Pub Date : 2025-03-21DOI: 10.1016/j.bmcl.2025.130191
Masaki Meguro , Fuminao Doi , Tsuyoshi Soneda , Shinji Furuzono , Masahiro Konishi , Jun Harada , Jun Tanaka , Shinichi Inoue , Makoto Ono , Katsuji Kagechika
The glucose transporter 4 (GLUT4) is a high-affinity glucose transporter that is predominantly expressed in the skeletal muscle, myocardium, and adipose tissue, and is the rate-limiting transporter of insulin-stimulated glucose uptake. Compounds that enhance the process of GLUT4 translocation in skeletal muscle would provide a novel treatment for type 2 diabetes mellitus. After a high-throughput screening (HTS) campaign and medicinal chemistry efforts, we identified the xanthene compound DS-1150b (16·tBuNH2) as a novel potent GLUT4 translocation enhancer. DS-1150b was found to promote GLUT4 translocation in L6-myotubes in rats and showed a glucose-lowering effect in an oral glucose tolerance test (oGTT) in a Zucker fatty rat model. Identification of naphthalene analog DS20060511 is also briefly described.
{"title":"Discovery of DS-1150b, a novel xanthene compound for activating GLUT4 translocation","authors":"Masaki Meguro , Fuminao Doi , Tsuyoshi Soneda , Shinji Furuzono , Masahiro Konishi , Jun Harada , Jun Tanaka , Shinichi Inoue , Makoto Ono , Katsuji Kagechika","doi":"10.1016/j.bmcl.2025.130191","DOIUrl":"10.1016/j.bmcl.2025.130191","url":null,"abstract":"<div><div>The glucose transporter 4 (GLUT4) is a high-affinity glucose transporter that is predominantly expressed in the skeletal muscle, myocardium, and adipose tissue, and is the rate-limiting transporter of insulin-stimulated glucose uptake. Compounds that enhance the process of GLUT4 translocation in skeletal muscle would provide a novel treatment for type 2 diabetes mellitus. After a high-throughput screening (HTS) campaign and medicinal chemistry efforts, we identified the xanthene compound DS-1150b (16·<em>t</em>BuNH<sub>2</sub>) as a novel potent GLUT4 translocation enhancer. DS-1150b was found to promote GLUT4 translocation in L6-myotubes in rats and showed a glucose-lowering effect in an oral glucose tolerance test (oGTT) in a Zucker fatty rat model. Identification of naphthalene analog DS20060511 is also briefly described.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130191"},"PeriodicalIF":2.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143684849","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 : 2025-03-21DOI: 10.1016/j.bmcl.2025.130194
Panagiotis Theodosis-Nobelos, Eleni A Rekka
Oxidative stress induces the signaling of inflammatory and apoptotic pathways leading to the progression of degenerative disorders, whilst lipid increase and oxidation is an important factor for their development and propagation. L-tyrosine and L-proline amino acids and their derivatives have shown to be implicated in several of these aspects in a positive manner. In this prospect, methyl esters of these amino acids, amidated with the antioxidants trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (hydroxylated cinnamic acid compound), as well as the classical NSAID diclofenac, were prepared and evaluated as antioxidant, anti-inflammatory and anti-hyperlipidemic agents. Almost all compounds presented high or moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and lipid peroxidation inhibitory activity, reaching up to 12 fold (in the lipid peroxidation inhibition) that of the parent antioxidant acids, such as trolox, whilst the insertion of the tyrosine moiety seemed to offer additional antioxidant potency, especially in the case of the NSAID derivative (compound 3). The majority of them displayed significant in vivo acute inflammation reduction (decrease of paw oedema, induced by carrageenan, 33-78 % at 150 μmol/kg) ability. The most active trolox-proline hybrid (compound 4) exhibited more than two fold increased inhibition in comparison to the well-established NSAIDs ibuprofen and diclofenac. They were also moderate inhibitors of soybean lipoxygenase, however active, in several cases, compared to their parent acid molecules. The most profound activity of the compounds was the reduction of the plasma lipidemic indices (Triton-induced hyperlipidemia in rats). Compound 5 was the most potent, with decrease in triglycerides, total cholesterol and low density lipoprotein, by 56 %, 87 %, and 72 %, respectively at 150 μmol/kg (i.p.), slightly better than that of simvastatin. Thus, the insertion of proline and tyrosine moieties seem to improve the anti-inflammatory activity of parent acids and NSAIDs, resulting in compounds with two or more pharmacological features (including hypolipidemic activity), which might be beneficial in cases characterized by inflammatory, oxidative, hyperlipidemic and degenerative conditions.
