Pub Date : 2025-04-10DOI: 10.1016/j.bmcl.2025.130239
Thang M. Le , Huyen N. Nguyen , Ngoc T. Vu , Phong Q. Le
Cabraleahydroxylactone (1a) and 3-epi-cabraleahydroxylactone (1b) are naturally diastereomers found in Aglaia abbreviata, known for their biological potential. While 1b has been synthesized and studied as an anti-diabetic agent, the activity of 1a remained unexplored. This study successfully enhanced 1a in the reaction mixture through the reduction of cabralealactone (2), increasing its ratio from trace levels to 9.5:1 (1b:1a). Molecular docking revealed distinct binding interactions of these diastereomers with α-glucosidase allosteric sites, suggesting a drug synergy mechanism. Kinetic studies confirmed non-competitive inhibition by both compounds, with 1a exhibiting superior binding affinity (lower Ki). Synergistic α-glucosidase inhibition was observed in specific 1b:1a ratios (9:1, 8:2, 2:8, and 1:9). Furthermore, these combinations displayed reduced hemolytic toxicity compared to individual compounds. The findings highlight the 1b:1a diastereomeric combination as a promising lead for anti-diabetic drug development, offering enhanced efficacy and safety through synergistic interactions.
{"title":"Synthesis and biological evaluation of diastereomeric natural products: Discovery of a novel synergistic combination for α-glucosidase inhibition","authors":"Thang M. Le , Huyen N. Nguyen , Ngoc T. Vu , Phong Q. Le","doi":"10.1016/j.bmcl.2025.130239","DOIUrl":"10.1016/j.bmcl.2025.130239","url":null,"abstract":"<div><div>Cabraleahydroxylactone (<strong>1a</strong>) and 3-epi-cabraleahydroxylactone (<strong>1b</strong>) are naturally diastereomers found in <em>Aglaia abbreviata</em>, known for their biological potential. While <strong>1b</strong> has been synthesized and studied as an anti-diabetic agent, the activity of <strong>1a</strong> remained unexplored. This study successfully enhanced <strong>1a</strong> in the reaction mixture through the reduction of cabralealactone (<strong>2</strong>), increasing its ratio from trace levels to 9.5:1 (<strong>1b</strong>:<strong>1a</strong>). Molecular docking revealed distinct binding interactions of these diastereomers with α-glucosidase allosteric sites, suggesting a drug synergy mechanism. Kinetic studies confirmed non-competitive inhibition by both compounds, with <strong>1a</strong> exhibiting superior binding affinity (lower Ki). Synergistic α-glucosidase inhibition was observed in specific <strong>1b</strong>:<strong>1a</strong> ratios (9:1, 8:2, 2:8, and 1:9). Furthermore, these combinations displayed reduced hemolytic toxicity compared to individual compounds. The findings highlight the <strong>1b</strong>:<strong>1a</strong> diastereomeric combination as a promising lead for anti-diabetic drug development, offering enhanced efficacy and safety through synergistic interactions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130239"},"PeriodicalIF":2.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-09DOI: 10.1016/j.bmcl.2025.130219
Weijie Ren , Lifang Cen , Xinyue Li , Jiajie Yu , Shiqi Wu , Jing Liu , Luhua Wang , Xiangying Kong , Yi Zou , Yungen Xu
Janus kinase 3 (JAK3), a member of the Janus kinase family, plays a pivotal role in the signaling pathways of various pro-inflammatory cytokines such as IL-2 and IFN-γ. Compared to non-selective JAK inhibitors, selective JAK3 inhibitors specifically target distinct signaling pathways, thereby reducing the broad inhibition of other cytokines and minimizing potential side effects. This selectivity renders them potentially advantageous for the treatment of autoimmune and inflammatory disease. In this study, we describe the discovery of compound X15, a novel JAK3 inhibitor with potent JAK3 inhibitory activity (IC50 = 14.56 nM) and an acceptable pharmacokinetic profile (F = 27.38 %, T1/2 = 20.33 h). Furthermore, compound X15 alleviated the symptoms of dermatitis in a DNCB-induced atopic dermatitis Balb/c mice model, with reduced ear thickness at a high dose (90 mg/kg, 0.038 mm) compared to the model group (0.106 mm). Preliminary mechanistic studies indicated that compound X15 inhibited the production of inflammatory cytokines IL-2 and IL-6 when compared to the model group. Collectively, our findings suggest that compound X15 is a novel covalent JAK3 inhibitor with promising in vitro and in vivo efficacy, potentially serving as a valuable molecular tool for exploring the biological functions of JAK3.
