Bioorganic Chemistry最新文献_第5页

Recent developments of pyrimidine appended HIV-1 non-nucleoside reverse transcriptase inhibitors

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-17 DOI: 10.1016/j.bioorg.2025.108273

S. Maheen Abdul Rahman , Gurpreet Singh , Mhd Shabbu Khan , Arun Kumar Balasubramaniam , Vikramdeep Monga

Acquired Immune Deficiency Syndrome (AIDS) is an ailment that progressively weakens the immune system and is responsible for being the sole cause of 630,000 deaths worldwide in 2023. It is a potentially fatal condition that promotes the growth of malignancies and secondary infection. Viruses like Human Immunodeficiency Virus (HIV-1) and Hepatitis B virus (HBV) employ an enzyme, reverse transcriptase (RT), to replicate their genomes and spread across the host genome. RT has proved to be one of the most important therapeutic targets for the treatment of AIDS as well as for the development of new HIV-1 medications. The pyrimidine nucleus has been described as a dynamic cornerstone in developing new anti-HIV-1 medications and represents a familiar motif found in various marketed anti-HIV-1 drugs, such as diaryl pyrimidines (DAPYs). The rapid emergence of drug-resistant viral strains due to mutations in the HIV-1 RT structure along with their unfavourable pharmacokinetics present new challenges. Recent years have witnessed tremendous progress in the design and discovery of new substituted pyrimidines as potent and selective non-nucleoside reverse transcriptase inhibitors (NNRTIs). Further, the current developments in the field of X-ray crystallography and molecular modeling have remarkably augmented the design strategies, with simultaneous improvement in the resistance profiles. This article comprehensively reviews recent trends in the design and development of pyrimidine-based HIV-1 NNRTIs. The study emphasizes their biological activities, structure-activity relationship, and docking studies to guide the rational design of NNRTIs with desired potency, safety, and efficacy.

{"title":"Recent developments of pyrimidine appended HIV-1 non-nucleoside reverse transcriptase inhibitors","authors":"S. Maheen Abdul Rahman , Gurpreet Singh , Mhd Shabbu Khan , Arun Kumar Balasubramaniam , Vikramdeep Monga","doi":"10.1016/j.bioorg.2025.108273","DOIUrl":"10.1016/j.bioorg.2025.108273","url":null,"abstract":"<div><div>Acquired Immune Deficiency Syndrome (AIDS) is an ailment that progressively weakens the immune system and is responsible for being the sole cause of 630,000 deaths worldwide in 2023. It is a potentially fatal condition that promotes the growth of malignancies and secondary infection. Viruses like Human Immunodeficiency Virus (HIV-1) and Hepatitis B virus (HBV) employ an enzyme, reverse transcriptase (RT), to replicate their genomes and spread across the host genome. RT has proved to be one of the most important therapeutic targets for the treatment of AIDS as well as for the development of new HIV-1 medications. The pyrimidine nucleus has been described as a dynamic cornerstone in developing new anti-HIV-1 medications and represents a familiar motif found in various marketed anti-HIV-1 drugs, such as diaryl pyrimidines (DAPYs). The rapid emergence of drug-resistant viral strains due to mutations in the HIV-1 RT structure along with their unfavourable pharmacokinetics present new challenges. Recent years have witnessed tremendous progress in the design and discovery of new substituted pyrimidines as potent and selective non-nucleoside reverse transcriptase inhibitors (NNRTIs). Further, the current developments in the field of X-ray crystallography and molecular modeling have remarkably augmented the design strategies, with simultaneous improvement in the resistance profiles. This article comprehensively reviews recent trends in the design and development of pyrimidine-based HIV-1 NNRTIs. The study emphasizes their biological activities, structure-activity relationship, and docking studies to guide the rational design of NNRTIs with desired potency, safety, and efficacy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108273"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534538","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

Characterization and application in recombinant N-GlcNAc-protein production of a novel endo-β-N-acetylglucosaminidase from Listeria booriae

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-17 DOI: 10.1016/j.bioorg.2025.108290

Weian Mao , Yongheng Rong , Hongmei Zhang , Fang Yuan , Yankang Wang , Mei Wang , Linhan Wang , Peng George Wang , Min Chen , Shengjun Wang , Yun Kong

