ChemMedChem最新文献

{"title":"Structural Basis of Saccharin Derivative Inhibition of Carbonic Anhydrase IX","authors":"Dr. Janis Leitans,&nbsp;Dr. Andris Kazaks,&nbsp;Janis Bogans,&nbsp;Prof. Claudiu T. Supuran,&nbsp;Inara Akopjana,&nbsp;Dr. Jekaterina Ivanova,&nbsp;Dr. Raivis Zalubovskis,&nbsp;Dr. Kaspars Tars","doi":"10.1002/cmdc.202300454","DOIUrl":"10.1002/cmdc.202300454","url":null,"abstract":"<p>This study explores the binding mechanisms of saccharin derivatives with human carbonic anhydrase IX (hCA IX), an antitumor drug target, with the aim of facilitating the design of potent and selective inhibitors. Through the use of crystallographic analysis, we investigate the structures of hCA IX-saccharin derivative complexes, unveiling their unique binding modes that exhibit both similarities to sulfonamides and distinct orientations of the ligand tail. Our comprehensive structural insights provide information regarding the crucial interactions between the ligands and the protein, shedding light on interactions that dictate inhibitor binding and selectivity. Through a comparative analysis of the binding modes observed in hCA II and hCA IX, isoform-specific interactions are identified, offering promising strategies for the development of isoform-selective inhibitors that specifically target tumor-associated hCA IX. The findings of this study significantly deepen our understanding of the binding mechanisms of hCA inhibitors, laying a solid foundation for the rational design of more effective inhibitors.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 22","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186509","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}

{"title":"Protein-Porphyrin Complex Photosensitizers for Anticancer and Antimicrobial Photodynamic Therapies","authors":"Dr. Taiga Yamada,&nbsp;Prof. Teruyuki Komatsu","doi":"10.1002/cmdc.202300373","DOIUrl":"10.1002/cmdc.202300373","url":null,"abstract":"<p>Photodynamic therapy (PDT) efficiently induces apoptosis through visible-light irradiation of photosensitizers (PSs) within tumors and microbial cells. Porphyrin analogues serve as widely utilized photosensitizing agents with their therapeutic abilities being governed by molecular structures and central metal ions. However, these macrocyclic compounds tend to agglutinate and form stacks in aqueous environments, resulting in a loss of photochemical activity. To overcome this limitation, encapsulation within liposomes and polymer micelles enables the dispersion of porphyrins as monomolecular entities in aqueous solutions, preventing undesirable deactivation. Recently, the use of reconstituted hemoproteins containing various metal-porphyrins and protein cages incorporating porphyrins has garnered significant interest as a new generation of biocompatible PSs. In this concept paper, we provide a comprehensive review of recent developments and trends of protein-porphyrin complex PSs for applications in anticancer and antimicrobial PDTs.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 23","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186508","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}

{"title":"Discovery of a Dual-Target Inhibitor of CDK7 and HDAC1 That Induces Apoptosis and Inhibits Migration in Colorectal Cancer**","authors":"Yao Chen,&nbsp;Shuangqian Zhang,&nbsp;Zhijia Li,&nbsp;Bo Yin,&nbsp;Yi Liu,&nbsp;Prof. Dr. Lan Zhang","doi":"10.1002/cmdc.202300281","DOIUrl":"10.1002/cmdc.202300281","url":null,"abstract":"<p>Aberrant expression or dysfunction of cyclin-dependent kinase 7(CDK7) and histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 23","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186425","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}

{"title":"Moving out of CF3-Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF5) Group","authors":"Katarzyna Witoszka,&nbsp;Dr. Joanna Matalińska,&nbsp;Prof. Aleksandra Misicka,&nbsp;Prof. Piotr F. J. Lipiński","doi":"10.1002/cmdc.202300315","DOIUrl":"10.1002/cmdc.202300315","url":null,"abstract":"<p>The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including emesis, pain, and cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF₃ groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF₅ group, and so we designed, synthesized, and tested ten novel SF₅-containing compounds for NK1R affinity. All analogues exhibit detectable NK1R binding, with the best of them, compound <b>5 a</b>, (3-bromo-5-(pentafluoro-λ⁶-sulfanyl)benzyl acetyl-L-tryptophanate) binding only slightly worse (IC₅₀=34.3 nM) than the approved NK1R-targeting drug, aprepitant (IC₅₀=27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF₅ group in our compounds occupies a position similar to that of one of the CF₃ groups of aprepitant as found in the crystal structure. Additionally, we checked whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF₅ group in the design of NK1R ligands.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 23","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186507","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}

