European Journal of Medicinal Chemistry Reports最新文献

{"title":"Structure-activity study of oncocins modified with cationic polar moieties at the termini","authors":"Johan Storm Jørgensen ,&nbsp;Anita Wester ,&nbsp;Carina Sofia Silva Matias ,&nbsp;Lina Maria Cavaco ,&nbsp;Carina Vingsbo Lundberg ,&nbsp;Camilla Brolin ,&nbsp;Elnaz Harifi Mood ,&nbsp;Dorota Żabicka ,&nbsp;Magdalena Tomczak ,&nbsp;Malgorzata Urbas ,&nbsp;Fredrik Björkling ,&nbsp;Peter E. Nielsen ,&nbsp;Henrik Franzyk","doi":"10.1016/j.ejmcr.2025.100284","DOIUrl":"10.1016/j.ejmcr.2025.100284","url":null,"abstract":"<div><div>The critical emergence of antimicrobial resistance is aggravated by a pipeline deficient in novel antibiotic classes against Gram-negative pathogens. Proline-rich antimicrobial peptides (PrAMPs) are attractive starting points for novel antibiotics, capable of targeting Gram-negative pathogens. Here, we explored a series of oncocin analogs, which were modified with bacteria-penetrating moieties to promote transporter-independent antibacterial activity. Elongation with arginine-rich motifs conferred 2- to 8-fold improved potency against the Gram-negative <em>Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa</em> and <em>Acinetobacter baumannii</em>. The highest degree of enhancement was seen for <em>K. pneumoniae</em>, in which the most active analogs had minimal inhibitory concentrations of 0.25 μg/mL (∼0.05 μM).</div><div>Notably, antibacterial activity proved considerably less dependent on the inner-membrane peptide transporter SbmA, being the main transporter involved in internalization of PrAMPs. Permeabilization experiments showed that these cationic modifications did not alter the original intracellular mode of action of oncocin itself towards a membrane-disruptive mechanism for these analogs. Importantly, their effect on human cell viability remained low for the best analogs (i.e., below 5 % hemolysis at 400 μg/mL and IC₅₀ values ≥ 1280 μg/mL in HepG2 cells). Moreover, the frequencies of existing resistance of best analogs in <em>E. coli</em> and <em>K. pneumoniae</em> were low (i.e., 1-5 × 10⁻¹⁰). Finally, two analogs were tested in a mouse peritonitis model with <em>E. coli</em>, while one analog was tested in a model with <em>K. pneumoniae</em>. This showed efficacy comparable to that of colistin in the <em>E. coli</em> model, while a lower efficacy than that of colistin was seen in the <em>K. pneumoniae</em> model.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100284"},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563102","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":"Key determinants of the chemo-sensitizing activity of novel Telmisartan derivatives","authors":"Maximilian Gebhart ,&nbsp;Christian A. Elvert ,&nbsp;Anna M. Schoepf ,&nbsp;Alexandra Scheiber ,&nbsp;Stefan Schwaiger ,&nbsp;Cornelia A. Karg ,&nbsp;Ronald Gust ,&nbsp;Stefan Salcher","doi":"10.1016/j.ejmcr.2025.100281","DOIUrl":"10.1016/j.ejmcr.2025.100281","url":null,"abstract":"<div><div>Despite the success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), resistance remains a major challenge due to target mutations and drug efflux. To counter this, chemo-sensitizers - non-cytotoxic agents that restore drug sensitivity - are being explored. A promising approach involves Telmisartan (<strong>1</strong>)-based cell death modulators, which may help overcome TKI resistance. Modification of the 2-COOH group of Telmisartan to a carboxamide (2-CONH₂, Telmiamide (<strong>2</strong>)) or methyl ester (2-CO₂CH₃, Telmiester (<strong>3</strong>)) transformed these derivatives into potent inhibitors of the efflux transporter ABCB1 and the STAT5 protein - two critical mediators of CML persistence during TKI therapy. Both compounds successfully restored Imatinib (<strong>Im</strong>) sensitivity in TKI-resistant CML cells. The present structure-activity relationship (SAR) analysis demonstrated that substituent modifications at 2-CONH₂ and 2-CO₂CH₃ significantly influenced biological efficacy, stability in cell culture medium, cellular uptake in CML cells, and inhibition of ABCB1 and STAT5. Among the tested compounds, propyl-, butyl-, phenyl-, and 4-phenoxyphenyl-substituted Telmiamides (<strong>2a-d</strong>) and Telmiesters (<strong>3a-d</strong>) exhibited strong chemo-sensitizing potential <em>in vitro</em>, with a half-maximal sensitizing concentration (SC₅₀) &lt; 0.5 