{"title":"Discovery of novel JAK3 inhibitors for the treatment of atopic dermatitis","authors":"Weijie Ren , Lifang Cen , Xinyue Li , Jiajie Yu , Shiqi Wu , Jing Liu , Luhua Wang , Xiangying Kong , Yi Zou , Yungen Xu","doi":"10.1016/j.bmcl.2025.130219","DOIUrl":"10.1016/j.bmcl.2025.130219","url":null,"abstract":"<div><div>Janus kinase 3 (JAK3), a member of the Janus kinase family, plays a pivotal role in the signaling pathways of various pro-inflammatory cytokines such as IL-2 and IFN-<em>γ</em>. Compared to non-selective JAK inhibitors, selective JAK3 inhibitors specifically target distinct signaling pathways, thereby reducing the broad inhibition of other cytokines and minimizing potential side effects. This selectivity renders them potentially advantageous for the treatment of autoimmune and inflammatory disease. In this study, we describe the discovery of compound <strong>X15</strong>, a novel JAK3 inhibitor with potent JAK3 inhibitory activity (IC<sub>50</sub> = 14.56 nM) and an acceptable pharmacokinetic profile (F = 27.38 %, T<sub>1/2</sub> = 20.33 h). Furthermore, compound <strong>X15</strong> alleviated the symptoms of dermatitis in a DNCB-induced atopic dermatitis Balb/c mice model, with reduced ear thickness at a high dose (90 mg/kg, 0.038 mm) compared to the model group (0.106 mm). Preliminary mechanistic studies indicated that compound <strong>X15</strong> inhibited the production of inflammatory cytokines IL-2 and IL-6 when compared to the model group. Collectively, our findings suggest that compound <strong>X15</strong> is a novel covalent JAK3 inhibitor with promising <em>in vitro</em> and <em>in vivo</em> efficacy, potentially serving as a valuable molecular tool for exploring the biological functions of JAK3.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130219"},"PeriodicalIF":2.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-09DOI: 10.1016/j.bmcl.2025.130238
Seong Hyun Kim , Yong Hwan Kim , Joon Bum Kim , Na Yeon Park , Jun Hee So , Daeun Park , Dong Kyu Choi , Eunbyul Yeom , Youngdae Gwon , Doo Sin Jo , Jin-A Lee , Ji-Eun Bae , Dong-Hyung Cho
Stress granules (SGs) are membrane-less cytoplasmic structures that form in response to various stress stimuli and play a critical role in maintaining cellular homeostasis. Dysregulation of SG dynamics has been implicated in several diseases, including neurodegenerative and inflammatory conditions; however, their role in skin biology remains largely unexplored. In this study, we identified pyridoxal hydrochloride, a form of vitamin B6, as a novel regulator of SG formation through a metabolite library screening. Our results demonstrate that pyridoxal hydrochloride significantly suppresses oxidative stress-induced SG formation in skin fibroblasts, exhibiting effects comparable to G3Ia, a known SG inhibitor. Furthermore, pyridoxal hydrochloride mitigates oxidative stress by reducing reactive oxygen species (ROS) accumulation and preventing cell toxicity. Notably, it also attenuates ROS-induced upregulation of MMP1, thereby preserving collagen1 stability. These findings suggest the crucial role of SGs in skin fibroblast homeostasis and suggest that pyridoxal hydrochloride may serve as a potential therapeutic agent for oxidative stress-related skin disorders.
