Pub Date : 2024-11-12DOI: 10.1016/j.ejmech.2024.117031
Feng-Teng Gao , Ming Zhang , Yuna Shimadate , Atsushi Kato , Yi-Xian Li , Yue-Mei Jia , Chu-Yi Yu
Six C-6 fluorinated d-swainsonine derivatives and their enantiomers have been designed based on initial docking calculations, and synthesized from enantiomeric ribose-derived aldehydes, respectively. Glycosidase inhibition assay of these derivatives with d-swainsonine (1) and l-swainsonine (ent-1) as contrasts found that the C-6 fluorinated d-swainsonine derivatives with C-8 configurations as R (α) showed specific and potent inhibitions of jack bean α-mannosidase (model enzyme of Golgi α-mannosidase II); whereas their enantiomers with C-8 configurations as S (β) were powerful and selective α-l-rhamnosidase inhibitors. Molecular docking calculations found the C-6 fluorinatedd-swainsonine derivatives 21, 24 and 25 with highly coincident binding conformations with d-swainsonine (1) in their interactions with the active site of α-mannosidase (PDB ID: 1HWW). Reliability of the docking results were confirmed by Molecular Dynamics (MD) simulation. Additionally, solid interactions with residues Gln-392 and Tyr-393 in the active site of α-l-rhamnosidase (PDB ID: 3W5N) were proved to be vital for potent α-l-rhamnosidase inhibitions of the l-swainsonine derivatives. The role of C-6 fluorines in swainsonine derivatives well demonstrated the “mimic effect” of fluorine to hydrogen by minimal influence on the binding conformations and effective compensation for any possible lost interactions. This work contributes to a comprehensive understanding of the structure-activity relationship (SAR) of the fluorinated swainsonines and ever reported branched swainsonines, and has laid good foundation for development of more potent α-mannosidase and α-l-rhamnosidase inhibitors.
{"title":"Enantiomeric C-6 fluorinated swainsonine derivatives as highly selective and potent inhibitors of α-mannosidase and α-l-rhamnosidase: Design, synthesis and structure-activity relationship study","authors":"Feng-Teng Gao , Ming Zhang , Yuna Shimadate , Atsushi Kato , Yi-Xian Li , Yue-Mei Jia , Chu-Yi Yu","doi":"10.1016/j.ejmech.2024.117031","DOIUrl":"10.1016/j.ejmech.2024.117031","url":null,"abstract":"<div><div>Six C-6 fluorinated <span>d</span>-swainsonine derivatives and their enantiomers have been designed based on initial docking calculations, and synthesized from enantiomeric ribose-derived aldehydes, respectively. Glycosidase inhibition assay of these derivatives with <span>d</span>-swainsonine (<strong>1</strong>) and <span>l</span>-swainsonine (<strong><em>ent</em>-1</strong>) as contrasts found that the C-6 fluorinated <span>d</span>-swainsonine derivatives with C-8 configurations as <em>R</em> (α) showed specific and potent inhibitions of jack bean α-mannosidase (model enzyme of Golgi α-mannosidase II); whereas their enantiomers with C-8 configurations as <em>S</em> (β) were powerful and selective α-<span>l</span>-rhamnosidase inhibitors. Molecular docking calculations found the C-6 fluorinated<span>d</span>-swainsonine derivatives <strong>21</strong>, <strong>24</strong> and <strong>25</strong> with highly coincident binding conformations with <span>d</span>-swainsonine (<strong>1</strong>) in their interactions with the active site of α-mannosidase (PDB ID: <span><span>1HWW</span><svg><path></path></svg></span>). Reliability of the docking results were confirmed by Molecular Dynamics (MD) simulation. Additionally, solid interactions with residues Gln-392 and Tyr-393 in the active site of α-<span>l</span>-rhamnosidase (PDB ID: <span><span>3W5N</span><svg><path></path></svg></span>) were proved to be vital for potent α-<span>l</span>-rhamnosidase inhibitions of the <span>l</span>-swainsonine derivatives. The role of C-6 fluorines in swainsonine derivatives well demonstrated the “mimic effect” of fluorine to hydrogen by minimal influence on the binding conformations and effective compensation for any possible lost interactions. This work contributes to a comprehensive understanding of the structure-activity relationship (SAR) of the fluorinated swainsonines and ever reported branched swainsonines, and has laid good foundation for development of more potent α-mannosidase and α-<span>l</span>-rhamnosidase inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117031"},"PeriodicalIF":6.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ejmech.2024.117042
Yunjie Wu , Lu Yang , Jing You , Chenyu Tian , Shengyong Yang , Linli Li
Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use. Herein, we report the discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors. Structure-activity relationship of these series compounds led to the discovery of the most active compound 13l with an EC50 value of 0.0007 μM. Mechanistically, 13l could inhibit NCOA4-mediated ferritinophagy, hence protecting cells from ferroptosis. Notably, in the acetaminophen-induced acute liver injury model, 13l showed an excellent therapeutic effect. Overall, this compound reported here could be a promising lead compound for drug discovery targeting ferroptosis.