μM. Additionally, most derivatives showed improved stability in cell culture, enhancing their suitability for future <em>in vivo</em> studies. When considering cellular uptake in CML cells, these compounds displayed ABCB1 inhibition comparable to the efflux transporter inhibitor Elacridar (<strong>E</strong>). Notably, their dual mode of action, combining potent ABCB1 and STAT5 inhibition with low cytotoxicity, offers a distinct advantage over Elacridar (<strong>E</strong>). ADME (absorption, distribution, metabolism, and excretion) studies identified significant limitations in the phenyl carboxamide derivative (<strong>2c</strong>), revealing low permeability and high metabolism due to the bound phenyl ring. These findings indicate that aromatic residues at the 2-CONH-R group may compromise bioavailability, highlighting a key structural constraint to address in the future optimization of Telmisartan derivatives for therapeutic development. Overall, the study highlights Telmisartan-based derivatives as promising candidates for overcoming TKI resistance in CML and warrants further optimization for clinical translation.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100281"},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563101","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":"Anti-scarring drug discovery: potential targets and therapeutic opportunities","authors":"Meiling Feng ,&nbsp;Xiaotian Niu ,&nbsp;Shan Wang ,&nbsp;Liuxin Lu ,&nbsp;Xilong Feng ,&nbsp;Xiaoying Jiang ,&nbsp;Wenchao Chen ,&nbsp;Renren Bai","doi":"10.1016/j.ejmcr.2025.100283","DOIUrl":"10.1016/j.ejmcr.2025.100283","url":null,"abstract":"<div><div>Scar formation is a ubiquitous pathological response during the skin wound healing process. While physical therapy can effectively mitigate scar development, it is often accompanied by issues such as poor patient compliance and a range of side effects. Consequently, there is an urgent clinical need for the discovery of effective anti-scarring drugs. However, this need has not been fully addressed to date. This review delves systematically and comprehensively into the characteristics of scars, the underlying mechanisms of their formation, and potential therapeutic targets. Additionally, it reviews drug repurposing efforts, natural products and small molecule compounds in the drug discovery stage with anti-scarring effects. The information presented herein will offer valuable insights and enlightenment for exploring potential targets and pathways, as well as viable lead compounds for the discovery and development of novel anti-scarring drugs.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100283"},"PeriodicalIF":0.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490946","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":"Repurposing of compound libraries yields new inhibitors of NDM-1 metallo-β-lactamase with diverse zinc-binding moieties","authors":"Vid Kavaš ,&nbsp;Philip Hinchliffe ,&nbsp;Maša Zorman ,&nbsp;Alen Krajnc ,&nbsp;Matic Proj ,&nbsp;Majda Golob ,&nbsp;Martina Hrast Rambaher ,&nbsp;James Spencer ,&nbsp;Stanislav Gobec","doi":"10.1016/j.ejmcr.2025.100282","DOIUrl":"10.1016/j.ejmcr.2025.100282","url":null,"abstract":"<div><div>Antimicrobial resistance has emerged as a critical global public health threat, impacting human, animal and environmental health. An important mechanism of resistance is the production of β-lactamases, enzymes that hydrolyze the β-lactam ring, rendering β-lactam antibiotics ineffective. Metallo-β-lactamases (MBLs), which contain zinc ions in their active sites, are particularly challenging to counter as there are currently no inhibitors targeting these enzymes available on the market. Therefore, there is an urgent need for innovative drug discovery strategies to develop MBL-targeted therapies. New Delhi Metallo-β-Lactamase 1 (NDM-1) is the most widely disseminated MBL, with a global distribution in <em>Enterobacterales</em>. In this study, we used our library of fragment-sized chloroacetamides as a starting point to synthesize mercaptoacetamides as potential NDM-1 inhibitors. This resulted in a compound (<strong>14a</strong>) with an IC₅₀ of 20 μM, which crystallography shows binds to NDM-1 in two different poses. Using this structure as a starting point for <em>in silico</em> design, we developed a series of larger thiol-based compounds designed to occupy more space in the active site and to utilize other novel zinc-binding groups. Although some showed minimal inhibition (which makes them valuable as decoys for metalloenzyme studies) one compound exhibited an IC₅₀ of 14 μM, with crystallography indicating that an additional aromatic group, compared to <strong>14a</strong>, interacts with hydrophobic residues on an NDM-1 active site loop. These data identify promising scaffolds for the further development of potent MBL inhibitors and show the utility of repurposing chemical libraries to target clinically important enzymes.