{"title":"Suppression of stress granule assembly by pyridoxal hydrochloride attenuates oxidative damage in skin fibroblasts","authors":"Seong Hyun Kim , Yong Hwan Kim , Joon Bum Kim , Na Yeon Park , Jun Hee So , Daeun Park , Dong Kyu Choi , Eunbyul Yeom , Youngdae Gwon , Doo Sin Jo , Jin-A Lee , Ji-Eun Bae , Dong-Hyung Cho","doi":"10.1016/j.bmcl.2025.130238","DOIUrl":"10.1016/j.bmcl.2025.130238","url":null,"abstract":"<div><div>Stress granules (SGs) are membrane-less cytoplasmic structures that form in response to various stress stimuli and play a critical role in maintaining cellular homeostasis. Dysregulation of SG dynamics has been implicated in several diseases, including neurodegenerative and inflammatory conditions; however, their role in skin biology remains largely unexplored. In this study, we identified pyridoxal hydrochloride, a form of vitamin B6, as a novel regulator of SG formation through a metabolite library screening. Our results demonstrate that pyridoxal hydrochloride significantly suppresses oxidative stress-induced SG formation in skin fibroblasts, exhibiting effects comparable to G3Ia, a known SG inhibitor. Furthermore, pyridoxal hydrochloride mitigates oxidative stress by reducing reactive oxygen species (ROS) accumulation and preventing cell toxicity. Notably, it also attenuates ROS-induced upregulation of MMP1, thereby preserving collagen1 stability. These findings suggest the crucial role of SGs in skin fibroblast homeostasis and suggest that pyridoxal hydrochloride may serve as a potential therapeutic agent for oxidative stress-related skin disorders.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130238"},"PeriodicalIF":2.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-07DOI: 10.1016/j.bmcl.2025.130218
Miloš Svirčev , Mirjana Popsavin , Bojan Levovnik , Sanja Djokić , Jelena Kesić , Ivana Kovačević , Goran Benedeković , Bojana Srećo Zelenović , Velimir Popsavin , Vesna Kojić
Several new goniofufurone (1) and 7-epi-goniofufurone (2) mimics in which the benzene ring has been replaced with a thiazole residue have been designed, synthesized and evaluated for their antiproliferative activity against a panel of human tumour cell lines. The key steps of the synthesis represent the initial condensation of suitably protected furanose urononitriles with cysteine ethyl ester hydrochloride, followed by the subsequent oxidation of resulting C-4′ epimeric thiazolines with BrCCl3 and DBU, to build up the thiazole ring. Biological studies have shown that the HeLa cell line is most sensitive to the action of synthesized analogues with IC50 values in the range of 0.01–7.67 μM. The most active compound in this cell culture was 7-epi-goniofufurone mimic 28, with a thiazole-carboxamide function at C-7 and a benzyloxy group at the C-5 position. Compound 28 exhibited 89-fold higher antiproliferative potency in this cell line than lead 2 and was 7-fold more active than the commercial antitumour agent doxorubicin. A SAR study identified structural features responsible for the antiproliferative activity of synthesized analogues. The analogues 3–28 are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 4.1 to 17,470.7.
{"title":"Synthesis and antiproliferative activity of thiazole bioisosteres of goniofufurone and 7-epi-goniofufurone","authors":"Miloš Svirčev , Mirjana Popsavin , Bojan Levovnik , Sanja Djokić , Jelena Kesić , Ivana Kovačević , Goran Benedeković , Bojana Srećo Zelenović , Velimir Popsavin , Vesna Kojić","doi":"10.1016/j.bmcl.2025.130218","DOIUrl":"10.1016/j.bmcl.2025.130218","url":null,"abstract":"<div><div>Several new goniofufurone (<strong>1</strong>) and 7-<em>epi</em>-goniofufurone (<strong>2</strong>) mimics in which the benzene ring has been replaced with a thiazole residue have been designed, synthesized and evaluated for their antiproliferative activity against a panel of human tumour cell lines. The key steps of the synthesis represent the initial condensation of suitably protected furanose urononitriles with cysteine ethyl ester hydrochloride, followed by the subsequent oxidation of resulting C-4′ epimeric thiazolines with BrCCl<sub>3</sub> and DBU, to build up the thiazole ring. Biological studies have shown that the HeLa cell line is most sensitive to the action of synthesized analogues with IC<sub>50</sub> values in the range of 0.01–7.67 μM. The most active compound in this cell culture was 7-<em>epi</em>-goniofufurone mimic <strong>28</strong>, with a thiazole-carboxamide function at C-7 and a benzyloxy group at the C-5 position. Compound <strong>28</strong> exhibited 89-fold higher antiproliferative potency in this cell line than lead <strong>2</strong> and was 7-fold more active than the commercial antitumour agent doxorubicin. A SAR study identified structural features responsible for the antiproliferative activity of synthesized analogues. The analogues <strong>3</strong>–<strong>28</strong> are completely inactive toward the normal MRC-5 cell line. Their selectivity indexes (SI) range from 4.1 to 17,470.7.