{"title":"Discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors and efficacy evaluation on a mouse model of liver injury","authors":"Yunjie Wu , Lu Yang , Jing You , Chenyu Tian , Shengyong Yang , Linli Li","doi":"10.1016/j.ejmech.2024.117042","DOIUrl":"10.1016/j.ejmech.2024.117042","url":null,"abstract":"<div><div>Ferroptosis is an iron-dependent regulated cell death, which has been implicated in the onset and progression of numerous diseases. Ferroptosis inhibitors are thought as potential agents for treating these related diseases. However, the majority of currently available ferroptosis inhibitors are antioxidants or iron chelators (called classical ferroptosis inhibitors), which might have potential risks of side effects during clinical use. Herein, we report the discovery of phenazine derivatives as a new class of non-classical ferroptosis inhibitors. Structure-activity relationship of these series compounds led to the discovery of the most active compound <strong>13l</strong> with an EC<sub>50</sub> value of 0.0007 μM. Mechanistically, <strong>13l</strong> could inhibit NCOA4-mediated ferritinophagy, hence protecting cells from ferroptosis. Notably, in the acetaminophen-induced acute liver injury model, <strong>13l</strong> showed an excellent therapeutic effect. Overall, this compound reported here could be a promising lead compound for drug discovery targeting ferroptosis.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117042"},"PeriodicalIF":6.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ejmech.2024.117047
Jisook Kim, Seung Hyun Jung, Joo Chan Lee, Won Jeoung Kim, Jooyun Byun, Younggil Ahn, Hyun-Ju Park
The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound 7n was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC50 values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that 7n form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound 7n exhibited a favorable pharmacokinetic profile and significant in vivo antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).