{"title":"Tyrosine and proline conjugated trolox, hydroxy-cinnnamic acid and diclofenac hybrids as strong hypolipidemic and anti-inflammatory agents.","authors":"Panagiotis Theodosis-Nobelos, Eleni A Rekka","doi":"10.1016/j.bmcl.2025.130194","DOIUrl":"https://doi.org/10.1016/j.bmcl.2025.130194","url":null,"abstract":"<p><p>Oxidative stress induces the signaling of inflammatory and apoptotic pathways leading to the progression of degenerative disorders, whilst lipid increase and oxidation is an important factor for their development and propagation. L-tyrosine and L-proline amino acids and their derivatives have shown to be implicated in several of these aspects in a positive manner. In this prospect, methyl esters of these amino acids, amidated with the antioxidants trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (hydroxylated cinnamic acid compound), as well as the classical NSAID diclofenac, were prepared and evaluated as antioxidant, anti-inflammatory and anti-hyperlipidemic agents. Almost all compounds presented high or moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and lipid peroxidation inhibitory activity, reaching up to 12 fold (in the lipid peroxidation inhibition) that of the parent antioxidant acids, such as trolox, whilst the insertion of the tyrosine moiety seemed to offer additional antioxidant potency, especially in the case of the NSAID derivative (compound 3). The majority of them displayed significant in vivo acute inflammation reduction (decrease of paw oedema, induced by carrageenan, 33-78 % at 150 μmol/kg) ability. The most active trolox-proline hybrid (compound 4) exhibited more than two fold increased inhibition in comparison to the well-established NSAIDs ibuprofen and diclofenac. They were also moderate inhibitors of soybean lipoxygenase, however active, in several cases, compared to their parent acid molecules. The most profound activity of the compounds was the reduction of the plasma lipidemic indices (Triton-induced hyperlipidemia in rats). Compound 5 was the most potent, with decrease in triglycerides, total cholesterol and low density lipoprotein, by 56 %, 87 %, and 72 %, respectively at 150 μmol/kg (i.p.), slightly better than that of simvastatin. Thus, the insertion of proline and tyrosine moieties seem to improve the anti-inflammatory activity of parent acids and NSAIDs, resulting in compounds with two or more pharmacological features (including hypolipidemic activity), which might be beneficial in cases characterized by inflammatory, oxidative, hyperlipidemic and degenerative conditions.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130194"},"PeriodicalIF":2.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690488","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 : 2025-03-17DOI: 10.1016/j.bmcl.2025.130189
Zhengyi Li , Xingchen Yang , Shun Wang , Hongzhao Ma , Ke Yang , Jing Shi , Xin Wang
This study aims to design and develop novel and efficient anti-hypoxic cell tumor drugs. Using the TH-302 as lead compound, structural modifications are conducted to synthesize a series of novel derivatives to investigate the structural activity relationship (SAR) against ovarian cancer cell line (SKOV3) and glioblastoma cell line (U87MG) in vitro. The structural modifications mainly include four aspects: changes in substituents on N; changes in isomers; changes in nitro group position; changes in substituting halogens in phosphoramide mustard. The results of CCK-8 assay indicate that the steric hindrance and electronic effects of substituents on N have significant impacts on the activity, while changes in nitro group positions have minimal effects on the activity, and Bromo-phosphoramide mustard exhibits better activity than Chloro-phosphoramide mustard. Compounds 15c and 16d exhibit significantly superior antitumor activity compared to TH-302, with IC50 values of 42 μM and 32 μM for SKOV3 cells, and IC50 values of 47 μM and 41 μM for U87MG cells, respectively.