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130218"},"PeriodicalIF":2.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143800084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-07DOI: 10.1016/j.bmcl.2025.130231
Chongyun Zhou , Jiayun Wang , Lili Zhou , Hanxue Li , Xing Liu , Sen Wang , Xingyu Zhang , Xiaoqing Ye , Hongyu Ren , Kaile Zeng , Xiuming Li , Dan Wang , Jing Ji
The tumor suppressor protein p53 plays a crucial role in the pathogenesis of breast cancer; however, its function is often compromised due to MDM2 overexpression or mutations in the p53 gene, which occurs in approximately 30–35 % of breast cancer cases. Piperine, a natural bioactive compound, has shown potential in inhibiting breast cancer cell growth by upregulating p53 expression. However, its clinical application is hindered by poor bioavailability, potential toxicity, and the risk of undesirable drug interactions. In the present study, a novel derivative of Piperine, YL-1-9, was synthesized and evaluated for its anticancer activity against breast cancer. YL-1-9, a bicyclic amide derivative of Piperine, was evaluated for antitumor effects both in vitro and in vivo using MTT assays and the chick embryo chorioallantoic membrane (CAM) model. Further investigations into its effects on breast cancer cell clonogenicity, adhesion, invasion, and migration were conducted through colony formation assays, EdU assays, cell adhesion and invasion studies, and wound healing experiments. Western blot analysis was performed to elucidate the effects of YL-1-9 on the cell cycle and apoptosis, which were further validated using YO-PRO-1 and propidium iodide dual staining. YL-1-9 significantly inhibited breast cancer cell proliferation, adhesion, invasion, and migration, while inducing cell cycle arrest and promoting apoptosis. Mechanistically, YL-1-9 downregulated critical proteins in the CDK4/6-cyclin D-Rb-E2F pathway and the Caspase 3/Bax/Bcl-2 apoptosis signaling pathway. These findings position YL-1-9 as a promising candidate for breast cancer therapy; however, further clinical studies are necessary to fully assess its therapeutic potential.
{"title":"The novel Piperine derivative YL-1-9 exhibits anti-breast Cancer effects by inducing apoptosis via the p53/p21 pathway","authors":"Chongyun Zhou , Jiayun Wang , Lili Zhou , Hanxue Li , Xing Liu , Sen Wang , Xingyu Zhang , Xiaoqing Ye , Hongyu Ren , Kaile Zeng , Xiuming Li , Dan Wang , Jing Ji","doi":"10.1016/j.bmcl.2025.130231","DOIUrl":"10.1016/j.bmcl.2025.130231","url":null,"abstract":"<div><div>The tumor suppressor protein p53 plays a crucial role in the pathogenesis of breast cancer; however, its function is often compromised due to MDM2 overexpression or mutations in the p53 gene, which occurs in approximately 30–35 % of breast cancer cases. Piperine, a natural bioactive compound, has shown potential in inhibiting breast cancer cell growth by upregulating p53 expression. However, its clinical application is hindered by poor bioavailability, potential toxicity, and the risk of undesirable drug interactions. In the present study, a novel derivative of Piperine, <strong>YL-1-9</strong>, was synthesized and evaluated for its anticancer activity against breast cancer. <strong>YL-1-9</strong>, a bicyclic amide derivative of Piperine, was evaluated for antitumor effects both in vitro and in vivo using MTT assays and the chick embryo chorioallantoic membrane (CAM) model. Further investigations into its effects on breast cancer cell clonogenicity, adhesion, invasion, and migration were conducted through colony formation assays, EdU assays, cell adhesion and invasion studies, and wound healing experiments. Western blot analysis was performed to elucidate the effects of <strong>YL-1-9</strong> on the cell cycle and apoptosis, which were further validated using YO-PRO-1 and propidium iodide dual staining. <strong>YL-1-9</strong> significantly inhibited breast cancer cell proliferation, adhesion, invasion, and migration, while inducing cell cycle arrest and promoting apoptosis. Mechanistically, <strong>YL-1-9</strong> downregulated critical proteins in the CDK4/6-cyclin D-Rb-E2F pathway and the Caspase 3/Bax/Bcl-2 apoptosis signaling pathway. These findings position <strong>YL-1-9</strong> as a promising candidate for breast cancer therapy; however, further clinical studies are necessary to fully assess its therapeutic potential.