Endo-β-N-acetylglucosaminidases (ENGases) are essential enzymes for hydrolyzing N-glycans, with applications in protein N-glycosylation analysis and glycoprotein synthesis. In this study, a novel GH18 family ENGase, Endo-LB, was identified from Listeria booriae FSL A5–0281. Composed of 593 amino acids (65.78 kDa), Endo-LB features with two domains: an Endo S-like catalytic domain and a mucin-binding protein (MucBP) domain. Recombinant Endo-LB, expressed in Escherichia coli BL21 (DE3) pLysS, exhibited a specific activity of 198.25 U/mg and hydrolyzed high mannose-type N-glycans at a temperature from 4 °C to 60 °C with optimal activity at 37 °C and pH 6.0 (range 3.0 to 10.0), making it versatile for various environmental conditions. The MucBP domain does not affect soluble Endo-LB activity but influences interaction with mucin on cell surface, suggesting potential application in targeting specific glycoproteins in complex biological environments. To address the heterogeneity of N-glycans in Pichia pastoris (Komagataella phaffii) expression, Endo-LB was further expressed in the Golgi of P. pastoris, efficiently producing glycoproteins, such as Erythropoietin (EPO) (37 mg/L) and Darbepoetin α (53 mg/L) with nearly complete N-glycans truncation, which can be further extended to generate diverse N-glycan structures. These findings highlight the versatility and potential utility of Endo-LB in glycoprotein engineering and biotechnological applications.

{"title":"Characterization and application in recombinant N-GlcNAc-protein production of a novel endo-β-N-acetylglucosaminidase from Listeria booriae","authors":"Weian Mao , Yongheng Rong , Hongmei Zhang , Fang Yuan , Yankang Wang , Mei Wang , Linhan Wang , Peng George Wang , Min Chen , Shengjun Wang , Yun Kong","doi":"10.1016/j.bioorg.2025.108290","DOIUrl":"10.1016/j.bioorg.2025.108290","url":null,"abstract":"<div><div>Endo-β-<em>N</em>-acetylglucosaminidases (ENGases) are essential enzymes for hydrolyzing <em>N</em>-glycans, with applications in protein <em>N</em>-glycosylation analysis and glycoprotein synthesis. In this study, a novel GH18 family ENGase, Endo-LB, was identified from <em>Listeria booriae</em> FSL A5–0281. Composed of 593 amino acids (65.78 kDa), Endo-LB features with two domains: an Endo S-like catalytic domain and a mucin-binding protein (MucBP) domain. Recombinant Endo-LB, expressed in <em>Escherichia coli</em> BL21 (DE3) pLysS, exhibited a specific activity of 198.25 U/mg and hydrolyzed high mannose-type <em>N</em>-glycans at a temperature from 4 °C to 60 °C with optimal activity at 37 °C and pH 6.0 (range 3.0 to 10.0), making it versatile for various environmental conditions. The MucBP domain does not affect soluble Endo-LB activity but influences interaction with mucin on cell surface, suggesting potential application in targeting specific glycoproteins in complex biological environments. To address the heterogeneity of <em>N</em>-glycans in <em>Pichia pastoris</em> (<em>Komagataella phaffii</em>) expression, Endo-LB was further expressed in the Golgi of <em>P. pastoris</em>, efficiently producing glycoproteins, such as Erythropoietin (EPO) (37 mg/L) and Darbepoetin α (53 mg/L) with nearly complete <em>N</em>-glycans truncation, which can be further extended to generate diverse <em>N</em>-glycan structures. These findings highlight the versatility and potential utility of Endo-LB in glycoprotein engineering and biotechnological applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108290"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453212","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

Targeted discovery of diterpene compounds ostamycins with anti-influenza a viral activity from a deepsea-derived Streptomyces strain

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-17 DOI: 10.1016/j.bioorg.2025.108268

Lukuan Hou , Shuyao Wang , Yuanhang Zhang , Xue Yang , Zihui Chen , Yuxuan Gao , Wenli Li

Heterologous expression of a nonconventional terpene biosynthetic gene cluster from the deepsea-derived Streptomyces amphotericinicus DS22–01 led to the production of a novel cyclic diterpene, ostamycin A (1). Anti-influenza A virus activity evaluation revealed that compound 1 showed significant activity with an IC₅₀ value of 4.72 μM, which was much stronger than that of the positive control ribavirin (IC₅₀ = 20.80 μM). Inspired by its intriguing activity, yield optimization was achieved through a combined approach involving promoter engineering and codon modification in a stepwise manner. This strategy led to a ∼ 13-fold increase in the production of ostamycin A (1), as well as the concurrent accumulation of another novel cyclic diterpene, ostamycin B (2), which also displayed anti-influenza A virus activity with an IC₅₀ value of 195.59 μM. The planar structures and stereochemistry of compounds 1 and 2 were established through extensive MS and NMR spectroscopic analyses together with ECD calculations. Further investigations revealed that compound 1 inhibits the influenza A virus (A/Puerto Rico/8/34) replication by directly targeting the nucleoprotein (NP). These findings highlight compound 1 as a promising lead for the development of novel influenza virus inhibitors.