{"title":"Design, synthesis, and biological evaluation of hypoxic-activation prodrug TH-302 derivatives","authors":"Zhengyi Li , Xingchen Yang , Shun Wang , Hongzhao Ma , Ke Yang , Jing Shi , Xin Wang","doi":"10.1016/j.bmcl.2025.130189","DOIUrl":"10.1016/j.bmcl.2025.130189","url":null,"abstract":"<div><div>This study aims to design and develop novel and efficient anti-hypoxic cell tumor drugs. Using the TH-302 as lead compound, structural modifications are conducted to synthesize a series of novel derivatives to investigate the structural activity relationship (SAR) against ovarian cancer cell line (SKOV3) and glioblastoma cell line (U87MG) in vitro. The structural modifications mainly include four aspects: changes in substituents on N; changes in isomers; changes in nitro group position; changes in substituting halogens in phosphoramide mustard. The results of CCK-8 assay indicate that the steric hindrance and electronic effects of substituents on N have significant impacts on the activity, while changes in nitro group positions have minimal effects on the activity, and Bromo-phosphoramide mustard exhibits better activity than Chloro-phosphoramide mustard. Compounds <strong>15c</strong> and <strong>16d</strong> exhibit significantly superior antitumor activity compared to TH-302, with IC<sub>50</sub> values of 42 μM and 32 μM for SKOV3 cells, and IC<sub>50</sub> values of 47 μM and 41 μM for U87MG cells, respectively.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130189"},"PeriodicalIF":2.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661869","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 : 2025-03-17DOI: 10.1016/j.bmcl.2025.130190
Hongtao Xu , Dong Ding , Xingchun Han , Kun Miao , Chungen Liang , Hongying Yun , Wei Zhu , Fabian Dey , Dan Zhao , Yao Wu , Michael Reutlinger , June Yang , Guanglei Zhai , Zhaohu Lin , Chiho Li , Waikong Wu , Bruce Xu , Li Han , Shuai Chen , Xinyi Huang , Ge Zou
Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10–100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.
{"title":"Discovery of ATP competitive PDHK1/2 dual inhibitors","authors":"Hongtao Xu , Dong Ding , Xingchun Han , Kun Miao , Chungen Liang , Hongying Yun , Wei Zhu , Fabian Dey , Dan Zhao , Yao Wu , Michael Reutlinger , June Yang , Guanglei Zhai , Zhaohu Lin , Chiho Li , Waikong Wu , Bruce Xu , Li Han , Shuai Chen , Xinyi Huang , Ge Zou","doi":"10.1016/j.bmcl.2025.130190","DOIUrl":"10.1016/j.bmcl.2025.130190","url":null,"abstract":"<div><div>Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10–100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130190"},"PeriodicalIF":2.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661870","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}
Lipopeptides with different fatty acids (palmitic, palmitoleic, stearic, oleic, and linoleic acids) conjugated to CHSPKKKRKV were synthesised by a solid-phase peptide method using the Fmoc strategy (Fmoc-SPPS) on 2-CTC (2-chlorotritylchloride) resin. The lipopeptides were purified by RP-HPLC and characterised by ToF-ESI-MS and 1D-NMR. The capability of the lipopeptide to interact with the plasmid was evaluated by DNA agarose gel electrophoresis. The particle size of the lipopeptide/DNA complexes was determined by dynamic light scattering assay and TEM analysis. The biological activities including cytotoxicity, nitrite oxide (NO) release, and IL-6 and TNF-α production were evaluated in RAW 264.7 cells. ToF-ESI-MS revealed [M + 2H]2+ and [M + 3H]3+ ion peaks which were validated by 1H NMR and 13C NMR, confirming the lipopeptide molecular structure. All lipopeptides condensed and protected the DNA plasmid from enzymatic degradation at the lipopeptide/DNA mass ratio of 2:1. In addition, the size of the cationic lipopeptide/DNA complexes ranged from ∼250 to 700 nm. The lipopeptides showed moderate cytotoxicity with IC50 values ranging from 120 to 190 ppm, induced NO release (275–1060 ppm) and IL-6 (40–497 pg) and TNF-α (150–270 pg) production with the highest level achieved by C(18,0)-CHSPKKKRKV. In conclusion, CHSPKKKRKV-based lipopeptides with different fatty acids are potential adjuvant candidates but further evaluation in animal models is required.