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130231"},"PeriodicalIF":2.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-06DOI: 10.1016/j.bmcl.2025.130222
Jiaojiao Tu , Wa Cheng , Zhenghu Ban, Jiayi Ning, Xiangduan Tan
The farnesoid X receptor (FXR) is a promising therapeutic target for the treatment of non-alcoholic fatty liver disease (NAFLD). Salvia miltiorrhiza, a traditional Chinese medicine, has demonstrated significant efficacy in the prevention and treatment of liver diseases. Consequently, investigating the potential effects of Salvia miltiorrhiza on FXR could provide new insights for NAFLD treatment. This study explores whether active ingredients from Salvia miltiorrhiza can target FXR and serve as therapeutic agents for treating NAFLD. The findings revealed that cynaroside and lithospermic acid displayed strong FXR antagonistic activity, with IC50 values of 5.41 ± 1.08 μM and 16.92 ± 2.68 μM, respectively. Salvianolic acid A also showed moderate activity (IC50 = 56.35 ± 4.54 μM). MTT assays demonstrated that these three compounds were non-toxic to HepG2 and LO2 cells at a concentration of 200 μM. Molecular dynamics simulations were conducted to elucidate the interaction mechanisms of cynaroside and lithospermic acid with FXR. These results suggest that cynaroside and lithospermic acid from Salvia miltiorrhiza may be potential candidates for targeting FXR in treating NAFLD.
{"title":"Discovery of farnesoid X receptor antagonists from Salvia miltiorrhiza based on virtual screening and activity verification","authors":"Jiaojiao Tu , Wa Cheng , Zhenghu Ban, Jiayi Ning, Xiangduan Tan","doi":"10.1016/j.bmcl.2025.130222","DOIUrl":"10.1016/j.bmcl.2025.130222","url":null,"abstract":"<div><div>The farnesoid X receptor (FXR) is a promising therapeutic target for the treatment of non-alcoholic fatty liver disease (NAFLD). <em>Salvia miltiorrhiza</em>, a traditional Chinese medicine, has demonstrated significant efficacy in the prevention and treatment of liver diseases. Consequently, investigating the potential effects of <em>Salvia miltiorrhiza</em> on FXR could provide new insights for NAFLD treatment. This study explores whether active ingredients from <em>Salvia miltiorrhiza</em> can target FXR and serve as therapeutic agents for treating NAFLD. The findings revealed that cynaroside and lithospermic acid displayed strong FXR antagonistic activity, with IC<sub>50</sub> values of 5.41 ± 1.08 μM and 16.92 ± 2.68 μM, respectively. Salvianolic acid A also showed moderate activity (IC<sub>50</sub> = 56.35 ± 4.54 μM). MTT assays demonstrated that these three compounds were non-toxic to HepG2 and LO2 cells at a concentration of 200 μM. Molecular dynamics simulations were conducted to elucidate the interaction mechanisms of cynaroside and lithospermic acid with FXR. These results suggest that cynaroside and lithospermic acid from <em>Salvia miltiorrhiza</em> may be potential candidates for targeting FXR in treating NAFLD.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130222"},"PeriodicalIF":2.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-06DOI: 10.1016/j.bmcl.2025.130230
Junzhen Lin , Fuling Xiao , Sheng Han , Youhong Hu , Jianping Zuo , Xiankun Tong , Wuhong Chen
Novel Ebola entry inhibitors were designed and synthesized based on decahydroisoquinolines by streamlining non-essential functional groups that do not compromise activity. All novel derivatives were evaluated for their anti-Ebola activities and cytotoxicitiies in a defective Ebola virus model. A novel tetrahydroisoquinoline Ebola virus entry inhibitor, Hu7, was readily available with antiviral activity comparable to previous findings, while demonstrating a marked reduction in toxicity. Such new compounds with simple and easy-to-synthesize structures could be potential leads for further optimizing the development of anti-Ebola drugs.