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引用次数: 0

Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-17 DOI: 10.1016/j.bioorg.2025.108286

Chao Zhang , Shuling Peng , Ziyou Zheng , Zhenqiang Chen , Mingyue Li , Nengneng Huang , Zhijun Liu , Mao-Xun Yang , Heru Chen

Multidrug resistance (MDR) represents a bottleneck in the treatment of breast cancer. Although the potential of aldose reductase inhibitors (ARIs) as sensitizers against MDR has been explored in recent decades, the intrinsic mechanism still needs to be elucidated, and promising agents in the clinic need to be developed. In this study, three novel ARIs (5a-c), characterized by bis-pocket binding, were designed and synthesized. Inhibitory activity is positively correlated with antioxidation and benefits from rigid spacers. Only 5a with less activities in inhibition and antioxidation was demonstrated as a stronger sensitizer against doxorubicin (DOX)-resistant MCF-7 cells (MCF-7/ADR) than epalrestat (EPA). Either 5a or EPA may decrease GSH abundance and increase ROS, Fe²⁺, and lipid peroxidation levels. The restorative effects of both ARIs may be blocked by N-acetyl cysteine (NAC). These data suggest that both 5a and EPA may restore the sensitivity of MCF-7/ADR cells to DOX by increasing ferroptosis activity. Furthermore, the inhibition of AKR1B1 by 5a, as well as by EPA, dramatically decreased both p-STAT3 and SLC7A11 expression. Gene knockdown of AKR1B1 has the same effects as AKR1B1 inhibition. This evidence indicates that both ARIs can suppress MCF-7/ADR cell growth via the upregulation of ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis. Additionally, 5a was found to increase the accumulation of intramolecular DOX by inhibiting ABCB1, but EPA did not. These results support that 5a is a promising sensitizing agent against multidrug resistance in breast cancer.

{"title":"Novel bis-pocket binding aldose reductase inhibitors sensitize MCF-7/ADR cells to doxorubicin in a dual-role manner","authors":"Chao Zhang , Shuling Peng , Ziyou Zheng , Zhenqiang Chen , Mingyue Li , Nengneng Huang , Zhijun Liu , Mao-Xun Yang , Heru Chen","doi":"10.1016/j.bioorg.2025.108286","DOIUrl":"10.1016/j.bioorg.2025.108286","url":null,"abstract":"<div><div>Multidrug resistance (MDR) represents a bottleneck in the treatment of breast cancer. Although the potential of aldose reductase inhibitors (ARIs) as sensitizers against MDR has been explored in recent decades, the intrinsic mechanism still needs to be elucidated, and promising agents in the clinic need to be developed. In this study, three novel ARIs (<strong>5a-c</strong>), characterized by bis-pocket binding, were designed and synthesized. Inhibitory activity is positively correlated with antioxidation and benefits from rigid spacers. Only <strong>5a</strong> with less activities in inhibition and antioxidation was demonstrated as a stronger sensitizer against doxorubicin (DOX)-resistant MCF-7 cells (MCF-7/ADR) than epalrestat (EPA). Either <strong>5a</strong> or EPA may decrease GSH abundance and increase ROS, Fe<sup>2+</sup>, and lipid peroxidation levels. The restorative effects of both ARIs may be blocked by <em>N</em>-acetyl cysteine (NAC). These data suggest that both <strong>5a</strong> and EPA may restore the sensitivity of MCF-7/ADR cells to DOX by increasing ferroptosis activity. Furthermore, the inhibition of AKR1B1 by <strong>5a</strong>, as well as by EPA, dramatically decreased both <em>p</em>-STAT3 and SLC7A11 expression. Gene knockdown of AKR1B1 has the same effects as AKR1B1 inhibition. This evidence indicates that both ARIs can suppress MCF-7/ADR cell growth via the upregulation of ferroptosis activity via the AKR1B1/STAT3/SLC7A11 axis. Additionally, <strong>5a</strong> was found to increase the accumulation of intramolecular DOX by inhibiting ABCB1, but EPA did not. These results support that <strong>5a</strong> is a promising sensitizing agent against multidrug resistance in breast cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108286"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453211","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

Exploring the larvicidal and pupicidal activities of new functionalized pyridines against Culex pipiens L. referring to molecular docking and SAR studies

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-17 DOI: 10.1016/j.bioorg.2025.108283

Safaa I. Elewa , Doaa R. Abdel-Haleem , Ahmed H. Tantawy , Hany I. Mohamed , Walaa H. Lashin

