strong>, and <strong>8D1</strong>) exhibited inhibitory effects on α-glucosidase with IC<sub>50</sub> values ranging from 5.43 ± 0.16 to 42.61 ± 0.17 μM. Among them, compound <strong>8D1</strong> with IC<sub>50</sub> value of 5.43 ± 0.16 μM showed about 40 times stronger than the positive control, acarbose with an IC<sub>50</sub> of 217.07 ± 1.92 μM in α-glucosidase inhibitory assays. These fundings not only enrich the structure diversity of dimethylallylated stilbenoids but also lay the foundation for the discovery of potential candidate compounds for the treatment of diabetes and anti-obesity drugs.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108261"},"PeriodicalIF":4.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379059","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}
引用次数: 0
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Bioorganic Chemistry
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