{"title":"Discovery of novel Ebola entry inhibitors with 1,2,3,4-tetrahydroisoquinoline-3-carboxamide based on (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold","authors":"Junzhen Lin , Fuling Xiao , Sheng Han , Youhong Hu , Jianping Zuo , Xiankun Tong , Wuhong Chen","doi":"10.1016/j.bmcl.2025.130230","DOIUrl":"10.1016/j.bmcl.2025.130230","url":null,"abstract":"<div><div>Novel Ebola entry inhibitors were designed and synthesized based on decahydroisoquinolines by streamlining non-essential functional groups that do not compromise activity. All novel derivatives were evaluated for their anti-Ebola activities and cytotoxicitiies in a defective Ebola virus model. A novel tetrahydroisoquinoline Ebola virus entry inhibitor, <strong>Hu7</strong>, was readily available with antiviral activity comparable to previous findings, while demonstrating a marked reduction in toxicity. Such new compounds with simple and easy-to-synthesize structures could be potential leads for further optimizing the development of anti-Ebola drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130230"},"PeriodicalIF":2.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-05DOI: 10.1016/j.bmcl.2025.130221
Rainer E. Martin , Alexander L. Satz , Christoph Kuratli, Daniel Hunziker , Patrizio Mattei , Jérôme Hert , Christoph Ullmer , Markus G. Rudolph , André M. Alker, Remo Hochstrasser, Andreas Marx, Martin Binder, Stephan Müller
In recent years, lysophospholipase autotaxin (ATX) has emerged as an attractive target for treating a variety of human diseases, including inflammation, neurodegeneration, angiogenesis, cancer, ocular and fibrotic diseases, among others. Starting with the quinazolinone hit structure 1, which emerged from a DNA-encoded library screen, the potent, non-Zn2+ binding ATX inhibitor 31 with good overall physicochemical properties has been developed. This compound demonstrated a sustained reduction of lysophosphatidic acid (LPA) in an in vivo rat experiment, qualifying it as a proof-of-concept compound for further mechanistic studies.
{"title":"Optimization of a DNA encoded library derived autotaxin inhibitor hit to a potent in vivo LPA lowering quinazolinone compound with a non‑zinc binding mode","authors":"Rainer E. Martin , Alexander L. Satz , Christoph Kuratli, Daniel Hunziker , Patrizio Mattei , Jérôme Hert , Christoph Ullmer , Markus G. Rudolph , André M. Alker, Remo Hochstrasser, Andreas Marx, Martin Binder, Stephan Müller","doi":"10.1016/j.bmcl.2025.130221","DOIUrl":"10.1016/j.bmcl.2025.130221","url":null,"abstract":"<div><div>In recent years, lysophospholipase autotaxin (ATX) has emerged as an attractive target for treating a variety of human diseases, including inflammation, neurodegeneration, angiogenesis, cancer, ocular and fibrotic diseases, among others. Starting with the quinazolinone hit structure <strong>1,</strong> which emerged from a DNA-encoded library screen, the potent, non-Zn<sup>2+</sup> binding ATX inhibitor <strong>31</strong> with good overall physicochemical properties has been developed. This compound demonstrated a sustained reduction of lysophosphatidic acid (LPA) in an <em>in vivo</em> rat experiment, qualifying it as a proof-of-concept compound for further mechanistic studies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130221"},"PeriodicalIF":2.5,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The significant threat posed by Staphylococcus aureus (MRSA) is attributed to various antibiotic resistance and its role in severe infections. As an approach to combat this, a series of novel β-carboline-benzofuran based molecular hybrids were designed, synthesized, and evaluated for their antibacterial activity against Staphylococcus aureus ATCC 29213. Among the series, the minimum inhibitory concentration (MIC) of key compounds 13e, 13h, and 13q was determined to be 4 μg/mL, compared to ciprofloxacin 0.125 μg/mL. The docking results also supported the potent compounds' ability to inhibit DNA gyrase. These compounds demonstrated bacteriostatic effects at higher concentrations, with significant inhibition of biofilm formation (MBIC50 ranging from 12.78 to 30.68 μg/mL). Additionally, the compounds displayed minimal cytotoxicity against HepG2 cells and inhibited DNA gyrase, which is proven by DNA supercoiling assays and molecular docking studies. In addition, ADMET predictions indicated favorable drug-like properties, adhering to Lipinski's rule of five. These findings suggest that the synthesized β-carboline-benzofuran hybrids possess significant potential as leads for developing new antibacterial agents against MRSA.
