MedChemComm最新文献

{"title":"Introduction to the themed collection on ‘Induced-Proximity Pharmacology’","authors":"Ingo V. Hartung, Lindsey I. James and Lyn H. Jones","doi":"10.1039/D5MD90023A","DOIUrl":"10.1039/D5MD90023A","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2311-2313"},"PeriodicalIF":3.597,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Trypanosoma brucei acting derivatives incorporating 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane†","authors":"Konstantina Stavropoulou, Angeliki Kaimaki, Maria Nikolaou, Ana K. Brown, Andrew Tsotinis, Martin C. Taylor, John M. Kelly and Ioannis P. Papanastasiou","doi":"10.1039/D5MD00135H","DOIUrl":"10.1039/D5MD00135H","url":null,"abstract":"<p >In this work, we describe the design, synthesis and evaluation of novel functionalised 1-(4-phenyl)adamantane and 1-(4-phenoxyphenyl)adamantane derivatives. Based on previous findings, we incorporated a phenyl ring between the adamantane core and the pharmacophoric side chain to enhance the activity and selectivity index (SI). The aromatic imidazolines <strong>1a–d</strong> and the linear amidines <strong>2a</strong>,<strong>b</strong> and <strong>3a</strong>,<strong>b</strong> exhibited notable activity against <em>T. brucei</em>. The 1-(4-phenyl)adamantane 1-(4-phenoxyphenyl)adamantane core was further functionalized with the aminoguanylhydrazone and thiosemicarbazone moieties. 2-[(<em>E</em>)-4-(1-adamantyl)benzylidene]hydrazine-1-carbothioamide <strong>4c</strong> emerged as a promising trypanocidal agent with an EC<small>₅₀</small> of 0.16 μM and an SI of 17. Future studies will focus on optimizing the length and the distance of the side chain between the aromatic ring and the chromophores to further enhance the activity and selectivity of these molecules.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2441-2451"},"PeriodicalIF":3.597,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human chitinases and chitinase-like proteins as emerging drug targets – a medicinal chemistry perspective","authors":"Önder Kurç, Nick Rähse, Holger Gohlke and Jonathan Cramer","doi":"10.1039/D4MD01050G","DOIUrl":"10.1039/D4MD01050G","url":null,"abstract":"<p >Human chitinases and chitinase-like proteins (CLPs) provide the immune system with the ability to recognize or process chitin originating from chitinous pathogens. In addition to their role in host defense, most members of this protein family have evolved pleiotropic cellular effector functions broadly related to immune homeostasis, cell proliferation, and tissue remodeling. This wide-ranging ability to modulate crucial cellular processes proceeds <em>via</em> the activation of cellular signal transduction cascades and appears to be fully independent of chitin recognition. Dysregulation of chitinase/CLP functions has been linked to a plethora of inflammatory diseases, such as allergic airway diseases and asthma, fibrosis, as well as cancer. This fact predetermines certain members of this protein family as prime targets for pharmacological intervention. Here, we provide an extensive review of medicinal chemistry efforts targeting the most widely studied members of the human chitinase/CLP family, namely acidic mammalian chitinase (AMCase), chitotriosidase (CHIT1), and chitinase-3-like protein 1 (CHI3L1/YKL-40).</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2388-2402"},"PeriodicalIF":3.597,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New acridone derivatives to target telomerase and oncogenes – an anticancer approach†","authors":"Tiago J. S. Marques, Diana Salvador, Helena Oliveira, Vanda V. Serra, Nicholas Paradis, Chun Wu, Vera L. M. Silva and Catarina I. V. Ramos","doi":"10.1039/D4MD00959B","DOIUrl":"10.1039/D4MD00959B","url":null,"abstract":"<p >In this work, two new acridone derivatives, <strong>AcridPy</strong> and <strong>AcridPyMe</strong>, were synthesized, for the first time, aiming to evaluate their potential as quadruplex stabilizers and anticancer agents. <strong>AcridPy</strong> was synthesized through a very straightforward one-pot sequential chemical reaction involving the Heck cross-coupling reaction of (<em>E</em>)-3-iodo-2-(4-methoxystyryl)-1-methylquinolin-4(1<em>H</em>)-one with a vinyl pyridine followed by <em>in situ</em> electrocyclization and