European Journal of Medicinal Chemistry最新文献

{"title":"Rational design and synthesis of novel N-benzylindole-based epalrestat analogs as selective aldose reductase inhibitors: An unexpected discovery of a new glucose-lowering agent (AK-4) acting as a mitochondrial uncoupler","authors":"Antonios Kousaxidis ,&nbsp;Paolo Paoli ,&nbsp;Lucia Kovacikova ,&nbsp;Massimo Genovese ,&nbsp;Alice Santi ,&nbsp;Milan Stefek ,&nbsp;Anthi Petrou ,&nbsp;Ioannis Nicolaou","doi":"10.1016/j.ejmech.2024.117035","DOIUrl":"10.1016/j.ejmech.2024.117035","url":null,"abstract":"<div><div>Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (<strong>AK-1-4</strong>) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. <strong>AK-1-4</strong> were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of <strong>AK-4</strong> sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under <em>ex vivo</em> conditions. We further investigated the ability of <strong>AK-4</strong> to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (<strong>AK-4</strong>) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies <em>in silico</em> revealed optimal properties of <strong>AK-4</strong> for oral administration without potential side effects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117035"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596872","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}

{"title":"Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors","authors":"Arun K. Ghosh ,&nbsp;Yueyi Chen ,&nbsp;Ranjith Kumar Gadi ,&nbsp;Amol Sonawane ,&nbsp;Sandali Piladuwa Gamage ,&nbsp;JohnJ.G. Tesmer","doi":"10.1016/j.ejmech.2024.117024","DOIUrl":"10.1016/j.ejmech.2024.117024","url":null,"abstract":"<div><div>G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"282 ","pages":"Article 117024"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596847","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}

{"title":"Synthesis and pharmacodynamic evaluation of 2-aminoindole derivatives against influenza A virus in vitro/vivo","authors":"Zhongmou Zhang ,&nbsp;Nanfang Wang ,&nbsp;Jiejie Lu ,&nbsp;Ying Qu ,&nbsp;Yihui Song ,&nbsp;Xinyu Yang ,&nbsp;Zhanyong Wei ,&nbsp;Qi Zhang ,&nbsp;Piet Herdewijn ,&nbsp;Junbiao Chang ,&nbsp;Xiao-Na Wang ,&nbsp;Zhenya Wang","doi":"10.1016/j.ejmech.2024.117044","DOIUrl":"10.1016/j.ejmech.2024.117044","url":null,"abstract":"<div><div>Influenza virus is a kind of respiratory pathogen with high morbidity and mortality, which still threatens human health. Existing anti-influenza drugs have various limitations, such as the inability to alleviate body injury and side effects. There remains an urgent need to develop a novel antiviral drug to efficiently inhibit viral infection while avoiding body injury. A series of 2-aminoindole derivatives were synthesized via the TMSOTf-catalyzed reactions of <em>N</em>-arylynamides with sulfilimines and evaluated for their anti-influenza virus activity. The experimental results showed that 2-aminoindole <strong>3h</strong> had significant antiviral activity (EC₅₀ = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC₅₀ = 669.26 ± 11.42 μM) <em>in vitro</em>. 2-Aminoindole <strong>3h</strong> could inhibit viral replication by effectively binding to RNA-dependent RNA polymerase (RdRp), and could also directly target host cells to inhibit cytokine storms and apoptosis induced by viral infection, thereby improving host cell survival rate. In addition, viral load and organ injury in the lung tissue of infected mice were effectively reduced by 2-aminoindole <strong>3h</strong> with satisfactory biosafety. These findings highlight the potential of a valuable therapeutic option against influenza infection while also laying the foundation for further research and development in this area.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117044"},"PeriodicalIF":6.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596873","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}

{"title":"Optimization of a novel series of ENaC inhibitors, leading to the selection of the long-acting inhaled clinical candidate ETD001, a potential new treatment for cystic fibrosis.","authors":"Henry Danahay, Martin Gosling, Roy Fox, Sarah Lilley, Holly Charlton, Jonathan D. Hargrave, Thomas B. Schofield, Duncan A. Hay, Naomi Went, Pearl McMahon, Frederic Marlin, John Scott, Julia Vile, Steve Hewison, Sarah Ellam, Samantha Brown, Juan Sabater, Guy Kennet, Sean Lightowler, Stephen P. Collingwood","doi":"10.1016/j.ejmech.2024.117040","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117040","url":null,"abstract":"Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimization of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13% of the delivered dose retained after 6h) following intratracheal administration and potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED₁₀₀ (4-6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596846","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}