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100282"},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144364922","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":"Aurones as versatile enzyme Inhibitors: Recent advancements, structural insights, mechanisms, and therapeutic potential","authors":"Bhavna Saroha ,&nbsp;Gourav Kumar ,&nbsp;Suresh Kumar","doi":"10.1016/j.ejmcr.2025.100280","DOIUrl":"10.1016/j.ejmcr.2025.100280","url":null,"abstract":"<div><div>Aurones belong to the flavonoid-based heterocyclic class of plant origin and are full of therapeutic potential. Characterized by their unique benzofuranone core structure and α,β unsaturated carbonyl group, aurones possess exceptional structural adaptability and electronic characteristics, making them excellent candidates for enzyme targeting and promising agents for drug development. Recent research has highlighted their ability to inhibit key enzymes, including cholinesterase, cathepsin B, monoamine oxidase, cyclooxygenase, and various digestive enzymes. This demonstrates their potential in treating cancer, neurodegenerative diseases, and metabolic disorders associated with the overexpression of these enzymes. The ability to functionalize the aurone scaffold further enhances its adaptability for selective and potent enzyme targeting. This review examines the structural features of aurones, their enzyme-inhibitory effects, an overview of their molecular mechanisms, and the structure-activity relationships (SAR) underlying their enzyme inhibition, supported by computational approaches. Although several review articles have addressed the synthetic and general biological profile of aurones, none have specifically focused on their enzyme inhibitory potential, which is the central theme of this review. This review offers a strong foundation and rationale for the design, synthesis, and optimization of novel aurone-based compounds aimed at achieving desirable therapeutic outcomes by targeting specific enzymes.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100280"},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330496","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":"Structure optimization at position five of 4-thiazolidinone resulted in new potent PIM1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities for combating colorectal cancer","authors":"Ahmed K. Al-Kubeisi ,&nbsp;Saad R. El-Zemity ,&nbsp;Marwa M. Abu-Serie ,&nbsp;Aly A. Hazzaa ,&nbsp;Mostafa M.M. El-Miligy","doi":"10.1016/j.ejmcr.2025.100279","DOIUrl":"10.1016/j.ejmcr.2025.100279","url":null,"abstract":"<div><div>New thymol – 5-phenylthiazolidin-4-one hybrids were synthesized aiming to interact with the lipophilic flexible p-loop of PIM kinase active site via induced-fit binding mode to increase affinity hence anticancer activity against colorectal cancer (CRC). All target compounds were screened for their cytotoxicity against normal human lung fibroblasts and anticancer activity against CRC Caco-2 cell lines. <strong>6c</strong> and <strong>6e</strong> exhibited the highest anticancer activity at doses less than their EC₁₀₀ on normal human cells. In addition, <strong>6c</strong> and <strong>6e</strong> were further tested against liver cancer cell line (HepG-2) and breast cancer cell line (MCF-7) and proved their potent anticancer activities. Furthermore, both induced apoptosis in Caco-2 cell lines by 39 and 55 % and enhanced caspase 3/7 activation by 43 and 65 %, respectively. Besides, <strong>6c</strong> and <strong>6e</strong> revealed <em>in vitro</em> inhibitory activity against PIM1 kinase more than PIM2 kinase. Furthermore, induced fit docking and molecular dynamics simulation of <strong>6c</strong> and <strong>6e</strong> predicted enhanced PIM1 kinase activity via interaction to flexible p-loop. Moreover, both could act as PIM1 kinase competitive non-ATP mimetics as they interacted with Lys67.