oxidation, while the synthesis of <strong>AcridPyMe</strong> involved an additional <em>N</em>-methylation of the pyridine ring. Their ability to stabilize G-quadruplex DNA structures, which are associated with the regulation of oncogenes, was assessed using biophysical methods. Both compounds demonstrated significant quadruplex stabilization properties, showing selectivity to G-quadruplexes over duplex DNA. Molecular dynamics simulation experiments supported the preferential binding of <strong>AcridPyMe</strong> to MYC. The cytotoxicity of these derivatives was further evaluated <em>in vitro</em> in two distinct pancreatic tumor cell lines, PanC-1 and MIA PaCa-2, the lung tumor A549 cell line, the melanoma A375 cell line, and the immortalized human keratinocyte HaCaT cell line, through the evaluation of cell viability. For PanC-1 and MIA PaCa-2, the cell cycle dynamics and apoptotic cell death along with colocalization were also evaluated. The results revealed that <strong>AcridPyMe</strong> exhibited anticancer activity, correlated with its quadruplex stabilization ability and, although not exclusive, nuclear co-localization was observed. These findings suggest that the newly synthesized cationic acridone is a promising candidate for the development of novel anticancer therapies targeting G-quadruplex structures.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2785-2807"},"PeriodicalIF":3.597,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12004264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The development of a PET radiotracer for imaging alpha synuclein aggregates in Parkinson's disease†","authors":"Gui-Long Tian, Chia-Ju Hsieh, Dinahlee Saturnino Guarino, Thomas J. A. Graham, Zsofia Lengyel-Zhand, Alexander Schmitz, Wai Kit Chia, Anthony J. Young, John-Grey Crosby, Konstantinos Plakas, Tianyu Huang, Hao Jiang, Yanbo Yu, Catherine Hou, Hsiaoju Lee, E. James Petersson, Sam Giannakoulias, Jennifer O'Shea, Paul Kotzbauer, Zhude Tu, Chester A. Mathis and Robert H. Mach","doi":"10.1039/D5MD00057B","DOIUrl":"10.1039/D5MD00057B","url":null,"abstract":"<p > <strong>M503-1619</strong> was identified as a promising ligand for positron emission tomography (PET) imaging of α-synuclein (α-Syn) pathology in Parkinson's disease (PD). An exemplar for binding site 9 (residues GLY-86, ILE-88, PHE-94 and LYS-96) of α-Syn fibrils was generated. An <em>in silico</em> ultrahigh throughput screening campaign was conducted using a 42 million compound library. Secondary <em>in silico</em> methods followed by visual inspection were used to select 6 compounds as candidates for <em>in vitro</em> binding studies. <strong>M503-1619</strong> was found to have a high binding affinity (<em>K</em><small>_i</small> = 6.5 nM <em>versus</em> the site 9 radioligand [<small>³</small>H]BF-2846) to α-Syn fibrils and low affinity for beta amyloid (<em>K</em><small>_i</small> = 390 nM <em>versus</em> [<small>³</small>H]PiB) in competition binding assays. Saturation binding assays of <strong>[<small>³</small>H]M503-1619</strong> in human tissues confirmed its high affinity to α-Syn (PD tissue, <em>K</em><small>_D</small> = 2.5 nM; Alzheimer's disease tissue, <em>K</em><small>_D</small> = 37 nM; progressive supranuclear palsy tissue, <em>K</em><small>_D</small> = 55 nM). Autoradiography studies demonstrated a higher binding of this radioligand in PD brain sections than in multiple system atrophy brain sections. PET studies with <strong>[<small>¹¹</small>C]M503-1619</strong> showed high brain uptake and rapid washout (whole brain peak to 60 min ratio = 3.2) in non-human primates. The results of this study suggest that <strong>[<small>¹¹</small>C]M503-1619</strong> is a lead compound for radiotracer development imaging α-Syn with PET.