{"title":"Design and synthesis of β-carboline-benzofuran based hybrids as antibacterial agents against Staphylococcus aureus","authors":"Mursalim Ali Khan , Kishan Kumar Parida , Dastari Sowmya , Naveen Chand Rallabandi , Nitin Pal Kalia , Nagula Shankaraiah","doi":"10.1016/j.bmcl.2025.130220","DOIUrl":"10.1016/j.bmcl.2025.130220","url":null,"abstract":"<div><div>The significant threat posed by <em>Staphylococcus aureus</em> (MRSA) is attributed to various antibiotic resistance and its role in severe infections. As an approach to combat this, a series of novel β-carboline-benzofuran based molecular hybrids were designed, synthesized, and evaluated for their antibacterial activity against <em>Staphylococcus aureus</em> ATCC 29213. Among the series, the minimum inhibitory concentration (MIC) of key compounds <strong>13e</strong>, <strong>13</strong> <strong>h</strong>, and <strong>13q</strong> was determined to be 4 μg/mL, compared to ciprofloxacin 0.125 μg/mL. The docking results also supported the potent compounds' ability to inhibit DNA gyrase. These compounds demonstrated bacteriostatic effects at higher concentrations, with significant inhibition of biofilm formation (MBIC<sub>50</sub> ranging from 12.78 to 30.68 μg/mL). Additionally, the compounds displayed minimal cytotoxicity against HepG2 cells and inhibited DNA gyrase, which is proven by DNA supercoiling assays and molecular docking studies. In addition, ADMET predictions indicated favorable drug-like properties, adhering to Lipinski's rule of five. These findings suggest that the synthesized β-carboline-benzofuran hybrids possess significant potential as leads for developing new antibacterial agents against MRSA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130220"},"PeriodicalIF":2.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-03DOI: 10.1016/j.bmcl.2025.130216
Ruel E. McKnight , Gavin S. Gullickson , Benjamin Kasper , Kevin Siegenthaler , Duanne A.C. Biggs , Roy B. Porter
A group of four structurally related abietane diterpenes (including royleanone and 7-acetoxy-horminone) were investigated for their DNA binding capabilities using isothermal titration calorimetry (ITC), circular dichroism (CD) and fluorescence displacement spectroscopy, and a topoisomerase DNA-unwinding assay. Both ITC and CD spectroscopy data indicate that the abietane diterpenes of this study exhibit strong binding to DNA, likely preferring a DNA-groove binding mode. Binding constants (K) were found to be in the order of 106–8 M−1 and were strongly enthalpically driven. The binding of all compounds to DNA was accompanied by large negative enthalpy changes (more than −20 kcal/mol) and negative entropy changes. The substituent at the 7th position of the abietane ring system was important in determining both the magnitude of binding and the propensity to stack within their DNA binding sites, with derivatives 7-one/ene > 7-OAc/H. This is significant given the reports that the identity of the substituent at position-7 is a strong determinant for bioactivity. Although the specific CD data observed was compound-dependent, most showed strong signal perturbations around one or both of the DNA signature wavelengths (245 and 280 nm). However, we do not attribute these perturbations to DNA intercalation. Compounds that were capable of self-stacking (i.e., 7-ene and 7-one) were also able to elicit very strong positively induced CD signal (ICD) around 330 nm, as well as perturbations at higher wavelengths. Additionally, topoisomerase DNA-unwinding and ethidium fluorescence displacement assays were used to corroborate the DNA binding mode, which was found to be consistent with the abietane diterpene compounds adopting a non-intercalative DNA binding mode.