{"title":"Structure–Activity Relationship Studies of Imidazo[1′,2′:1,6]pyrido[2,3-d]pyrimidine Derivatives to Develop Selective FGFR Inhibitors as Anticancer Agents for FGF19-overexpressed Hepatocellular Carcinoma","authors":"Jisook Kim, Seung Hyun Jung, Joo Chan Lee, Won Jeoung Kim, Jooyun Byun, Younggil Ahn, Hyun-Ju Park","doi":"10.1016/j.ejmech.2024.117047","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117047","url":null,"abstract":"The aberrant activation of fibroblast growth factor (FGF) and FGF receptor (FGFR)-mediated signaling pathways are associated with cancer development, including hepatocellular carcinoma (HCC). A novel series of imidazo[1′,2′:1,6]pyrido[2,3-<em>d</em>]pyrimidine, containing an acrylamide covalent warhead, were synthesized as selective FGFR 1-4 inhibitors. Compound <strong>7n</strong> was identified as the most potent inhibitor against FGFR1, 2, and 4, with IC<sub>50</sub> values of 8/4 nM (FGFR1/2) and 3.8 nM (FGFR4), and the covalent docking analyses suggested that <strong>7n</strong> form a covalent adduct with cysteine residue on the hinge or p-loop of FGFR. Compound <strong>7n</strong> exhibited a favorable pharmacokinetic profile and significant <em>in vivo</em> antitumor efficacy in human liver cancer xenograft mouse models (xenograft, FGF/FGFR-dependent HCC cells).","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"57 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.ejmech.2024.117049
Miyuan Zhang , Yuefeng Yang , Zhishuai Yang , Xin Wen , Cong Zhang , Peng Xiao , Yibo Wang , Jinpeng Sun , Hongshuang Wang , Xiaohui Wang
Recent advancements in the study of mushroom-derived tryptamines, particularly psilocybin and its metabolite psilocin, highlight their unique psychedelic properties and potential therapeutic applications, especially for mental health conditions like depression. This study examines how the position of the hydroxyl group on the indole ring affects the 5-HT2A receptor activity and psychedelic-like effects of psilocin analogs. Chemically synthesized psilocin (1) and its analogs bufotenine (2), 6-OH-DMT (3), and 7-OH-DMT (4) were assessed for 5-HT2A receptor agonistic activity using the Gαq-Gγ dissociation bioluminescence resonance energy transfer (BRET) assay and for psychedelic-like effects through the head-twitch response assay. Results show that compounds with hydroxyl group at the 4th and 5th positions exhibit significantly higher 5-HT2A agonistic and psychedelic-like activities than those with hydroxyl group at the 6th and 7th positions. Funnel metadynamics simulations revealed that psilocin (1) and bufotenine (2) have lower binding free energies, correlating with experimental data. Analysis of the simulation trajectories reveals that the formation of a hydrogen bond with residue L229 is crucial for guiding psilocin (1) and bufotenine (2) into the 5-HT2AR binding site. In contrast, analogs 3 and 4, which lack this interaction, fail to be directed into the orthosteric site. Furthermore, psilocin (1) and bufotenine (2) establish a stable salt bridge and hydrogen bond with residue D155. These interactions are more stable compared to those formed by ligands 3 and 4, contributing to the latter's poor 5-HT2AR activities. These findings underscore the critical role of the hydroxyl group position on the indole ring in modulating 5-HT2A receptor activity and the corresponding psychedelic-like effects, offering valuable insights for the development of targeted therapeutics.
{"title":"Structural insights into tryptamine psychedelics: The role of hydroxyl indole ring site in 5-HT2A receptor activation and psychedelic-like activity","authors":"Miyuan Zhang , Yuefeng Yang , Zhishuai Yang , Xin Wen , Cong Zhang , Peng Xiao , Yibo Wang , Jinpeng Sun , Hongshuang Wang , Xiaohui Wang","doi":"10.1016/j.ejmech.2024.117049","DOIUrl":"10.1016/j.ejmech.2024.117049","url":null,"abstract":"<div><div>Recent advancements in the study of mushroom-derived tryptamines, particularly psilocybin and its metabolite psilocin, highlight their unique psychedelic properties and potential therapeutic applications, especially for mental health conditions like depression. This study examines how the position of the hydroxyl group on the indole ring affects the 5-HT<sub>2A</sub> receptor activity and psychedelic-like effects of psilocin analogs. Chemically synthesized psilocin (<strong>1</strong>) and its analogs bufotenine (<strong>2</strong>), 6-OH-DMT (<strong>3</strong>), and 7-OH-DMT (<strong>4</strong>) were assessed for 5-HT<sub>2A</sub> receptor agonistic activity using the Gα<sub>q</sub>-Gγ dissociation bioluminescence resonance energy transfer (BRET) assay and for psychedelic-like effects through the head-twitch response