{"title":"Novel frontiers through nitrogen substitution at 6th, 10th and 11th position of artemisinin: Synthetic approaches and antimalarial activity","authors":"Priyanka Yadav ,&nbsp;Varun Rawat ,&nbsp;Shalini Kaushik Love ,&nbsp;Ved Prakash Verma","doi":"10.1016/j.ejmech.2024.117032","DOIUrl":"10.1016/j.ejmech.2024.117032","url":null,"abstract":"<div><div>Malaria pertains to an array of catastrophic illnesses spurred on by the <em>Plasmodium</em> spp. Artemisinin (ART) is currently prescribed in conjunction with another medication as part of therapeutic regimens for acute malaria. These currently prescribed pharmaceuticals have been around for a while, even after lack of required thermos-metabolic stabilities, alongside fresh proclaims about surfacing resistance and neurotoxicity linked with sequential administration of such combination therapies. Over the years, ARTs seem to have gained popularity through the accelerated reduction in parasitaemia, thus dictating use of differentially stable ART derivatives, in combination or alone, to control the proliferation of malaria. The endoperoxide bridge in the ART pharmacophore plays a non-negotiable role in its action against multiple stages in the parasitic life cycle. However, shorter half-lives and limited bioavailability tend to open doors for another class of endoperoxides. Nitrogen substitution at 6th, 10th and 11th positions of ART draws attention as the best replacements through their disparate stabilities and inability to demonstrate <em>in vivo</em> hydrolytic decomposition into DHA. Discussions pertaining such azaartemisinins and aminoartemisinins reported over the past 30 years have been strongly focused upon, on account of their synthetic methodologies and antimalarial efficacies, in order to assign future candidature to the meritorious moiety.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117032"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596848","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}

{"title":"Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile","authors":"Jiaojiao Dai ,&nbsp;Xiangyi Jiang ,&nbsp;Heng Gao ,&nbsp;Boshi Huang ,&nbsp;Erik De Clercq ,&nbsp;Christophe Pannecouque ,&nbsp;Shaoqing Du ,&nbsp;Xinyong Liu ,&nbsp;Peng Zhan","doi":"10.1016/j.ejmech.2024.117033","DOIUrl":"10.1016/j.ejmech.2024.117033","url":null,"abstract":"<div><div>As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported <strong>XJ-18b1</strong> as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound <strong>3k</strong> exhibited prominent inhibitory activity against wild-type HIV-1 (EC₅₀ = 0.0019 μM) and common mutant strains including K103 N (EC₅₀ = 0.0019 μM), L100I (EC₅₀ = 0.0087 μM), E138K (EC₅₀ = 0.011 μM), along with low cytotoxicity and high selectivity index (CC₅₀ = 21.95 μM, SI = 11478). Additionally, compound <strong>3k</strong> demonstrated antiviral activity against HIV-2 with EC₅₀ value of 6.14 μM. The enzyme-linked immunosorbent assay validated that <strong>3k</strong> could significantly inhibit the activity of HIV-1 reverse transcriptase (IC₅₀ = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-<strong>3k</strong> complex, and <em>in silico</em> prediction revealed that <strong>3k</strong> possessed favorable drug-like profiles. Collectively, <strong>3k</strong> proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117033"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594472","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}

{"title":"Discovery of novel thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies","authors":"Gleyton Leonel Silva Sousa ,&nbsp;Nathalia Fonseca Nadur ,&nbsp;Larissa de Almeida Peixoto Ferreira ,&nbsp;Thiago da Silva Honório ,&nbsp;Alice Simon ,&nbsp;Lucio Mendes Cabral ,&nbsp;Maria Luiza Móra Santos ,&nbsp;Bruna Andrade ,&nbsp;Emanuelle V. de Lima ,&nbsp;Julia R. Clarke ,&nbsp;Rosane Nora Castro ,&nbsp;Ricardo Olímpio de Moura ,&nbsp;Arthur Eugen Kümmerle","doi":"10.1016/j.ejmech.2024.117030","DOIUrl":"10.1016/j.ejmech.2024.117030","url":null,"abstract":"<div><div>Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC₅₀ value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC₅₀ = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC₅₀ = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an <em>in vitro</em> oxidative stress model induced by H₂O₂. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117030"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596874","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}