{"title":"Development of Photoswitchable Tethered Ligands that Target the μ-Opioid Receptor","authors":"Ranit Lahmy,&nbsp;Dr. Harald Hübner,&nbsp;Dr. Daniel Lachmann,&nbsp;Prof. Dr. Peter Gmeiner,&nbsp;Prof. Dr. Burkhard König","doi":"10.1002/cmdc.202300228","DOIUrl":"10.1002/cmdc.202300228","url":null,"abstract":"<p>Converting known ligands into photoswitchable derivatives offers the opportunity to modulate compound structure with light and hence, biological activity. In doing so, these probes provide unique control when evaluating G-protein-coupled receptor (GPCR) mechanism and function. Further conversion of such compounds into covalent probes, known as photoswitchable tethered ligands (PTLs), offers additional advantages. These include localization of the PTLs to the receptor binding pocket. Covalent localization increases local ligand concentration, improves site selectivity and may improve the biological differences between the respective isomers. This work describes chemical, photophysical and biochemical characterizations of a variety of PTLs designed to target the μ-opioid receptor (μOR). These PTLs were modeled on fentanyl, with the lead disulfide-containing agonist found to covalently interact with a cysteine-enriched mutant of this medically-relevant receptor.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 23","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202300228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41186424","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}

{"title":"Design of Balanced Cyclooxygenase Inhibitors Based on Natural Anti-inflammatory Ascidian Metabolites and Celecoxib","authors":"Jingjie Fang,&nbsp;Ziyi Shang,&nbsp;Kumaravel Kaliaperumal,&nbsp;Prof. Zhiran Ju,&nbsp;Prof. Fen-Er Chen","doi":"10.1002/cmdc.202300468","DOIUrl":"10.1002/cmdc.202300468","url":null,"abstract":"<p>The serious adverse effects caused by non-selective and selective cyclooxygenase-2 (COX-2) inhibitors remain significant concerns for current anti-inflammatory drugs. In this study, we present the design and synthesis of a novel series of celecoxib analogs incorporating a hydrazone linker, which were subjected to <i>in silico</i> analysis to compare their binding poses with those of clinically used nonsteroidal anti-inflammatory drugs (NSAIDs) against COX-1 and COX-2. The synthesized analogs were evaluated for their inhibitory activity against both COX enzymes, and compound <b>6 m</b>, exhibiting potent balanced inhibition, was selected for subsequent <i>in vitro</i> anti-inflammatory assays. Treatment with <b>6 m</b> effectively suppressed the NF-κB signaling pathway in lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages, resulting in reduced expression of pro-inflammatory factors such as inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-<span>α</span> (TNF-α), interleukin-6 (IL-6), IL-1β, as well as decreased production of prostaglandin E₂ (PGE₂), nitric oxide (NO), and reactive oxygen species (ROS). However, <b>6 m</b> has no effect on the MAPK signaling pathway. Therefore, due to its potent <i>in vitro</i> anti-inflammatory activity coupled with lack of cytotoxicity, <b>6 m</b> represents a promising candidate for further development as a new lead compound targeting inflammation.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 23","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41181535","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}

{"title":"Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa","authors":"Casey N. Kellogg,&nbsp;Bryce A. Pugh,&nbsp;Isaak M. Starr,&nbsp;Dhruvi J. Parmar,&nbsp;A'Zane D. Troxler,&nbsp;Dr. Amanda L. Wolfe","doi":"10.1002/cmdc.202300496","DOIUrl":"10.1002/cmdc.202300496","url":null,"abstract":"<p>Due to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram-negative pathogens, such as <i>Pseudomonas aeruginosa</i>, is especially challenging due to their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, primary amines, imidazolines, and imidazoles, promote antibiotic and adjuvant activity in Gram-negative bacteria, but few of these have been targeted towards <i>Pseudomonas aeruginosa</i> specifically despite this pathogen being deemed a critical threat by the United States Centers for Disease Control and Prevention. Herein, we examined a small series of known and unknown nitrogenous dimers, with guanidine, amidine, dimethyl amine, and pyridine functionality, for antibacterial activity against multidrug resistant <i>Pseudomonas aeruginosa</i>. We found that two, with bisbenzguanidine and bisbenzamidine functionality, are potent against clinical isolates of multidrug resistant and biofilm forming <i>Pseudomonas aeruginosa</i>.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 24","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202300496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093225","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}