Pesticides are intensively employed to manage pests, but they pose a great challenge, developing pesticide resistance. So, searching for novel chemical structures is crucial to overcoming insecticide resistance. Herein, a new functionalized pyridine derivative 4 was effectively constructed in a one-step reaction through reacting four components, including piperonal, ethyl cyanoacetate, 2-acetylthiophene, and ammonium acetate, under ultrasonic conditions. Treatment of the derivative 5 with hydrazine hydrate in ethanol afforded the acetohydrazide derivative 8 that was utilized as a key precursor for the synthesis of Schiff^'s bases and other nicotinonitriles. Moreover, new acetohydrazone derivatives (19–21) were furnished by the reaction of 8 with isatin, n-vinylpyrrolididone, and galactose, respectively. The data obtained from the spectral measurements was the basis for elucidating the structures of the new derivatives. The larvicidal and pupicidal potencies of the synthesized thienyl pyridine derivatives were assessed against Culex pipiens L., and most exhibited moderate to good activity. The larvae were more susceptible to 17, 19, 6 and 13 with LC₅₀ of 1.57, 1.91, 2.36 and 2.90 ppm, respectively, while pupae were less susceptible with LC₅₀ of 4.17, 5.03, 6.16 and 7.45 ppm, respectively. The various functional groups connected to the pyridine ring led to variations in the toxicity of synthesized compounds, which were clarified through the SAR study. At the same time, a molecular docking study was performed to demonstrate the compound's mode of action and the effect of inserted moieties on binding with the nicotinic acetylcholine receptors (nAChRs). Collectively, the results imply that the thienyl pyridine derivatives could be used as mosquitocidal agents against C. pipiens larvae and pupae.

{"title":"Exploring the larvicidal and pupicidal activities of new functionalized pyridines against Culex pipiens L. referring to molecular docking and SAR studies","authors":"Safaa I. Elewa , Doaa R. Abdel-Haleem , Ahmed H. Tantawy , Hany I. Mohamed , Walaa H. Lashin","doi":"10.1016/j.bioorg.2025.108283","DOIUrl":"10.1016/j.bioorg.2025.108283","url":null,"abstract":"<div><div>Pesticides are intensively employed to manage pests, but they pose a great challenge, developing pesticide resistance. So, searching for novel chemical structures is crucial to overcoming insecticide resistance. Herein, a new functionalized pyridine derivative <strong>4</strong> was effectively constructed in a one-step reaction through reacting four components, including piperonal, ethyl cyanoacetate, 2-acetylthiophene, and ammonium acetate, under ultrasonic conditions. Treatment of the derivative <strong>5</strong> with hydrazine hydrate in ethanol afforded the acetohydrazide derivative <strong>8</strong> that was utilized as a key precursor for the synthesis of Schiff<sup>'</sup>s bases and other nicotinonitriles. Moreover, new acetohydrazone derivatives <strong>(19–21)</strong> were furnished by the reaction of <strong>8</strong> with isatin, <em>n</em>-vinylpyrrolididone, and galactose, respectively. The data obtained from the spectral measurements was the basis for elucidating the structures of the new derivatives. The larvicidal and pupicidal potencies of the synthesized thienyl pyridine derivatives were assessed against <em>Culex pipiens</em> L., and most exhibited moderate to good activity. The larvae were more susceptible to <strong>17</strong>, <strong>19</strong>, <strong>6</strong> and <strong>13</strong> with LC<sub>50</sub> of 1.57, 1.91, 2.36 and 2.90 ppm, respectively, while pupae were less susceptible with LC<sub>50</sub> of 4.17, 5.03, 6.16 and 7.45 ppm, respectively. The various functional groups connected to the pyridine ring led to variations in the toxicity of synthesized compounds, which were clarified through the SAR study. At the same time, a molecular docking study was performed to demonstrate the compound's mode of action and the effect of inserted moieties on binding with the nicotinic acetylcholine receptors (<em>n</em>AChRs). Collectively, the results imply that the thienyl pyridine derivatives could be used as mosquitocidal agents against <em>C. pipiens</em> larvae and pupae.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108283"},"PeriodicalIF":4.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437046","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

Punicalagin as an Artemis inhibitor synergizes with photodynamic therapy in tumor suppression

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-16 DOI: 10.1016/j.bioorg.2025.108282

Xuening Chen , Changkun Chen , Zuoan Li , Chun Liu , Zhonghui Lin

Photodynamic therapy (PDT) is a minimally invasive treatment that utilizes a photosensitizer, specific light wavelengths, and oxygen to generate reactive oxygen species (ROS), causing oxidative damage and tumor cell death. However, the effectiveness of PDT can be reduced by the intrinsic antioxidant and DNA repair mechanisms of tumor cells. Artemis (SNM1C/DCLRE1C) is an endonuclease essential for repairing DNA double-strand breaks (DSBs) via non-homologous end-joining (NHEJ). Herein, we conducted a high-throughput small-molecule screening and identified Punicalagin (PUG), a natural polyphenol from pomegranate, as a novel Artemis inhibitor with an IC₅₀ value of 296.1 nM. We also investigated the effects of PUG combined with PDT in tumor treatment, using the pentalysine β‐carbonylphthalocyanine zinc (ZnPc5K) as the photosensitizer. In HeLa cells, ZnPc5K-based PDT induced significant DSBs, which could be repaired by the intrinsic DNA repair mechanisms within 12 h. Co-treatment with PUG compromised DNA repair, promoted cell apoptosis, inhibited cell invasion, and suppressed the growth of various tumor cells. Furthermore, in a mouse xenograft model, the combination of PUG and ZnPc5K-PDT effectively inhibited tumor growth with minimal side effects. These findings suggest that PUG, as an Artemis inhibitor, can enhance the therapeutic efficacy of PDT in tumor suppression by impairing DNA repair through the NHEJ pathway.

