Atefeh Saadabadi, Marja Rantanen, Parthiban Marimuthu, Ari-Pekka Koivisto, Patrik C Eklund, Outi M H Salo-Ahen
Natural stilbenoids, polyphenolic compounds notably found in Scots pine and Norway spruce, have been shown to exhibit analgesic and anti-inflammatory effects through the TRPA1 channel, making them promising hits for the development of novel agents to treat inflammatory diseases and pain. In this study, we computationally investigated the putative binding sites of natural stilbenoids at the TRPA1 channel. Specifically, we employed molecular docking and MD simulation approaches to explore three known ligand binding sites at TRPA1. Furthermore, the biological effect of the studied compounds on TRPA1 was assessed in vitro using a fluorescent imaging plate reader (FLIPR™) calcium assay. Our modeling results suggest the stilbenoids exhibit higher affinity to the two agonist binding sites than the antagonistic site. Consistent with this, the in vitro results showed that the stilbenoids act as moderate TRPA1 channel agonists and likely inhibit the channel through a desensitization mechanism rather than act as pure TRPA1 antagonists. Additionally, our bias-force pulling simulations proposed an additional binding pocket for the natural stilbenoids that is distinct from the known ligand binding sites at TRPA1. The results of the study give useful insights into structure-based design and development of novel therapeutic TRPA1 modulators.
{"title":"Insights Into Molecular Interactions and Biological Effect of Natural Stilbenoids at The TRPA1 Ion Channel.","authors":"Atefeh Saadabadi, Marja Rantanen, Parthiban Marimuthu, Ari-Pekka Koivisto, Patrik C Eklund, Outi M H Salo-Ahen","doi":"10.1002/cmdc.202400501","DOIUrl":"https://doi.org/10.1002/cmdc.202400501","url":null,"abstract":"<p><p>Natural stilbenoids, polyphenolic compounds notably found in Scots pine and Norway spruce, have been shown to exhibit analgesic and anti-inflammatory effects through the TRPA1 channel, making them promising hits for the development of novel agents to treat inflammatory diseases and pain. In this study, we computationally investigated the putative binding sites of natural stilbenoids at the TRPA1 channel. Specifically, we employed molecular docking and MD simulation approaches to explore three known ligand binding sites at TRPA1. Furthermore, the biological effect of the studied compounds on TRPA1 was assessed in vitro using a fluorescent imaging plate reader (FLIPR™) calcium assay. Our modeling results suggest the stilbenoids exhibit higher affinity to the two agonist binding sites than the antagonistic site. Consistent with this, the in vitro results showed that the stilbenoids act as moderate TRPA1 channel agonists and likely inhibit the channel through a desensitization mechanism rather than act as pure TRPA1 antagonists. Additionally, our bias-force pulling simulations proposed an additional binding pocket for the natural stilbenoids that is distinct from the known ligand binding sites at TRPA1. The results of the study give useful insights into structure-based design and development of novel therapeutic TRPA1 modulators.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454110","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}
Laura M H Pascual, Jérôme Devy, Marius Colin, Lise Chazée, Alexandra Guillaneuf, Béatrice Marin, Richard Plantier-Royon, Sylvain Gatard
A series of xylose-based ligands was obtained using a convenient approach, in a few steps from D-xylose. The complexation properties of these ligands towards Au3+ cations have been studied through different methods (multinuclear NMR, mass spectrometry, elemental analysis). The biological properties (antibacterial and anti-tumoral) of all the isolated xyloside Au(III) complexes were investigated in vitro. The xyloside Au(III) complexes gave the highest activities against E. coli(vs P. aeruginosa, S. aureus and S. epidermidis). The study also revealed that the nature of the sugar may play an important role in determining the selectivity of the antibacterial effect. Preliminary anti-tumoral evaluations showed that one complex containing a polyamine chain, exhibited interesting anti-proliferative activities on breast tumor cell lines MDA-MB-231 and BT-20. The anti-migratory effect of this complex also showed an average 35% reduction in cell migration on the same two cancer cell lines.