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100279"},"PeriodicalIF":0.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144231741","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":"Towards \"unmakable\" psychedelics: SAR exploration of psilocin analogs obtained by a HATU-mediated amide coupling strategy","authors":"Judith Stirn ,&nbsp;Raphael Berger ,&nbsp;Harald Hübner ,&nbsp;Peter Gmeiner ,&nbsp;Christian D. Klein","doi":"10.1016/j.ejmcr.2025.100278","DOIUrl":"10.1016/j.ejmcr.2025.100278","url":null,"abstract":"<div><div>4-Hydroxytryptamines such as psilocin and its prodrug psilocybin are of considerable current interest for innovative antidepressant and other neuropsychiatric treatments. We here present a synthetic route towards 4-hydroxytryptamines displaying a high versatility for SAR exploration at the aliphatic nitrogen. The core concept is to apply HATU-mediated amide couplings to a readily accessible and stable <em>N</em>^<em>1</em>-Boc-indole-3-glyoxylic acid precursor followed by <em>N</em>-deprotection under mild conditions. We illustrate the versatility of this approach by the synthesis of various sterically hindered, conformationally constrained, chiral, and electron-deficient 4-hydroxytryptamines, including closely related congeners of iprocin. In addition, the structure-activity relationships of the obtained compounds are explored with a focus on their interaction with the serotonin receptors 1A and 2A (5-HT_1/2A). An increase in steric bulk at the aliphatic nitrogen appears to be detrimental to the affinity to the 5-HT_2A receptor, whereas azetidinyl tryptamines bearing a terminal aryl moiety demonstrated remarkably high affinity.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100278"},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144231740","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":"Isolation, synthesis, mechanism of action, and pharmacological activities of bisabolangelone and related bisabolenoids","authors":"Christian Bailly","doi":"10.1016/j.ejmcr.2025.100277","DOIUrl":"10.1016/j.ejmcr.2025.100277","url":null,"abstract":"<div><div>The bisabolene-type sesquiterpene bisabolangelone (BBG) can be found in several <em>Angelica</em> species, notably in the seeds of <em>A. silvestris</em> L. from which it was first isolated. BBG can be extracted from those plants or obtained by total synthesis from the monoterpenoid pulegone. Efficient procedures have been proposed to synthesize BBG and derivatives. The present review discusses the origin, bio- and chemical syntheses, and pharmacological properties of BBG. Three main activities have been reported, corresponding to three study periods. Initially, BBG was investigated as an insecticide active against <em>Dermatophagoides</em> (house dust mites) and a few other pest species. Later, the compound revealed marked hypopigmenting and anti-melanogenic activities of potential interest to treat hyperpigmented skin lesions. BBG was shown to competitively inhibit cAMP binding to the regulatory subunit of protein kinase A, to alter the functioning of transcription factors CREB and SOX9 implicated in melanogenesis. More recently, BBG was found to inhibit gastric H⁺/K⁺-ATPase, presumably via a direct binding to a site on the luminal surface of the proton pump. This mechanism of action, coupled with the antioxidant and anti-inflammatory effects, stimulated the design of more stable anti-ulcer BBG analogues with a reinforced H⁺/K⁺-ATPase inhibitory activity, such as oxime and hydrazone carboxamide derivatives. The better knowledge of the bioactivities and the mechanism of action of BBG should encourage studies of natural products with a similar scaffold, such as paniculides A-D, liginvolones A-D, osterivolones A-D, ashitabaol A and other bisabolenoids. Altogether, the review provides a complete survey of the chemistry and pharmacology of bisabolangelone to shed light on its potential therapeutic interest.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100277"},"PeriodicalIF":0.