assay. Results show that compounds with hydroxyl group at the 4th and 5th positions exhibit significantly higher 5-HT<sub>2A</sub> agonistic and psychedelic-like activities than those with hydroxyl group at the 6th and 7th positions. Funnel metadynamics simulations revealed that psilocin (<strong>1</strong>) and bufotenine (<strong>2</strong>) have lower binding free energies, correlating with experimental data. Analysis of the simulation trajectories reveals that the formation of a hydrogen bond with residue L229 is crucial for guiding psilocin (<strong>1</strong>) and bufotenine (<strong>2</strong>) into the 5-HT<sub>2A</sub>R binding site. In contrast, analogs <strong>3</strong> and <strong>4</strong>, which lack this interaction, fail to be directed into the orthosteric site. Furthermore, psilocin (<strong>1</strong>) and bufotenine (<strong>2</strong>) establish a stable salt bridge and hydrogen bond with residue D155. These interactions are more stable compared to those formed by ligands <strong>3</strong> and <strong>4</strong>, contributing to the latter's poor 5-HT<sub>2A</sub>R activities. These findings underscore the critical role of the hydroxyl group position on the indole ring in modulating 5-HT<sub>2A</sub> receptor activity and the corresponding psychedelic-like effects, offering valuable insights for the development of targeted therapeutics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117049"},"PeriodicalIF":6.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601766","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}
Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound S35. S35 exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC50 = 16.1 nM, fluorometric helicase assay IC50 = 23.5 nM). Additionally, S35 exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI50 = 36.4−306 nM), while the GI50 values for multiple microsatellite stability (MSS) cell lines were greater than 20000 nM. Furthermore, we observed that compound S35 induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.
{"title":"Design, Synthesis, and Structure−Activity Relationship Studies of Triazolo-pyrimidine Derivatives as WRN Inhibitors for the Treatment of MSI Tumors","authors":"Qibang Sui, Yuanyang Zhou, Manjia Li, Dan Wang, Rongrong Cui, Xiaoying Cai, Jia Liu, Xiaofeng Wang, Dan Teng, Jingyi Zhou, Hui Hou, Sulin Zhang, Mingyue Zheng","doi":"10.1016/j.ejmech.2024.117039","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117039","url":null,"abstract":"Werner syndrome RecQ helicase (WRN), a member of the RecQ helicase family, has recently been identified as a synthetic lethal target in microsatellite instability (MSI) tumors. The triazolo-pyrimidine compound <strong>HRO761</strong> is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited. Here, we designed a series of derivatives to systematically study the structure-activity relationship (SAR) of triazolo-pyrimidine scaffolds, leading to the discovery of compound <strong>S35</strong>. <strong>S35</strong> exhibited excellent WRN helicase inhibitory activity (ADP-Glo kinase assay IC<sub>50</sub> = 16.1 nM, fluorometric helicase assay IC<sub>50</sub> = 23.5 nM). Additionally, <strong>S35</strong> exhibited excellent cellular selectivity, with antiproliferative activity against multiple MSI cell lines (GI<sub>50</sub> = 36.4−306 nM), while the GI<sub>50</sub> values for multiple microsatellite stability (MSS) cell lines were greater than 20000 nM. Furthermore, we observed that compound <strong>S35</strong> induced DNA damage and caused G2/M cell cycle arrest in MSI cells, which did not occur in MSS cells. <strong>S35</strong> demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1016/j.ejmech.2024.117037
Giuseppe Cosentino , Maria Dichiara , Francesca Alessandra Ambrosio , Claudia Giovanna Leotta , Giosuè Costa , Francesca Procopio , Giuliana Costanzo , Alessandro Raffa , Antonia Artacho-Cordón , M. Carmen Ruiz-Cantero , Lorella Pasquinucci , Agostino Marrazzo , Giovanni Mario Pitari , Enrique J. Cobos , Stefano Alcaro , Emanuele Amata
The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compounds 12a (AD353) and 12c (AD408) exhibited negligible in vitro cellular toxicity and high potency both in a model of capsaicin-induced allodynia and in PGE2-induced mechanical hyperalgesia. Functional activity experiments showed that S1R antagonism is needed for the effects of these compounds, since the effect was reversed by PRE-084 or absent in KO mice. In addition, 12a exhibited a favorable pharmacokinetic profile, confirming its therapeutic value in treating allodynic conditions. Moreover, a computational model was developed in order to help the understanding about the mechanism of action of most active compounds.