{"title":"Design of 3-Phenylcoumarins and 3-Thienylcoumarins as Potent Xanthine Oxidase Inhibitors: Synthesis, Biological Evaluation, and Docking Studies","authors":"Prof. Antonella Fais,&nbsp;Prof. Francesca Pintus,&nbsp;Dr. Benedetta Era,&nbsp;Dr. Sonia Floris,&nbsp;Dr. Amit Kumar,&nbsp;Dr. Debapriyo Sarmadhikari,&nbsp;Prof. Valeria Sogos,&nbsp;Prof. Eugenio Uriarte,&nbsp;Dr. Shailendra Asthana,&nbsp;Prof. Maria João Matos","doi":"10.1002/cmdc.202300400","DOIUrl":"10.1002/cmdc.202300400","url":null,"abstract":"<p>Coumarin scaffold has proven to be promising in the development of bioactive agents, such as xanthine oxidase (XO) inhibitors. Novel hydroxylated 3-arylcoumarins were designed, synthesized, and evaluated for their XO inhibition and antioxidant properties. 3-(3’-Bromophenyl)-5,7-dihydroxycoumarin (compound <b>11</b>) proved to be the most potent XO inhibitor, with an IC₅₀ of 91 nM, being 162 times better than allopurinol, one of the reference controls. Kinetic analysis of compound <b>11</b> and compound <b>5</b> [3-(4’-bromothien-2’-yl)-5,7-dihydroxycoumarin], the second-best compound within the series (IC₅₀ of 280 nM), has been performed, and both compounds showed a mixed-type inhibition. Both compounds present good antioxidant activity (ability to scavenge ABTS radical) and are able to reduce reactive oxygen species (ROS) levels in H₂O₂-treated cells. In addition, they proved to be non-cytotoxic in a Caco-2 cells viability assay. Molecular docking studies have been carried out to correlate the compounds’ theoretical and experimental binding affinity to the XO binding pocket.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 21","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202300400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41097070","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}

{"title":"Design and Synthesis of Novel 2-Acetamido, 6-Carboxamide Substituted Benzothiazoles as Potential BRAFV600E Inhibitors – In vitro Evaluation of their Antiproliferative Activity","authors":"Yakinthi Batsi,&nbsp;Dr. Georgia Antonopoulou,&nbsp;Dr. Theano Fotopoulou,&nbsp;Kassandra Koumaki,&nbsp;Dr. Eftichia Kritsi,&nbsp;Dr. Constantinos Potamitis,&nbsp;Dr. Maria Goulielmaki,&nbsp;Salomi Skarmalioraki,&nbsp;Chara Papalouka,&nbsp;Eleni Poulou-Sidiropoulou,&nbsp;Vivian Kosmidou,&nbsp;Stavroula Douna,&nbsp;Maria-Sofia Vidali,&nbsp;Eleni-Fani Gkotsi,&nbsp;Dr. Aristotelis Chatziioannou,&nbsp;Dr. Vassilis L. Souliotis,&nbsp;Dr. Vasiliki Pletsa,&nbsp;Dr. Olga Papadodima,&nbsp;Dr. Vassilis Zoumpourlis,&nbsp;Dr. Panagiotis Georgiadis,&nbsp;Dr. Maria Zervou,&nbsp;Dr. Alexander Pintzas,&nbsp;Dr. Ioannis D. Kostas","doi":"10.1002/cmdc.202300322","DOIUrl":"10.1002/cmdc.202300322","url":null,"abstract":"<p>The oncogenic BRAFV600E kinase leads to abnormal activation of the MAPK signaling pathway and thus, uncontrolled cellular proliferation and cancer development. Based on our previous virtual screening studies which issued 2-acetamido-1,3 benzothiazole-6-carboxamide scaffold as active pharmacophore displaying selectivity against the mutated BRAF, eleven new substituted benzothiazole derivatives were designed and synthesized by coupling of 2-acetamidobenzo[d]thiazole-6-carboxylic acid with the appropriate amines in an effort to provide even more efficient inhibitors and tackle drug resistance often developed during cancer treatment. All derived compounds bore the benzothiazole scaffold substituted at position-2 by an acetamido moiety and at position-6 by a carboxamide functionality, the NH moiety of which was further linked through an alkylene linker to a sulfonamido (or amino) aryl (or alkyl) functionality or a phenylene linker to a sulfonamido aromatic (or non-aromatic) terminal pharmacophore in the order −C₆H₄−NHSO₂−R or reversely −C₆H₄−SO₂N(H)−R. These analogs were subsequently biologically evaluated as potential BRAFV600E inhibitors and antiproliferative agents in several colorectal cancer and melanoma cell lines. In all assays applied, one analog, namely 2-acetamido-<i>N</i>-[3-(pyridin-2-ylamino)propyl]benzo[d]thiazole-6-carboxamide (<b>22</b>), provided promising results in view of its use in drug development.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 22","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202300322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093293","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}

{"title":"Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy","authors":"Chenyuan Xuan,&nbsp;Prof. Rong Hu","doi":"10.1002/cmdc.202300405","DOIUrl":"10.1002/cmdc.202300405","url":null,"abstract":"<p>Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type I interferon and initiates T cell-mediated adaptive immunity. The activated immune system converts “cold tumors” into “hot tumors” that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long-lasting antitumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"18 23","pages":""},"PeriodicalIF":3.4,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093023","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}