{"title":"Punicalagin as an Artemis inhibitor synergizes with photodynamic therapy in tumor suppression","authors":"Xuening Chen , Changkun Chen , Zuoan Li , Chun Liu , Zhonghui Lin","doi":"10.1016/j.bioorg.2025.108282","DOIUrl":"10.1016/j.bioorg.2025.108282","url":null,"abstract":"<div><div>Photodynamic therapy (PDT) is a minimally invasive treatment that utilizes a photosensitizer, specific light wavelengths, and oxygen to generate reactive oxygen species (ROS), causing oxidative damage and tumor cell death. However, the effectiveness of PDT can be reduced by the intrinsic antioxidant and DNA repair mechanisms of tumor cells. Artemis (SNM1C/DCLRE1C) is an endonuclease essential for repairing DNA double-strand breaks (DSBs) <em>via</em> non-homologous end-joining (NHEJ). Herein, we conducted a high-throughput small-molecule screening and identified Punicalagin (PUG), a natural polyphenol from pomegranate, as a novel Artemis inhibitor with an IC<sub>50</sub> value of 296.1 nM. We also investigated the effects of PUG combined with PDT in tumor treatment, using the pentalysine β‐carbonylphthalocyanine zinc (ZnPc5K) as the photosensitizer. In HeLa cells, ZnPc5K-based PDT induced significant DSBs, which could be repaired by the intrinsic DNA repair mechanisms within 12 h. Co-treatment with PUG compromised DNA repair, promoted cell apoptosis, inhibited cell invasion, and suppressed the growth of various tumor cells. Furthermore, in a mouse xenograft model, the combination of PUG and ZnPc5K-PDT effectively inhibited tumor growth with minimal side effects. These findings suggest that PUG, as an Artemis inhibitor, can enhance the therapeutic efficacy of PDT in tumor suppression by impairing DNA repair through the NHEJ pathway.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108282"},"PeriodicalIF":4.5,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437042","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

Design, synthesis and molecular modeling of new Pyrazolyl-Benzimidazolone hybrids targeting breast Cancer

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-15 DOI: 10.1016/j.bioorg.2025.108269

Mohamed Adardour , Al-Hassan M. Mustafa , Mehdi Oubahmane , Marouane Ait Lahcen , Emad M. Seif , Manal Abdel Fattah Ezzat , Elena Zaballos-García , Joel T. Mague , Ismail Hdoufane , Driss Cherqaoui , Oliver H. Krämer , Wolfgang Sippl , Hany S. Ibrahim , Abdesselam Baouid

Methyl-piperidino-pyrazole (MPP) is a pyrazole derivative acting as a lead estrogen receptor (ER) antagonist and has an anti-breast cancer effect. Since some benzimidazole derivatives were reported for their inhibitory activity against breast cancer, hybrids from these reported compounds (5a-c, 6a-c, 7a-c and 8a-c) were designed to develop anti-breast cancer agents. The synthesis involved 1,3-dipolar cycloaddition of nitrilimines on the benzimidazolone derivatives 2a-b and 3a-b which occurred with chemo- and regioselectivity depending on the dipole and was confirmed by an X-ray structure of 6b. In vitro biological testing of the newly prepared compounds against the 60-cell line panel showed that 5a-c and 6a-c with a partially unsaturated pyrazole ring possessed a high GI% in the T-47D breast cancer cell line with a selectivity margin against different cell lines. Five compounds were selected for apoptotic studies in T-47D cells, of which 6a arrested cells in G1 phase and caused more apoptosis than MPP. The MTT assay revealed that compound 6a has an IC₅₀ = 6.77 ± 0.03 μM against T-47D cells. Furthermore, 6a reduced the estrogen receptor 1 gene expression levels 3-fold in T-47D cells. Molecular dynamics simulations indicated that the complex of the active compound 6a remained stable over the last 150 ns. An analysis of the binding mode revealed that compound 6a exhibited a similar conformation compared to MPP and the co-ligand in the active site of via a specific pose involving noncovalent interactions.