{"title":"Development of selective sigma-1 receptor ligands with antiallodynic activity: A focus on piperidine and piperazine scaffolds","authors":"Giuseppe Cosentino , Maria Dichiara , Francesca Alessandra Ambrosio , Claudia Giovanna Leotta , Giosuè Costa , Francesca Procopio , Giuliana Costanzo , Alessandro Raffa , Antonia Artacho-Cordón , M. Carmen Ruiz-Cantero , Lorella Pasquinucci , Agostino Marrazzo , Giovanni Mario Pitari , Enrique J. Cobos , Stefano Alcaro , Emanuele Amata","doi":"10.1016/j.ejmech.2024.117037","DOIUrl":"10.1016/j.ejmech.2024.117037","url":null,"abstract":"<div><div>The design and synthesis of a series of piperidine and piperazine-based derivatives as selective sigma receptor (SR) ligands associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose features. The most promising compounds were subjected to <em>in vitro</em> toxicity testing and subsequently screened for <em>in vivo</em> analgesic properties. Compounds <strong>12a</strong> (AD353) and <strong>12c</strong> (AD408) exhibited negligible <em>in vitro</em> cellular toxicity and high potency both in a model of capsaicin-induced allodynia and in PGE2-induced mechanical hyperalgesia. Functional activity experiments showed that S1R antagonism is needed for the effects of these compounds, since the effect was reversed by PRE-084 or absent in KO mice. In addition, <strong>12a</strong> exhibited a favorable pharmacokinetic profile, confirming its therapeutic value in treating allodynic conditions. Moreover, a computational model was developed in order to help the understanding about the mechanism of action of most active compounds.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117037"},"PeriodicalIF":6.0,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1016/j.ejmech.2024.117038
Thao NT. Ho, Thanh Hoa Tran, Le Hoang Sinh, Richard J. Lewis
Conotoxins, isolated from the venom of carnivorous marine snails of the Conus genus, are disulfide-rich peptides and proteins with well-defined three-dimensional structures. Conotoxins’ ability to target a wide range of ion channels and receptors, including voltage- and ligand-gated ion channels, G protein-coupled receptors, monoamine transporters, and enzyme, at exquisite potency and selectivity make them valuable research and therapeutic tools. Despite their potentials, Conus venom peptides are present in limited quantities in nature and possess structural complexity that raises significant synthetic challenges for both chemical synthesis and recombinant expression. Here, we document recent advances in the expression and synthesis of conotoxins, particularly focusing on directed formation of disulfide bonds, chemical ligation techniques, and the integration of non-native functional groups. These advances can provide access to even the most complex conotoxins, accelerating conotoxin-based drug discovery and functional analysis, as well as opening new avenues for the development of drug candidates.