{"title":"Biosourced Au(III) Complexes from D-Xylose: Synthesis and Biological Evaluation.","authors":"Laura M H Pascual, Jérôme Devy, Marius Colin, Lise Chazée, Alexandra Guillaneuf, Béatrice Marin, Richard Plantier-Royon, Sylvain Gatard","doi":"10.1002/cmdc.202400565","DOIUrl":"https://doi.org/10.1002/cmdc.202400565","url":null,"abstract":"<p><p>A series of xylose-based ligands was obtained using a convenient approach, in a few steps from D-xylose. The complexation properties of these ligands towards Au3+ cations have been studied through different methods (multinuclear NMR, mass spectrometry, elemental analysis). The biological properties (antibacterial and anti-tumoral) of all the isolated xyloside Au(III) complexes were investigated in vitro. The xyloside Au(III) complexes gave the highest activities against E. coli(vs P. aeruginosa, S. aureus and S. epidermidis). The study also revealed that the nature of the sugar may play an important role in determining the selectivity of the antibacterial effect. Preliminary anti-tumoral evaluations showed that one complex containing a polyamine chain, exhibited interesting anti-proliferative activities on breast tumor cell lines MDA-MB-231 and BT-20. The anti-migratory effect of this complex also showed an average 35% reduction in cell migration on the same two cancer cell lines.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454107","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}
Benzofuropyridines (BFP) are polycyclic compounds with known applications in neuronal diseases. However, its derivatization patterns and anticancer potential remains unexplored. Leveraging the idea of diversity-oriented synthesis (DOS), we developed a highly efficient synthetic route for BFP to increase the library of available analogs producing three compounds in one reaction set up, including the 2O-, 6O-, and the 1N-substituted species, also producing the unusual 2-pyridone derivatives. Key bromination reaction of the BFP moiety was successfully described which can widen the available variation in the compounds' structure. The cytotoxic activity of the compounds was assessed against SH-SY5Y (neuroblastoma), HepG2 (hepatocellular carcinoma), Kb (human oral epidermoid), HeLa (cervical) and MCF-7 (breast) cancer cell lines. In the series, the m-bromobenzyl (5b), methylcyano (5g) and propargyl (5h) 2O-derivatives demonstrated good selectivity against cancer cells with selectivity index (SI) of >71 for 5g against HeLa over the normal cells, as compared to the standard drug, Doxorubicin (SI = 6.7). The quantitative structure-activity relationship (QSAR) analysis revealed an impressive correlation of the defined descriptors with the bioactivity having an R2 value of 0.971 and 0.893 for Kb and HeLa respectively. Altogether, our work highlighted new information on the synthesis of BFP derivatives with potent cytotoxic activity.
{"title":"Diversity Oriented Strategy (DOS) for the Efficient Synthesis of Benzofuro[2,3-b]pyridine Derivatives with Anticancer Activity.","authors":"Reymark Ereje, Jantana Yahuafai, Theeranuch Jaroenchuensiri, Patcharaporn Supakijjanusorn, Sukanya Unson, Borwornlak Toopradab, Thanyada Rungrotmongkol, Somsak Pianwanit, Chanat Aonbangkhen, Tanatorn Khotavivattana","doi":"10.1002/cmdc.202400514","DOIUrl":"https://doi.org/10.1002/cmdc.202400514","url":null,"abstract":"<p><p>Benzofuropyridines (BFP) are polycyclic compounds with known applications in neuronal diseases. However, its derivatization patterns and anticancer potential remains unexplored. Leveraging the idea of diversity-oriented synthesis (DOS), we developed a highly efficient synthetic route for BFP to increase the library of available analogs producing three compounds in one reaction set up, including the 2O-, 6O-, and the 1N-substituted species, also producing the unusual 2-pyridone derivatives. Key bromination reaction of the BFP moiety was successfully described which can widen the available variation in the compounds' structure. The cytotoxic activity of the compounds was assessed against SH-SY5Y (neuroblastoma), HepG2 (hepatocellular carcinoma), Kb (human oral epidermoid), HeLa (cervical) and MCF-7 (breast) cancer cell lines. In the series, the m-bromobenzyl (5b), methylcyano (5g) and propargyl (5h) 2O-derivatives demonstrated good selectivity against cancer cells with selectivity index (SI) of >71 for 5g against HeLa over the normal cells, as compared to the standard drug, Doxorubicin (SI = 6.7). The quantitative structure-activity relationship (QSAR) analysis revealed an impressive correlation of the defined descriptors with the bioactivity having an R2 value of 0.971 and 0.893 for Kb and HeLa respectively. Altogether, our work highlighted new information on the synthesis of BFP derivatives with potent cytotoxic activity.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454109","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}
Therapeutic nucleic acids (TNAs) are a new class of drugs that exhibit different properties and mechanisms of action from those of small molecules or biological drugs. Over twenty oligonucleotide drugs and several COVID-19 vaccines have received regulatory approval for clinical use. A characteristic feature of these TNAs is that they are directed against one specific biological target and one specific RNA or DNA sequence. Consequently, TNAs currently used are administered as monotherapy. Due to the known advantages of multidrug therapy with low molecular weight drugs, it may be time to intensify work on such a treatment protocol, also in the case of TNAs.