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2743-2753"},"PeriodicalIF":3.597,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiproliferative effects, mechanism of action and tumor reduction studies in a lung cancer xenograft mouse model of an organometallic gold(i) alkynyl complex†","authors":"Uttara Basu, Anna Wilsmann, Sebastian Türck, Henrik Hoffmeister, Matthias Schiedel, Gilles Gasser and Ingo Ott","doi":"10.1039/D4MD00964A","DOIUrl":"10.1039/D4MD00964A","url":null,"abstract":"<p >Organometallic complexes offer a wide range of properties like structural variety, reaction kinetics, tunable lipophilicity and alternate mechanisms of activation under physiological conditions compared to platinum chemotherapeutics and are thus being explored for their potential anticancer applications. In this regard, gold(<small>I</small>) organometallics hold a pivotal position for their ability to act on biological targets different from DNA (which is the primary target of platinum therapeutics), such as thioredoxin reductase. Here, we report on the stability, <em>in vitro</em> antiproliferative effects, protein binding, cellular uptake, mechanism of action, effects on mitochondrial respiration of cancer cells as well as <em>in vivo</em> tolerance, toxicity and tumor reduction in an A549 lung cancer xenograft mouse model of an organometallic gold(<small>I</small>) complex (<strong>1</strong>) bearing 4-ethynylanisole and triethylphosphane as ligands. The complex, which was stable in DMSO and reactive towards <em>N</em>-acetylcysteine, triggered strong antiproliferative effects in various cancer cell lines and had a protein binding of approximately 65% that reduced its generally efficient uptake into tumor cells. Antimetastatic properties were indicated for <strong>1</strong> in a scratch assay and strong inhibition of thioredoxin reductase (TrxR) was confirmed for the purified enzyme as well as in A549 lung cancer cells, which strongly overexpress TrxR. Real time monitoring of the oxygen consumption rate in multiple cancer cell lines, using the Seahorse Mito stress assay, demonstrated that mitochondrial respiration was severely disrupted, showing a significantly low oxygen consumption rate. Other respiratory parameters, such as proton efflux, spare respiratory capacity and maximal respiration, were also attenuated upon treatment with <strong>1</strong>. The complex was well tolerated <em>in vivo</em> in mice at a dose of 10 mg kg<small>⁻¹</small> and showed tumor reduction compared to the control group of animals in a lung cancer xenograft model of nude mice. In summary, complex <strong>1</strong> represents a novel organometallic anticancer drug candidate with a mechanism related to TrxR inhibition and mitochondrial respiration inhibition, showing efficient <em>in vivo</em> antitumor efficacy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2663-2676"},"PeriodicalIF":3.597,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiochromenes and thiochromanes: a comprehensive review of their diverse biological activities and structure–activity relationship (SAR) insights","authors":"Jatin, Solai Murugappan, Shivani Kirad, Chandu Ala, Pranali Vijaykumar Kuthe, Chandra Sekhar Venkata Gowri Kondapalli and Murugesan Sankaranarayanan","doi":"10.1039/D4MD00995A","DOIUrl":"10.1039/D4MD00995A","url":null,"abstract":"<p >Thiochromene and thiochromane scaffolds, sulfur containing heterocycles, have gained significant attention in medicinal chemistry due to their diverse pharmacological activities. This review provides a comprehensive analysis of their antibacterial, antifungal, antiviral, anti-parasitic, and anticancer properties, emphasizing their therapeutic potential. SAR studies highlight key molecular modifications such as electron withdrawing substituents, sulfur oxidation, and tailored ring substitutions that enhance bioactivity, potency, and target specificity. Mechanistic insights reveal their ability to inhibit microbial enzymes, disrupt cellular pathways, and modulate key biological targets. By summarizing recent advancements, this review underscores the potential of thiochromene and thiochromane based therapeutics and encourages further research to address existing limitations and enhance their drug development prospects.