{"title":"Advances in the synthesis and engineering of conotoxins","authors":"Thao NT. Ho, Thanh Hoa Tran, Le Hoang Sinh, Richard J. Lewis","doi":"10.1016/j.ejmech.2024.117038","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117038","url":null,"abstract":"Conotoxins, isolated from the venom of carnivorous marine snails of the <em>Conus</em> genus, are disulfide-rich peptides and proteins with well-defined three-dimensional structures. Conotoxins’ ability to target a wide range of ion channels and receptors, including voltage- and ligand-gated ion channels, G protein-coupled receptors, monoamine transporters, and enzyme, at exquisite potency and selectivity make them valuable research and therapeutic tools. Despite their potentials, <em>Conus</em> venom peptides are present in limited quantities in nature and possess structural complexity that raises significant synthetic challenges for both chemical synthesis and recombinant expression. Here, we document recent advances in the expression and synthesis of conotoxins, particularly focusing on directed formation of disulfide bonds, chemical ligation techniques, and the integration of non-native functional groups. These advances can provide access to even the most complex conotoxins, accelerating conotoxin-based drug discovery and functional analysis, as well as opening new avenues for the development of drug candidates.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-09DOI: 10.1016/j.ejmech.2024.117046
Tianqing Liu , Chao Ren , Wantong Guo , Xiaojun Zhang , Yuying Li , Yan Wang , Qilei Zhang , Baian Chen , Jiapei Dai , Xiao-xin Yan , Jinming Zhang , Li Huo , Mengchao Cui
The presence of aggregated Tau in the brain is a dominant pathological hallmark of Tauopathies, particularly in Alzheimer's disease (AD). Therefore, developing ligands that can specifically and sensitively bind to Tau aggregates is essential for diagnosing and monitoring therapeutic interventions. In this study, we further investigated the structural optimization of the diarylamine skeleton, which exhibited promising binding characteristics and biological properties. We supplementarily explored the effects of the number and position of nitrogen atoms, types of heteroatoms and aromatic moieties, and radioactive positions on affinity for Tau. Through a structure-activity relationship (SAR) analysis based on 125I-labeled diarylamine derivatives, [125I]A6 was identified as a lead compound due to its desirable binding properties and ability to penetrate the brain, making it suitable for conversion into a18F-labeled PET tracer. Satisfactorily, [18F]FA1 fulfilled critical requirements as a Tau radiotracer, demonstrating high specificity and selectivity for Tau, a clean off-target profile against Aβ plaques and monoamine oxidase B (MAO-B), and favorable in vivo brain kinetics, as confirmed by dynamic PET studies in rodents and non-human primates.
大脑中存在聚集的 Tau 是 Tau 病，尤其是阿尔茨海默病（AD）的主要病理特征。因此，开发能特异、灵敏地与 Tau 聚集体结合的配体对于诊断和监测治疗干预措施至关重要。在本研究中，我们进一步研究了二芳基胺骨架的结构优化，它表现出了良好的结合特性和生物特性。我们还探索了氮原子的数量和位置、杂原子和芳香分子的类型以及放射性位置对 Tau 亲和力的影响。通过基于 125I 标记的二芳基胺衍生物的结构-活性关系（SAR）分析，[125I]A6 因其理想的结合特性和穿透大脑的能力而被确定为先导化合物，使其适合转化为 18F 标记的 PET 示踪剂。经啮齿动物和非人灵长类动物的动态 PET 研究证实，[18F]FA1 满足了 Tau 放射性示踪剂的关键要求，对 Tau 具有高度的特异性和选择性，对 Aβ 斑块和单胺氧化酶 B (MAO-B) 具有良好的脱靶特性，并且具有良好的体内脑动力学特性。
{"title":"Synthesis and preclinical evaluation of diarylamine derivative as Tau-PET radiotracer for Alzheimer's Disease","authors":"Tianqing Liu , Chao Ren , Wantong Guo , Xiaojun Zhang , Yuying Li , Yan Wang , Qilei Zhang , Baian Chen , Jiapei Dai , Xiao-xin Yan , Jinming Zhang , Li Huo , Mengchao Cui","doi":"10.1016/j.ejmech.2024.117046","DOIUrl":"10.1016/j.ejmech.2024.117046","url":null,"abstract":"<div><div>The presence of aggregated Tau in the brain is a dominant pathological hallmark of Tauopathies, particularly in Alzheimer's disease (AD). Therefore, developing ligands that can specifically and sensitively bind to Tau aggregates is essential for diagnosing and monitoring therapeutic interventions. In this study, we further investigated the structural optimization of the diarylamine skeleton, which exhibited promising binding characteristics and biological properties. We supplementarily explored the effects of the number and position of nitrogen atoms, types of heteroatoms and aromatic moieties, and radioactive positions on affinity for Tau. Through a structure-activity relationship (SAR) analysis based on <sup>125</sup>I-labeled diarylamine derivatives, [<sup>125</sup>I]<strong>A6</strong> was identified as a lead compound due to its desirable binding properties and ability to penetrate the brain, making it suitable for conversion into a<sup>18</sup>F-labeled PET tracer. Satisfactorily, [<sup>18</sup>F]<strong>FA1</strong> fulfilled critical requirements as a Tau radiotracer, demonstrating high specificity and selectivity for Tau, a clean off-target profile against Aβ plaques and monoamine oxidase B (MAO-B), and favorable <em>in vivo</em> brain kinetics, as confirmed by dynamic PET studies in rodents and non-human primates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117046"},"PeriodicalIF":6.