{"title":"In-vitro evaluation of cationic Lipopeptides as adjuvant candidate for DNA plasmid vaccine","authors":"Syahrul Febrian Hasbullah , Ace Tatang Hidayat , Tarwadi , Adinda Nurhidayatul Fajri , Nurlelasari , Desi Harneti , Kindi Farabi , Unang Supratman , Rani Maharani","doi":"10.1016/j.bmcl.2025.130183","DOIUrl":"10.1016/j.bmcl.2025.130183","url":null,"abstract":"<div><div>Lipopeptides with different fatty acids (palmitic, palmitoleic, stearic, oleic, and linoleic acids) conjugated to CHSPKKKRKV were synthesised by a solid-phase peptide method using the Fmoc strategy (Fmoc-SPPS) on 2-CTC (2-chlorotritylchloride) resin. The lipopeptides were purified by RP-HPLC and characterised by ToF-ESI-MS and 1D-NMR. The capability of the lipopeptide to interact with the plasmid was evaluated by DNA agarose gel electrophoresis. The particle size of the lipopeptide/DNA complexes was determined by dynamic light scattering assay and TEM analysis. The biological activities including cytotoxicity, nitrite oxide (NO) release, and IL-6 and TNF-α production were evaluated in RAW 264.7 cells. ToF-ESI-MS revealed [M + 2H]<sup>2+</sup> and [M + 3H]<sup>3+</sup> ion peaks which were validated by <sup>1</sup>H NMR and <sup>13</sup>C NMR, confirming the lipopeptide molecular structure. All lipopeptides condensed and protected the DNA plasmid from enzymatic degradation at the lipopeptide/DNA mass ratio of 2:1. In addition, the size of the cationic lipopeptide/DNA complexes ranged from ∼250 to 700 nm. The lipopeptides showed moderate cytotoxicity with IC<sub>50</sub> values ranging from 120 to 190 ppm, induced NO release (275–1060 ppm) and IL-6 (40–497 pg) and TNF-α (150–270 pg) production with the highest level achieved by C<sub>(18,0)</sub>-CHSPKKKRKV. In conclusion, CHSPKKKRKV-based lipopeptides with different fatty acids are potential adjuvant candidates but further evaluation in animal models is required.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130183"},"PeriodicalIF":2.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143636525","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 treatment of non-small cell lung cancer (NSCLC) is significantly challenged by the development of acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors, such as Osimertinib, which limits their therapeutic efficacy. Using the EGFR L858R/T790M/C797S inhibitor Brigatinib as a reference compound, we designed and synthesized 24 target compounds with aminopyrimidine as the core structure. Among these, the representative compound IIB-5 demonstrated potent inhibition of EGFRL858R/T790M/C797S, achieving an IC50 value of 18.81 nM. It also exhibited strong inhibition against Ba/F3-EGFRL858R/T790M/C797S cells with an IC50 of 97.12 nM, showing a five-fold potency increase over Brigatinib. Compound IIB-5 provides a valuable reference for further research on EGFR inhibitors.
{"title":"Design, synthesis, and biological evaluation of novel aminopyrimidine derivatives as EGFR inhibitors","authors":"Huabing Wang , Yule Gui , Shengkai Cui, Xinyi Long, Weizheng Fan, Chunlei Tang","doi":"10.1016/j.bmcl.2025.130188","DOIUrl":"10.1016/j.bmcl.2025.130188","url":null,"abstract":"<div><div>The treatment of non-small cell lung cancer (NSCLC) is significantly challenged by the development of acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors, such as Osimertinib, which limits their therapeutic efficacy. Using the EGFR <sup>L858R/T790M/C797S</sup> inhibitor Brigatinib as a reference compound, we designed and synthesized 24 target compounds with aminopyrimidine as the core structure. Among these, the representative compound <strong>IIB-5</strong> demonstrated potent inhibition of EGFR<sup>L858R/T790M/C797S</sup>, achieving an IC<sub>50</sub> value of 18.81 nM. It also exhibited strong inhibition against Ba/F3-EGFR<sup>L858R/T790M/C797S</sup> cells with an IC<sub>50</sub> of 97.12 nM, showing a five-fold potency increase over Brigatinib. Compound <strong>IIB-5</strong> provides a valuable reference for further research on EGFR inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130188"},"PeriodicalIF":2.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633300","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 : 2025-03-13DOI: 10.1016/j.bmcl.2025.130185
Lin Yuan , Qing-Ru Chu , Feng-Xin Li, Da-Kui Zhang, Ya-Xin Yu, Jing-Chang Liu
According to the bioisosterism principle and activity substructure splicing strategy, new pamicogrel derivatives were designed, synthesized, and evaluated for their antiplatelet aggregation activities in vitro. Bioassay results showed that compound SZ displayed superior in vitro antiplatelet aggregation activities induced by Arachidonic Acid (AA) and Collagen (COL) with the IC50 values of 3.44 and 2.23 mg/mL, respectively. Compound BMPA showed apparent antiplatelet aggregation towards Adenosine Diphosphate (ADP) with a IC50 value of 2.79 mg/mL. Significantly, compound K-10 exhibited the most antiplatelet aggregation activity to the aggregation of platelet induced by AA, ADP, and COL, representing a promising lead compound for further study.