{"title":"Discovery of 4-(4-(3-(1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole-2-yl)isoxazol-5-yl)phenyl)morpholine as a novel c-Myc inhibitor against lung cancer in vitro and in vivo","authors":"Jian Gao ,&nbsp;Jiacheng Yin ,&nbsp;Shihao Li ,&nbsp;Pingting Jia,&nbsp;Renjie Hong,&nbsp;Jiahui Chen,&nbsp;Xinxin Qu,&nbsp;Zihui Zhang,&nbsp;Mengting Li,&nbsp;Hui Zhao","doi":"10.1016/j.ejmech.2024.117023","DOIUrl":"10.1016/j.ejmech.2024.117023","url":null,"abstract":"<div><div>The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of <strong>D347</strong>–<strong>2761</strong>, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound <strong>A1</strong> displayed IC₅₀ values of 6.32 μM and 11.39 μM against the A549 and NCI–H1299 lung cancer cell lines, respectively, while compound <strong>A5</strong> exhibited IC₅₀ values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds <strong>A1</strong> and <strong>A5</strong> exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound <strong>A5</strong> demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound <strong>A5</strong> exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound <strong>A5</strong> holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117023"},"PeriodicalIF":6.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594539","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}

{"title":"Discovery of novel phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects","authors":"Kaizhen Wang ,&nbsp;Xiangyu Zhang ,&nbsp;Yingxin Hu,&nbsp;Jiazheng Guo,&nbsp;Guoqing Shen,&nbsp;Kuojun Zhang,&nbsp;Sheng Jiang,&nbsp;Tianyu Wang","doi":"10.1016/j.ejmech.2024.117036","DOIUrl":"10.1016/j.ejmech.2024.117036","url":null,"abstract":"<div><div>Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP2) is a non-receptor-type protein tyrosine phosphatase (PTP), which is recognized as potential and attractive cancer therapeutic target. Currently, no SHP2 inhibitors have been approved for clinical use, and colorectal cancer (CRC) cells exhibited frequent resistance to reported SHP2 inhibitors, such as <strong>SHP099</strong> and <strong>TNO155</strong>. Herein, we reported our discovery and optimization of phenyl urea as novel SHP2 inhibitors. <strong>A8</strong>, the most potential SHP2 inhibitor, exhibited great antiproliferative activities against <strong>SHP099</strong>/<strong>TNO155</strong>-insensitive tumor cell lines, and rescued PD-L1-mediated immunosuppression. <strong>A8</strong> significantly suppressed <em>in vivo</em> tumor growth in a CT26 mouse model and activated immunomodulatory effects in tumor microenvironment. Our work demonstrated that <strong>A8</strong> has the potential to be a lead compound for the further development of SHP2 inhibitor and the treatment of CRC.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117036"},"PeriodicalIF":6.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594470","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}

{"title":"Design and synthesis of glycofullerene derivatives as novel photosensitizer for potential application in PDT to treat cancer","authors":"Xue Bai ,&nbsp;Tian Yang ,&nbsp;Xinle Shao ,&nbsp;Bobo Jia ,&nbsp;Huifang Hao ,&nbsp;Faiz-Ur Rahman ,&nbsp;Yongmin Zhang","doi":"10.1016/j.ejmech.2024.117009","DOIUrl":"10.1016/j.ejmech.2024.117009","url":null,"abstract":"<div><div>Cancer is one of the most aggressive diseases known to humanity, characterized by low survival rates and poor prognoses. Currently, platinum-based anticancer drugs and traditional photosensitizers used in photodynamic therapy (PDT) are the most widely employed treatment modalities. However, the platinum-based medications, particularly cisplatin, the most commonly used agent, have several drawbacks. These drawbacks may include systemic toxicity, which can manifest as nephrotoxicity, neurotoxicity, ototoxicity, or emesis during treatment. Such side effects can severely impair patients and significantly diminish the overall effectiveness of therapeutic interventions. In contrast, photodynamic therapy does not present these disadvantages. PDT offers numerous benefits, including reduced long-term morbidity, minimal systemic toxicity, low invasiveness, negligible drug resistance, and temporal and geographic selectivity, all of which enhance patients' quality of life. Consequently, the search for novel, effective, and practical photosensitizers is essential. Fullerenes possess unique physicochemical properties that make them highly suitable as photosensitizers. In this study, we developed a comprehensive and straightforward synthesis for two water-soluble sugar fullerene derivatives, designated as <strong>12</strong> and <strong>13</strong>. Multiple analytical techniques, including ¹H NMR, ¹³C NMR, high-resolution mass spectrometry (HRMS), Fourier-transform infrared spectroscopy (FT-IR), and ultraviolet–visible (UV–Vis) spectroscopy, collectively confirmed the chemical structures of these derivatives and validated their successful synthesis. Upon exposure to white light irradiation at an intensity of 2.5J/cm², compound <strong>13</strong> demonstrated significant biological activity against three distinct tumor cell lines: HepG2, MKN45, and RPMI 4788, with IC₅₀ values of 5.65 μM, 2.43 μM, and 1.82 μM, respectively. This study establishes a foundation for the development of innovative clinical photosensitizers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117009"},"PeriodicalIF":6.0,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594471","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}