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.ejmech.2024.117045
Daniel Stopper , Susanna Buntrock , Kathrin Tan , Lais Pessanha de Carvalho , Linda Schäker-Hübner , Jana Held , Matthias U. Kassack , Finn K. Hansen
In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the Plasmodium falciparum strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC50 values (IC50 (3D7) = 0.023 μM; IC50 (Dd2) = 0.047 μM) and high parasite selectivity (SIMRC−5/Pf3D7 > 2174). HDAC inhibition assays confirmed substantial inhibition of the P. falciparum enzyme PfHDAC1 (IC50 = 0.037 μM) as well as of human HDAC1 (IC50 = 0.021 μM) and HDAC6 (IC50 = 0.25 μM). Docking studies suggested distinct binding modes of 18b in P. falciparum and human HDAC1. Additionally, the in vitro anticancer activity was evaluated in Cal27 (head-neck carcinoma), HepG2 (hepatocellular carcinoma), A2780 (ovarian carcinoma), and U87 (glioblastoma) cell lines. Compounds 9b, 9d, and 13f showed potent antiproliferative activity and caspase 3/7 activation, in contrast to 18b. Furthermore, these compounds caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified the HDAC inhibitor 18b with selective antiplasmodial and 9b, 9d, and 13f with selective anticancer activities, providing valuable hits for further drug development efforts aimed at creating derivatives with reduced cytotoxicity against non-cancer cells compared to quisinostat.
{"title":"Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors","authors":"Daniel Stopper , Susanna Buntrock , Kathrin Tan , Lais Pessanha de Carvalho , Linda Schäker-Hübner , Jana Held , Matthias U. Kassack , Finn K. Hansen","doi":"10.1016/j.ejmech.2024.117045","DOIUrl":"10.1016/j.ejmech.2024.117045","url":null,"abstract":"<div><div>In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the <em>Plasmodium falciparum</em> strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound <strong>18b</strong> of the type C series as the most potent. It demonstrated low nanomolar IC<sub>50</sub> values (IC<sub>50</sub> (3D7) = 0.023 μM; IC<sub>50</sub> (Dd2) = 0.047 μM) and high parasite selectivity (SI<sup>MRC−5/<em>Pf</em>3D7</sup> > 2174). HDAC inhibition assays confirmed substantial inhibition of the <em>P. falciparum</em> enzyme <em>Pf</em>HDAC1 (IC<sub>50</sub> = 0.037 μM) as well as of human HDAC1 (IC<sub>50</sub> = 0.021 μM) and HDAC6 (IC<sub>50</sub> = 0.25 μM). Docking studies suggested distinct binding modes of <strong>18b</strong> in <em>P. falciparum</em> and human HDAC1. Additionally, the <em>in vitro</em> anticancer activity was evaluated in Cal27 (head-neck carcinoma), HepG2 (hepatocellular carcinoma), A2780 (ovarian carcinoma), and U87 (glioblastoma) cell lines. Compounds <strong>9b</strong>, <strong>9d</strong>, and <strong>13f</strong> showed potent antiproliferative activity and caspase 3/7 activation, in contrast to <strong>18b</strong>. Furthermore, these compounds caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified the HDAC inhibitor <strong>18b</strong> with selective antiplasmodial and <strong>9b</strong>, <strong>9d</strong>, and <strong>13f</strong> with selective anticancer activities, providing valuable hits for further drug development efforts aimed at creating derivatives with reduced cytotoxicity against non-cancer cells compared to quisinostat.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117045"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.ejmech.2024.117034
Ebna Azizal Omar , R. Rajesh , Pronoy Kanti Das , Rohit Pal , Gurubasavaraja Swamy Purawarga Matada , Lalmohan Maji