{"title":"Design, synthesis, and biological evaluation of Pamicogrel derivatives as potential antiplatelet agents","authors":"Lin Yuan , Qing-Ru Chu , Feng-Xin Li, Da-Kui Zhang, Ya-Xin Yu, Jing-Chang Liu","doi":"10.1016/j.bmcl.2025.130185","DOIUrl":"10.1016/j.bmcl.2025.130185","url":null,"abstract":"<div><div>According to the bioisosterism principle and activity substructure splicing strategy, new pamicogrel derivatives were designed, synthesized, and evaluated for their antiplatelet aggregation activities <em>in vitro</em>. Bioassay results showed that compound <strong>SZ</strong> displayed superior <em>in vitro</em> antiplatelet aggregation activities induced by Arachidonic Acid (AA) and Collagen (COL) with the IC<sub>50</sub> values of 3.44 and 2.23 mg/mL, respectively. Compound <strong>BMPA</strong> showed apparent antiplatelet aggregation towards Adenosine Diphosphate (ADP) with a IC<sub>50</sub> value of 2.79 mg/mL. Significantly, compound <strong>K-10</strong> exhibited the most antiplatelet aggregation activity to the aggregation of platelet induced by AA, ADP, and COL, representing a promising lead compound for further study.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130185"},"PeriodicalIF":2.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629991","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 : 2025-03-13DOI: 10.1016/j.bmcl.2025.130184
Stéphane Dorich , Anick Auger , Li Wang , Jason Burch , Charles Pellerin , Silas Chan , Marianne Raymond , Lingling Zhang , Amandine Chefson , Marie-Anne Germain , Silvana Jananji , Valérie Dumais , Samuel Gaudreault , Alexandre Caron , Émilie Dumas-Bérubé , Michael. A. Crackower
NLRP3 is a key regulator of the innate immune system involved in sensing a variety of pathogen and danger signals. Priming and activation of NLRP3 leads to the release and maturation of pro-inflammatory cytokines, as well as gasdermin D-mediated cell death. Inhibition of dysregulated NLRP3 activity has been associated with promising therapeutic opportunities for a variety of systemic and neurological diseases including atherosclerosis and Parkinson's disease. Herein, we discuss how a high-throughput screen (HTS) allowed us to discover new chemical scaffolds that specifically bind to NLRP3 and inhibit its function in a selective manner. We also describe how an enantiomer of HTS hit 5, compound 11, demonstrated in vivo inhibition of NLRP3.
{"title":"Discovery of novel NLRP3 inhibitors enabled by a high-throughput screen","authors":"Stéphane Dorich , Anick Auger , Li Wang , Jason Burch , Charles Pellerin , Silas Chan , Marianne Raymond , Lingling Zhang , Amandine Chefson , Marie-Anne Germain , Silvana Jananji , Valérie Dumais , Samuel Gaudreault , Alexandre Caron , Émilie Dumas-Bérubé , Michael. A. Crackower","doi":"10.1016/j.bmcl.2025.130184","DOIUrl":"10.1016/j.bmcl.2025.130184","url":null,"abstract":"<div><div>NLRP3 is a key regulator of the innate immune system involved in sensing a variety of pathogen and danger signals. Priming and activation of NLRP3 leads to the release and maturation of pro-inflammatory cytokines, as well as gasdermin D-mediated cell death. Inhibition of dysregulated NLRP3 activity has been associated with promising therapeutic opportunities for a variety of systemic and neurological diseases including atherosclerosis and Parkinson's disease. Herein, we discuss how a high-throughput screen (HTS) allowed us to discover new chemical scaffolds that specifically bind to NLRP3 and inhibit its function in a selective manner. We also describe how an enantiomer of HTS hit <strong>5</strong>, compound <strong>11</strong>, demonstrated <em>in vivo</em> inhibition of NLRP3.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130184"},"PeriodicalIF":2.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633302","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 : 2025-03-12DOI: 10.1016/j.bmcl.2025.130186
David Hozain , Kevin Cottet , Yann Fromentin , Annabelle Dugay , Florence Souquet , Elisabeth Mouray , Philippe Grellier , Didier Buisson , Raimundo Gonçalves de Oliveira Junior , Marie-Christine Lallemand
This study introduces third-generation derivatives of guttiferone A, designed to enhance both bioactivity and selectivity against Plasmodium falciparum and Trypanosoma brucei. Following an optimized synthetic route, two dioxolane derivatives of 3,16-oxyguttiferone A were prepared: 14-monodioxolane-3,16-oxyguttiferone A (3) and 13,14-bisdioxolane-3,16-oxyguttiferone A (4). Biological evaluation revealed compound 3 to be the most effective, with a selectivity index (SI) of 457.1 against Trypanosoma brucei brucei strain and 57.1 against P. falciparum, significantly outperforming its precursors. Compound 4 also demonstrated substantial activity with an SI of 143.8 against T. brucei. These results highlight the potential of targeted structural modifications, particularly monodioxolane substitution, to improve the pharmacological profile of guttiferone A derivatives.