{"title":"Design, synthesis and molecular modeling of new Pyrazolyl-Benzimidazolone hybrids targeting breast Cancer","authors":"Mohamed Adardour , Al-Hassan M. Mustafa , Mehdi Oubahmane , Marouane Ait Lahcen , Emad M. Seif , Manal Abdel Fattah Ezzat , Elena Zaballos-García , Joel T. Mague , Ismail Hdoufane , Driss Cherqaoui , Oliver H. Krämer , Wolfgang Sippl , Hany S. Ibrahim , Abdesselam Baouid","doi":"10.1016/j.bioorg.2025.108269","DOIUrl":"10.1016/j.bioorg.2025.108269","url":null,"abstract":"<div><div>Methyl-piperidino-pyrazole (MPP) is a pyrazole derivative acting as a lead estrogen receptor (ER) antagonist and has an anti-breast cancer effect. Since some benzimidazole derivatives were reported for their inhibitory activity against breast cancer, hybrids from these reported compounds (<strong>5a-c</strong>, <strong>6a-c</strong>, <strong>7a-c</strong> and <strong>8a-c</strong>) were designed to develop anti-breast cancer agents. The synthesis involved 1,3-dipolar cycloaddition of nitrilimines on the benzimidazolone derivatives <strong>2a-b</strong> and <strong>3a-b</strong> which occurred with chemo- and regioselectivity depending on the dipole and was confirmed by an X-ray structure of <strong>6b</strong>. <em>In vitro</em> biological testing of the newly prepared compounds against the 60-cell line panel showed that <strong>5a-c</strong> and <strong>6a-c</strong> with a partially unsaturated pyrazole ring possessed a high GI% in the T-47D breast cancer cell line with a selectivity margin against different cell lines. Five compounds were selected for apoptotic studies in T-47D cells, of which <strong>6a</strong> arrested cells in G1 phase and caused more apoptosis than MPP. The MTT assay revealed that compound <strong>6a</strong> has an IC<sub>50</sub> = 6.77 ± 0.03 μM against T-47D cells. Furthermore, <strong>6a</strong> reduced the estrogen receptor 1 gene expression levels 3-fold in T-47D cells. Molecular dynamics simulations indicated that the complex of the active compound <strong>6a</strong> remained stable over the last 150 ns. An analysis of the binding mode revealed that compound <strong>6a</strong> exhibited a similar conformation compared to MPP and the co-ligand in the active site of <em>via</em> a specific pose involving noncovalent interactions.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108269"},"PeriodicalIF":4.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437097","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

Construction of a smart dual-responsive targeted drug nanocarrier for imaging and treatment of breast cancer cells

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-15 DOI: 10.1016/j.bioorg.2025.108284

Hongyu Qian , Sanxia Wang , Xin Chen , Ninghan Feng , Yuting Zhang , Xiaoli Wang , Nandi Zhou

Breast cancer has become one of the most common cancers worldwide, but the effectiveness of the conventional drug chemotherapy is still restricted. Therefore, precision imaging and targeted therapy against breast cancer cells have become a hot research topic. In this study, a dual-responsive nanocarrier system based on multi-functionalized gold nanoparticles (GNP) was developed for simultaneous diagnosis and treatment of breast cancer cells. The nanoparticles were modified with an aptamer which specifically recognizes MUC-1 protein on the surface of the breast cancer cell MCF-7, achieving precise cellular targeting. Upon entry into the cell, the decrease of pH in the intracellular environment causes the detachment of the i-motif sequence from GNP. Cy5 labeled at the end of i-motif, which is previously quenched by GNP thus restores its fluorescence, achieving the imaging of the cancer cells. Additionally, chemotherapeutic drug gemcitabine (GEM) is covalently attached to GNP through a rationally designed oligopeptide linker CGFLG. Cathepsin B, which is overexpressed in MCF-7 cells, can precisely cleave the CGFLG linker and release GEM to the cells, thereby achieving the targeted drug delivery and treatment. When 4 nM nanocarrier was applied, the inhibition rate of MCF-7 cells was approximately 70 %. This dual-responsive nanocarrier system integrates the targeting, imaging and therapeutic functions in a simple GNP platform. The high targeting efficiency of the nanocarrier reduces the non-specific binding and toxic effects on normal cells, while enhances the toxicity toward cancer cells. Therefore, it may have great prospects in medical applications.