One of the major obstacles to sustained cancer treatment effectiveness is the development of medication resistance. Current therapies that block proteins associated with cancer progression often lose their efficacy due to acquired drug resistance, which is frequently driven by mutated or overexpressed protein targets. Proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic strategy by hijacking the cell's ubiquitin-proteasome system to degrade disease-causing proteins, presenting several potential advantages. Over the past few years, PROTACs have been developed to target various cancer-related proteins, offering new treatment options for patients with previously untreatable malignancies and serving as a foundation for next-generation therapeutics. One of the notable benefits of PROTACs is their ability to overcome certain resistance mechanisms that limit the effectiveness of conventional targeted therapies, as shown in several recent studies. Additionally, research teams are investigating how PROTACs can selectively degrade mutant proteins responsible for resistance to first-line cancer therapies. In the pursuit of novel and effective treatments, this review highlights recent advancements in the development of PROTACs aimed at overcoming cancer resistance. When it comes to drug design, heterocyclic scaffolds often serve as a foundational framework, offering opportunities for modification and optimization of novel molecules. Researchers are similarly exploring various heterocyclic derivatives as “warheads” in the design of PROTACs has been instrumental in pushing the boundaries of targeted protein degradation. As warheads, these heterocyclic compounds are responsible for recognizing and binding to the target protein, which ultimately leads to its degradation via the ubiquitin-proteasome system. This study aims to provide a comprehensive overview of cutting-edge strategies in PROTAC design, offering detailed insights into key concepts and methodologies for creating effective PROTACs. Special emphasis is placed on structure-based rational design, the development of novel warheads, and their critical in influencing biological activity.
{"title":"Next-generation cancer therapeutics: PROTACs and the role of heterocyclic warheads in targeting resistance","authors":"Ebna Azizal Omar , R. Rajesh , Pronoy Kanti Das , Rohit Pal , Gurubasavaraja Swamy Purawarga Matada , Lalmohan Maji","doi":"10.1016/j.ejmech.2024.117034","DOIUrl":"10.1016/j.ejmech.2024.117034","url":null,"abstract":"<div><div>One of the major obstacles to sustained cancer treatment effectiveness is the development of medication resistance. Current therapies that block proteins associated with cancer progression often lose their efficacy due to acquired drug resistance, which is frequently driven by mutated or overexpressed protein targets. Proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic strategy by hijacking the cell's ubiquitin-proteasome system to degrade disease-causing proteins, presenting several potential advantages. Over the past few years, PROTACs have been developed to target various cancer-related proteins, offering new treatment options for patients with previously untreatable malignancies and serving as a foundation for next-generation therapeutics. One of the notable benefits of PROTACs is their ability to overcome certain resistance mechanisms that limit the effectiveness of conventional targeted therapies, as shown in several recent studies. Additionally, research teams are investigating how PROTACs can selectively degrade mutant proteins responsible for resistance to first-line cancer therapies. In the pursuit of novel and effective treatments, this review highlights recent advancements in the development of PROTACs aimed at overcoming cancer resistance. When it comes to drug design, heterocyclic scaffolds often serve as a foundational framework, offering opportunities for modification and optimization of novel molecules. Researchers are similarly exploring various heterocyclic derivatives as “warheads” in the design of PROTACs has been instrumental in pushing the boundaries of targeted protein degradation. As warheads, these heterocyclic compounds are responsible for recognizing and binding to the target protein, which ultimately leads to its degradation via the ubiquitin-proteasome system. This study aims to provide a comprehensive overview of cutting-edge strategies in PROTAC design, offering detailed insights into key concepts and methodologies for creating effective PROTACs. Special emphasis is placed on structure-based rational design, the development of novel warheads, and their critical in influencing biological activity.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117034"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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