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1941-1968"},"PeriodicalIF":3.597,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Near-infrared photochemical internalization: design of a distorted zinc phthalocyanine for efficient intracellular delivery of immunotoxins†","authors":"Mikako Hamabe, Wakako Dewa, Mizue Yuki, Eriko Yamada, Tamako Aiba, Keisuke Horikoshi, Takao Hamakubo, Riuko Ohashi and Akimitsu Okamoto","doi":"10.1039/D4MD00931B","DOIUrl":"10.1039/D4MD00931B","url":null,"abstract":"<p >In the treatment of cancer, the physical and mental stress on patients and the potential for strong side effects are serious problems; therefore, reliable delivery of drugs into cancer tissue cells is required. We have developed a near-infrared (NIR) photosensitizing dye, Zn6PTPc, for NIR-photochemical internalization (PCI) to achieve gentle and efficient endosomal escape and delivery of antibody drugs, which are known to have high targeting ability but low intracellular activity, into target cancer cells. Zn6PTPc allowed longer wavelengths to be used to achieve higher singlet oxygen generation efficiency by the molecular design based on a distorted π-electron system. The system effectively introduced immunotoxins into cells to significantly inhibit tumor tissue growth. The developed potent NIR photosensitizers facilitated NIR-PCI with high tumor-targeting ability.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2615-2626"},"PeriodicalIF":3.597,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methods for kinetic evaluation of reversible covalent inhibitors from time-dependent IC50 data†","authors":"Lavleen K. Mader and Jeffrey W. Keillor","doi":"10.1039/D5MD00050E","DOIUrl":"10.1039/D5MD00050E","url":null,"abstract":"<p >Potent reversible covalent inhibitors are often slow in establishing their covalent modification equilibrium, resulting in time-dependent inhibition. While these inhibitors are commonly assessed using IC<small>₅₀</small> values, there are no methods available to analyze their time-dependent IC<small>₅₀</small> data to provide their inhibition (<em>K</em><small>_i</small> and <img>) and covalent modification rate (<em>k</em><small>₅</small> and <em>k</em><small>₆</small>) constants, leading to difficulty in accurately ranking drug candidates. Herein, we present an implicit equation that can estimate these constants from incubation time-dependent IC<small>₅₀</small> values and a numerical modelling method, EPIC-CoRe, that can fit these kinetic parameters from pre-incubation time-dependent IC<small>₅₀</small> data. The application of these new methods is demonstrated by the evaluation of a known inhibitor, saxagliptin, providing results consistent with those obtained by other known methods. This work introduces two new practical methods of evaluation for time-dependent reversible covalent inhibitors, allowing for rigorous characterization to enable the fine-tuning of their binding and reactivity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2517-2531"},"PeriodicalIF":3.597,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the in vitro anticancer potential of bis(imino)acenaphthene–N-heterocyclic carbene transition metal complexes revealed TrxR inhibition and triggering of immunogenic cell death (ICD) for allyl palladates†","authors":"Chiara Donati, Ishfaq Ibni Hashim, Nestor Bracho Pozsoni, Laurens Bourda, Kristof Van Hecke, Catherine S. J. Cazin, Fabiano Visentin, Steven P. Nolan, Valentina Gandin and Thomas Scattolin","doi":"10.1039/D5MD00039D","DOIUrl":"10.1039/D5MD00039D","url":null,"abstract":"<p >Immunogenic cell death (ICD) is a regulated form of cell death that activates an immune response through the release of danger-associated molecular patterns (DAMPs), including calreticulin, ATP, and HMGB1. Gold complexes are known to induce ICD, but the ICD-inducing potential of palladium complexes remains largely unexplored. We report the first examples of palladium compounds capable of inducing ICD, specifically allyl palladates bearing bis(imino)acenaphthene–NHC (BIAN–NHC) ligands. Cytotoxicity tests on human cancer cell lines revealed that allyl palladates outperform their cinnamyl analogues and gold(<small>I</small>)/copper(<small>I</small>) BIAN–NHC complexes. Notably, [BIAN–IMes·H][PdCl<small>₂</small>(allyl)] <strong>2a</strong> showed excellent TrxR inhibition, reducing activity by 67% and surpassing auranofin. This inhibition strongly correlates with ICD induction, as evidenced by enhanced DAMP marker expression, including superior ATP and HMGB1 release compared to doxorubicin. These findings establish allyl palladates as a novel class of ICD inducers with dual anticancer activity and immune activation potential.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2592-2602"},"PeriodicalIF":3.597,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}