{"title":"Construction of a smart dual-responsive targeted drug nanocarrier for imaging and treatment of breast cancer cells","authors":"Hongyu Qian , Sanxia Wang , Xin Chen , Ninghan Feng , Yuting Zhang , Xiaoli Wang , Nandi Zhou","doi":"10.1016/j.bioorg.2025.108284","DOIUrl":"10.1016/j.bioorg.2025.108284","url":null,"abstract":"<div><div>Breast cancer has become one of the most common cancers worldwide, but the effectiveness of the conventional drug chemotherapy is still restricted. Therefore, precision imaging and targeted therapy against breast cancer cells have become a hot research topic. In this study, a dual-responsive nanocarrier system based on multi-functionalized gold nanoparticles (GNP) was developed for simultaneous diagnosis and treatment of breast cancer cells. The nanoparticles were modified with an aptamer which specifically recognizes MUC-1 protein on the surface of the breast cancer cell MCF-7, achieving precise cellular targeting. Upon entry into the cell, the decrease of pH in the intracellular environment causes the detachment of the i-motif sequence from GNP. Cy5 labeled at the end of i-motif, which is previously quenched by GNP thus restores its fluorescence, achieving the imaging of the cancer cells. Additionally, chemotherapeutic drug gemcitabine (GEM) is covalently attached to GNP through a rationally designed oligopeptide linker CGFLG. Cathepsin B, which is overexpressed in MCF-7 cells, can precisely cleave the CGFLG linker and release GEM to the cells, thereby achieving the targeted drug delivery and treatment. When 4 nM nanocarrier was applied, the inhibition rate of MCF-7 cells was approximately 70 %. This dual-responsive nanocarrier system integrates the targeting, imaging and therapeutic functions in a simple GNP platform. The high targeting efficiency of the nanocarrier reduces the non-specific binding and toxic effects on normal cells, while enhances the toxicity toward cancer cells. Therefore, it may have great prospects in medical applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108284"},"PeriodicalIF":4.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445245","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

Design, synthesis and anticancer evaluation of novel 1,3-imidazole-type phenylhistin derivatives: Dual mechanism via P53 induction and microtubulin inhibition

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-15 DOI: 10.1016/j.bioorg.2025.108271

Na Chen , Bo Wang , Shihao Wang , Gang Wang , Zhenlu Shen , Yongxiu Wen , Jiajia Li , Bo Zhang , FengLi , Wenbao Li , Wenqiang Yang , Jie Xin , Zhongpeng Ding

To enhance biological activity and deepen the understanding of the structure-activity relationship, a systematic study was conducted on the 5-position of the 1,3-imidazol-4-yl group in phenylahistin. The interaction between phenylahistin derivative 16j and the colchicine-binding site was first analyzed in detail, leading to the development of a fragment library to replace the tert-butyl group. A series of 20 novel phenylhistin derivatives were designed, synthesized, and characterized. In vitro activity screening using the NCI-H460 human non-small cell lung cancer line showed strong inhibitory activity for most compounds. Among these, compounds 8 f and 8 g exhibited superior activities, with IC₅₀ values of 10 nM and 2 nM, respectively. Notably, 8 f displayed activity comparable to that of plinabulin, while 8 g was five times more potent. Both compounds 8 f and 8 g were further evaluated across various tumor cell lines showing nanomolar-level potency. Furthermore, detailed biological assays revealed that 8 g and 8 f disrupted microtubule integrity and significantly affected the P53 signaling pathway, strongly inducing G2/M phase arrest, and simultaneously promoting apoptosis in NCI-H460 cells. Molecular docking studies confirmed higher binding scores and stronger affinities for these derivatives at the colchicine-binding site of α, β-tubulin. These findings suggest that the apoptosis-inducing and cytotoxic activities of these derivatives may offer potential clinical value for tumor therapy.

{"title":"Design, synthesis and anticancer evaluation of novel 1,3-imidazole-type phenylhistin derivatives: Dual mechanism via P53 induction and microtubulin inhibition","authors":"Na Chen , Bo Wang , Shihao Wang , Gang Wang , Zhenlu Shen , Yongxiu Wen , Jiajia Li , Bo Zhang , FengLi , Wenbao Li , Wenqiang Yang , Jie Xin , Zhongpeng Ding","doi":"10.1016/j.bioorg.2025.108271","DOIUrl":"10.1016/j.bioorg.2025.108271","url":null,"abstract":"<div><div>To enhance biological activity and deepen the understanding of the structure-activity relationship, a systematic study was conducted on the 5-position of the 1,3-imidazol-4-yl group in phenylahistin. The interaction between phenylahistin derivative <strong>16j</strong> and the colchicine-binding site was first analyzed in detail, leading to the development of a fragment library to replace the tert-butyl group. A series of 20 novel phenylhistin derivatives were designed, synthesized, and characterized. In vitro activity screening using the NCI-H460 human non-small cell lung cancer line showed strong inhibitory activity for most compounds. Among these, compounds <strong>8</strong> <strong>f</strong> and <strong>8</strong> <strong>g</strong> exhibited superior activities, with IC<sub>50</sub> values of 10 nM and 2 nM, respectively. Notably, <strong>8</strong> <strong>f</strong> displayed activity comparable to that of plinabulin, while <strong>8</strong> <strong>g</strong> was five times more potent. Both compounds <strong>8</strong> <strong>f</strong> and <strong>8</strong> <strong>g</strong> were further evaluated across various tumor cell lines showing nanomolar-level potency. Furthermore, detailed biological assays revealed that <strong>8</strong> <strong>g</strong> and <strong>8</strong> <strong>f</strong> disrupted microtubule integrity and significantly affected the P53 signaling pathway, strongly inducing G2/M phase arrest, and simultaneously promoting apoptosis in NCI-H460 cells. Molecular docking studies confirmed higher binding scores and stronger affinities for these derivatives at the colchicine-binding site of α, β-tubulin. These findings suggest that the apoptosis-inducing and cytotoxic activities of these derivatives may offer potential clinical value for tumor therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108271"},"PeriodicalIF":4.5,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520224","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