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138211","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":"Reversing TGF-β1-induced fibrotic phenotype in human lung fibroblasts using a PROTAC tool derived from an indoline-based HDAC6 inhibitor","authors":"Ilaria Cursaro ,&nbsp;Valerio Ciccone ,&nbsp;Valeria Tudino ,&nbsp;Chiara Papulino ,&nbsp;Laura Scalvini ,&nbsp;Sandra Donnini ,&nbsp;Lucia Morbidelli ,&nbsp;Luca Bini ,&nbsp;Claudia Landi ,&nbsp;Chiara Contri ,&nbsp;Silvia Pasquini ,&nbsp;Fabrizio Vincenzi ,&nbsp;Katia Varani ,&nbsp;Alessio Lodola ,&nbsp;Marco Mor ,&nbsp;Rosaria Benedetti ,&nbsp;Lucia Altucci ,&nbsp;Stefania Butini ,&nbsp;Gabriele Carullo ,&nbsp;Sandra Gemma ,&nbsp;Giuseppe Campiani","doi":"10.1016/j.ejmcr.2025.100276","DOIUrl":"10.1016/j.ejmcr.2025.100276","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating interstitial lung disease characterized by limited therapeutic options, with only two FDA-approved palliative agents currently available. Given its poor prognosis and the high incidence of lung transplantation, there is a pressing need to develop innovative and effective therapeutics. Histone deacetylase 6 (HDAC6) has been identified as a key driver of fibrotic progression in IPF, and selective inhibitors of this isoform were able to revert the fibrotic phenotypes. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that can trigger the degradation of a specific target in cells, including HDAC6 enzyme. Therefore, the application of PROTAC technology may represent a novel therapeutic strategy for IPF. We showcase the design, synthesis, and biological evaluation of a library of first-in-class antifibrotic HDAC6-targeting PROTACs, incorporating our <em>in-house</em> inhibitor <strong>1</strong> as the HDAC6 ligand. Newly developed PROTACs <strong>5a</strong> and <strong>5c</strong> showed effective degradation of HDAC6 in A549 lung cells and IMR-90 lung fibroblasts. <strong>5a</strong> and <strong>5c</strong> exhibited significant antifibrotic effects against the TGF-β1 induced fibrotic phenotype on IMR-90 cells, a model that mimics IPF conditions. The generation of putative ternary complexes involving PROTAC molecules, the E3-ligase cereblon (CRBN) and the HDAC6 target protein was supported by molecular modelling techniques, including protein-protein docking and molecular dynamics simulations. Mechanistic investigations, based on pull-down experiments, confirmed that the newly synthetized compounds were able to reduce HDAC6 levels through a proteasome- and CRBN-dependent mechanism as confirmed by experiments with neddylation and proteasome inhibitors. This pioneering exploration of targeted protein degradation in IPF-like conditions provides compelling evidence of its therapeutic promise, paving the way for a broader application of PROTACs in treating rare diseases.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100276"},"PeriodicalIF":0.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134767","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":"Mitochondria-targeting phosphonium salts of monensin A as the source of novel antiproliferative agents","authors":"Michał Sulik ,&nbsp;Marta Jędrzejczyk ,&nbsp;Magdalena Mielczarek-Puta ,&nbsp;Gwan Yong Lim ,&nbsp;Małgorzata Podsiad ,&nbsp;Jakub Hoser ,&nbsp;Piotr Bednarczyk ,&nbsp;Marta Struga ,&nbsp;Adam Huczyński","doi":"10.1016/j.ejmcr.2025.100275","DOIUrl":"10.1016/j.ejmcr.2025.100275","url":null,"abstract":"<div><div>Monensin A is a representative of natural ionophores, which exhibit a broad spectrum of biological properties, with the most fascinating being its potent anticancer activity. A very intriguing research direction is the rational chemical modification of the monensin A skeleton to obtain analogs with higher antiproliferative activity and selectivity indices. In this paper, synthetic access to monensin A conjugates with mitochondria-targeting chemical moieties, such as the triphenylphosphonium cation and its analogs, is presented. Furthermore, the obtained derivatives were screened for lead structures with improved anticancer properties and mitochondria-targeting ability. Some of the obtained compounds exhibited greater antiproliferative activity and selectivity than unmodified monensin. Furthermore, biological and biophysical studies have confirmed that the induction of apoptosis by the aforementioned hybrids is linked to targeting of mitochondria in cancer cells. These results prove that such a strategy is a promising approach for the search for new effective drug candidates.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100275"},"PeriodicalIF":0.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134766","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}