研究人员利用等温滴定量热法（ITC）、圆二色光谱法（CD）和荧光位移光谱法以及拓扑异构酶 DNA 解旋试验，对一组结构相关的四种阿比坦二萜（包括罗利酮和 7-乙酰氧基荷茗酮）的 DNA 结合能力进行了研究。ITC 和 CD 光谱数据都表明，本研究中的阿比坦二萜与 DNA 的结合力很强，可能更倾向于 DNA 沟槽结合模式。研究发现，结合常数（K）在 106-8 M-1 的数量级，具有很强的焓驱动性。所有化合物与 DNA 的结合都伴随着巨大的负焓变（超过 -20 kcal/mol）和负熵变。阿比坦环系统第 7 位上的取代基对决定其 DNA 结合位点的结合程度和堆叠倾向都很重要，其中衍生物 7-one/ene > 7-OAc/H。鉴于有报告称 7 号位取代基的特性是生物活性的重要决定因素，这一点意义重大。虽然观察到的特定 CD 数据取决于化合物，但大多数都在一个或两个 DNA 标志波长（245 和 280 nm）附近显示出强烈的信号扰动。不过，我们并没有将这些扰动归因于 DNA 插层。能够自叠层的化合物（即 7-ene 和 7-one）也能在 330 nm 附近引起非常强的正向诱导 CD 信号 (ICD)，并在更高波长处产生扰动。此外，研究人员还使用拓扑异构酶 DNA 解旋和乙酞荧光位移试验来证实 DNA 结合模式，结果表明阿比特烷二萜化合物采用了非交联 DNA 结合模式。
{"title":"DNA binding studies of abietane diterpenes natural products using isothermal titration calorimetry, circular dichroism, fluorescence and gel assays","authors":"Ruel E. McKnight , Gavin S. Gullickson , Benjamin Kasper , Kevin Siegenthaler , Duanne A.C. Biggs , Roy B. Porter","doi":"10.1016/j.bmcl.2025.130216","DOIUrl":"10.1016/j.bmcl.2025.130216","url":null,"abstract":"<div><div>A group of four structurally related abietane diterpenes (including royleanone and 7-acetoxy-horminone) were investigated for their DNA binding capabilities using isothermal titration calorimetry (ITC), circular dichroism (CD) and fluorescence displacement spectroscopy, and a topoisomerase DNA-unwinding assay. Both ITC and CD spectroscopy data indicate that the abietane diterpenes of this study exhibit strong binding to DNA, likely preferring a DNA-groove binding mode. Binding constants (<em>K</em>) were found to be in the order of 10<sup>6–8</sup> M<sup>−1</sup> and were strongly enthalpically driven. The binding of all compounds to DNA was accompanied by large negative enthalpy changes (more than −20 kcal/mol) and negative entropy changes. The substituent at the 7th position of the abietane ring system was important in determining both the magnitude of binding and the propensity to stack within their DNA binding sites, with derivatives 7-one/ene > 7-OAc/H. This is significant given the reports that the identity of the substituent at position-7 is a strong determinant for bioactivity. Although the specific CD data observed was compound-dependent, most showed strong signal perturbations around one or both of the DNA signature wavelengths (245 and 280 nm). However, we do not attribute these perturbations to DNA intercalation. Compounds that were capable of self-stacking (i.e., 7-ene and 7-one) were also able to elicit very strong positively induced CD signal (ICD) around 330 nm, as well as perturbations at higher wavelengths. Additionally, topoisomerase DNA-unwinding and ethidium fluorescence displacement assays were used to corroborate the DNA binding mode, which was found to be consistent with the abietane diterpene compounds adopting a non-intercalative DNA binding mode.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130216"},"PeriodicalIF":2.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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