Isatin-modified Calixarene derivatives: A comprehensive study on synthesis, enzyme inhibition, antioxidant, antimicrobial, and Antiproliferative activities

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2025-02-14 DOI: 10.1016/j.bioorg.2025.108280

Alev Oguz , Ahmet Uysal , Begum Nurpelin Saglik Özkan , Mehmet Oguz , Mustafa Yilmaz

In this article, a series of calix[4]arenes derivatized with isatin derivatives at the phenolic-O position were synthesized as potential theranostic molecules for antitumor therapy. The cytotoxic mechanism of action of the synthesized compounds was determined by Alamar Blue assay and flow cytometry using MCF-7, MDA-MB-231, DLD1, HeLa and A549 human cancer cell lines and their ability to penetrate into PNT1A healthy epithelial cells. To detect DNA damage, the Comet test was applied after the synthesized compounds interacted with the cells. As a result, it was found that treated cells had abnormal tail nuclei and damaged DNA structures compared with untreated cells. Within the scope of enzyme inhibition experiments, studies were carried out on aromatase and COX-2 enzymes and it was determined that the compounds in the series showed inhibitory activity at varying rates. Especially compounds CLX-A3, CLX-A4, CLX-B3 and CLX-B5 attract attention with their enzyme inhibitor potential. Also, the antioxidant activities of the compounds whose synthesis was completed were also investigated and it was observed that the examined derivatives also had antioxidant activity potential.

As a result of the antibacterial and antifungal test performed with broth microdilution, it was observed that the compounds had significant antibacterial and antifungal activity. The lowest MIC values were recorded as 0.006 mg/ml against Sarcina lutea and 0.048 against Candida albicans. In addition, the compound CLX-B3was observed to be effective against all strains including, Klebsiella pneumoniae and Salmonella enteritidis (Gram-negative pathogenic bacteria).

{"title":"Isatin-modified Calixarene derivatives: A comprehensive study on synthesis, enzyme inhibition, antioxidant, antimicrobial, and Antiproliferative activities","authors":"Alev Oguz , Ahmet Uysal , Begum Nurpelin Saglik Özkan , Mehmet Oguz , Mustafa Yilmaz","doi":"10.1016/j.bioorg.2025.108280","DOIUrl":"10.1016/j.bioorg.2025.108280","url":null,"abstract":"<div><div>In this article, a series of calix[4]arenes derivatized with isatin derivatives at the phenolic-O position were synthesized as potential theranostic molecules for antitumor therapy. The cytotoxic mechanism of action of the synthesized compounds was determined by Alamar Blue assay and flow cytometry using MCF-7, MDA-MB-231, DLD1, HeLa and A549 human cancer cell lines and their ability to penetrate into PNT1A healthy epithelial cells. To detect DNA damage, the Comet test was applied after the synthesized compounds interacted with the cells. As a result, it was found that treated cells had abnormal tail nuclei and damaged DNA structures compared with untreated cells. Within the scope of enzyme inhibition experiments, studies were carried out on aromatase and COX-2 enzymes and it was determined that the compounds in the series showed inhibitory activity at varying rates. Especially compounds <strong>CLX-A3</strong>, <strong>CLX-A4</strong>, <strong>CLX-B3</strong> and <strong>CLX-B5</strong> attract attention with their enzyme inhibitor potential. Also, the antioxidant activities of the compounds whose synthesis was completed were also investigated and it was observed that the examined derivatives also had antioxidant activity potential.</div><div>As a result of the antibacterial and antifungal test performed with broth microdilution, it was observed that the compounds had significant antibacterial and antifungal activity. The lowest MIC values were recorded as 0.006 mg/ml against Sarcina lutea and 0.048 against <em>Candida albicans</em>. In addition, the compound CLX-B3was observed to be effective against all strains including, <em>Klebsiella pneumoniae</em> and <em>Salmonella enteritidis</em> (Gram-negative pathogenic bacteria).</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108280"},"PeriodicalIF":4.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437044","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