{"title":"IS IT TIME FOR MULTI-DRUG THERAPY WITH COMBINATION OF THERAPEUTIC NUCLEIC ACIDS?","authors":"Zbigniew Jan Lesnikowski","doi":"10.1002/cmdc.202400493","DOIUrl":"https://doi.org/10.1002/cmdc.202400493","url":null,"abstract":"<p><p>Therapeutic nucleic acids (TNAs) are a new class of drugs that exhibit different properties and mechanisms of action from those of small molecules or biological drugs. Over twenty oligonucleotide drugs and several COVID-19 vaccines have received regulatory approval for clinical use. A characteristic feature of these TNAs is that they are directed against one specific biological target and one specific RNA or DNA sequence. Consequently, TNAs currently used are administered as monotherapy. Due to the known advantages of multidrug therapy with low molecular weight drugs, it may be time to intensify work on such a treatment protocol, also in the case of TNAs.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454111","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}
Mohamed Elnagar, Khaled S Abou-El-Sherbini, Safia Samir, Walid Sharmoukh, Mohamed S Abdel-Aziz, Yasser M Shaker
Ruthenium complexes incorporating 2,2':6',2''-terpyridine ligands have emerged as promising candidates due to their versatile biological activities including DNA-binding, anti-inflammatory, antimicrobial, and anticancer properties. In this study, three novel 4'-functionalized bis(terpyridine) ruthenium (II) complexes were synthesized. These complexes feature one ligand as 4-(2,2':6',2''-terpyridine-4'-yl) benzoic acid and the second ligand as either 4'-(2-thienyl)-2,2':6',2''-terpyridine, 4'-(3,4-dimethoxyphenyl)-2,2':6',2''-terpyridine, or 4'-(4-dimethylaminophenyl)-2,2':6',2''-terpyridine. Besides the chemical characterization by 1H and 13C NMR, mass spectrometry, and absorption and emission spectroscopy, the complexes were tested for their biological activity as anti-inflammatory, anticancer, and antimicrobial agents. Moreover, the toxicity of the Ru(II) complexes was assessed and benchmarked against diclofenac potassium and ibuprofen using a haemolysis assay. Biological evaluations demonstrate that these ruthenium complexes exhibit promising therapeutic potential with reduced haemolytic activity compared to standard drugs. They demonstrate substantial anti-inflammatory effects through inhibition of albumin denaturation along with moderate cytotoxicity against cancer cell lines and broad-spectrum antimicrobial activity. These findings highlight the multifaceted biomedical applications of 4'-functionalized bis(terpyridine) ruthenium (II) complexes, suggesting their potential for further development as effective and safe therapeutic agents.
{"title":"Synthesis, Characterization, and Biological Activity of New 4`-Functionalized Bis-Terpyridine Ruthenium(II) Complexes: Anti-inflammatory Activity Advances.","authors":"Mohamed Elnagar, Khaled S Abou-El-Sherbini, Safia Samir, Walid Sharmoukh, Mohamed S Abdel-Aziz, Yasser M Shaker","doi":"10.1002/cmdc.202400680","DOIUrl":"https://doi.org/10.1002/cmdc.202400680","url":null,"abstract":"<p><p>Ruthenium complexes incorporating 2,2':6',2''-terpyridine ligands have emerged as promising candidates due to their versatile biological activities including DNA-binding, anti-inflammatory, antimicrobial, and anticancer properties. In this study, three novel 4'-functionalized bis(terpyridine) ruthenium (II) complexes were synthesized. These complexes feature one ligand as 4-(2,2':6',2''-terpyridine-4'-yl) benzoic acid and the second ligand as either 4'-(2-thienyl)-2,2':6',2''-terpyridine, 4'-(3,4-dimethoxyphenyl)-2,2':6',2''-terpyridine, or 4'-(4-dimethylaminophenyl)-2,2':6',2''-terpyridine. Besides the chemical characterization by 1H and 13C NMR, mass spectrometry, and absorption and emission spectroscopy, the complexes were tested for their biological activity as anti-inflammatory, anticancer, and antimicrobial agents. Moreover, the toxicity of the Ru(II) complexes was assessed and benchmarked against diclofenac potassium and ibuprofen using a haemolysis assay. Biological evaluations demonstrate that these ruthenium complexes exhibit promising therapeutic potential with reduced haemolytic activity compared to standard drugs. They demonstrate substantial anti-inflammatory effects through inhibition of albumin denaturation along with moderate cytotoxicity against cancer cell lines and broad-spectrum antimicrobial activity. These findings highlight the multifaceted biomedical applications of 4'-functionalized bis(terpyridine) ruthenium (II) complexes, suggesting their potential for further development as effective and safe therapeutic agents.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454112","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}
Dr. Teodora Djikic-Stojsic, Guillaume Bret, Dr. Gaëlle Blond, Dr. Nicolas Girard, Dr. Clothilde Le Guen, Dr. Claire Marsol, Dr. Martine Schmitt, Séverine Schneider, Dr. Frederic Bihel, Dr. Dominique Bonnet, Dr. Mihaela Gulea, Prof. Dr. Esther Kellenberger
The cover represents an approach to creating a diverse chemical library with unique scaffolds. Combining the expertise of chemoinformaticians, organic synthetic chemists, and medicinal chemists, two libraries were developed. Starting with over 10000 in-stock compounds, the essential chemical library (eIMS) consists of 578 original and diverse compounds on plates, ready for high-throughput screening. Additionally, using chemoinformatics tools the virtual chemical library (vIMS) featuring 821070 unique, original, virtual compounds was created. This emphasized efficient hit-to-lead optimization, based on established synthetic pathways and medicinal chemistry guidelines. More details can be found in article 10.1002/cmdc.202400381 by Esther Kellenberger and co-workers. Cover design by Teodora Djikic-Stojsic.