{"title":"Third-generation analogues of Guttiferone A","authors":"David Hozain , Kevin Cottet , Yann Fromentin , Annabelle Dugay , Florence Souquet , Elisabeth Mouray , Philippe Grellier , Didier Buisson , Raimundo Gonçalves de Oliveira Junior , Marie-Christine Lallemand","doi":"10.1016/j.bmcl.2025.130186","DOIUrl":"10.1016/j.bmcl.2025.130186","url":null,"abstract":"<div><div>This study introduces third-generation derivatives of guttiferone A, designed to enhance both bioactivity and selectivity against <em>Plasmodium falciparum</em> and <em>Trypanosoma brucei</em>. Following an optimized synthetic route, two dioxolane derivatives of 3,16-oxyguttiferone A were prepared: 14-monodioxolane-3,16-oxyguttiferone A (<strong>3</strong>) and 13,14-bisdioxolane-3,16-oxyguttiferone A (<strong>4</strong>). Biological evaluation revealed compound <strong>3</strong> to be the most effective, with a selectivity index (SI) of 457.1 against <em>Trypanosoma brucei brucei</em> strain and 57.1 against <em>P. falciparum</em>, significantly outperforming its precursors. Compound <strong>4</strong> also demonstrated substantial activity with an SI of 143.8 against <em>T. brucei</em>. These results highlight the potential of targeted structural modifications, particularly monodioxolane substitution, to improve the pharmacological profile of guttiferone A derivatives.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130186"},"PeriodicalIF":2.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-12DOI: 10.1016/j.bmcl.2025.130187
Nan Zhang , Junyi Zhu , Xin Hu , Yuxuan Zhou , Qianhui Wang , Shuyue Cai , Quan Xie , Ling Qiu , Gaochao Lv , Jianguo Lin
Accurate identification of programmed cell death ligand 1 (PD-L1) expression is crucial for anti-tumor immunotherapy. However, the heterogeneity of PD-L1 expression in tumors makes it challenging to detect by immunohistochemistry. In this study, we developed two novel PD-L1 small-molecule PET tracers, [18F]LGT-1 and [18F]LGT-2, to enable the non-invasive and precise measurement of PD-L1 expression in tumors through PET imaging. The radiochemical yields for [18F]LGT-1 and [18F]LGT-2 were 12.54±2.73% and 10.54±2.21%, respectively, with both tracers exhibiting approximately 98% radiochemical purity and molar activities of 12.23±2.84 GBq/μmol and 11.41±1.47 GBq/μmol. Both tracers demonstrated good stability in PBS (pH 7.4) and mouse serum after 2 hours of incubation. In cellular uptake assays, [18F]LGT-1 achieved a maximum uptake of 5.47±0.03 %AD at 4 hours, which could be significantly inhibited by the non-radioactive compound LGT-1. In contrast, [18F]LGT-2 exhibited high non-specific uptake in tumor cells. PET imaging revealed that [18F]LGT-1 quickly accumulated in tumors within 5 minutes, achieving an uptake of 1.48±0.15 %ID/mL, and maintained a stable level for 60 minutes, while [18F]LGT-2 showed minimal tumor uptake. Additionally, [18F]LGT-1 had significantly lower liver uptake compared to [18F]LGT-2. Despite the high uptake in non-target tissues for [18F]LGT-1, which complicates its application, this study provides new insights for developing novel PD-L1 small-molecule tracers, with further optimization of the tracers currently in progress.
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