European Journal of Medicinal Chemistry最新文献_第5页

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 作为选择性醛糖还原酶抑制剂的新型 N-苄基吲哚类依帕司他类似物的合理设计与合成：作为线粒体解偶联剂的新型降糖药（AK-4）的意外发现

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-08 DOI: 10.1016/j.ejmech.2024.117035

Antonios Kousaxidis , Paolo Paoli , Lucia Kovacikova , Massimo Genovese , Alice Santi , Milan Stefek , Anthi Petrou , Ioannis Nicolaou

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 (AK-1-4) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. AK-1-4 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 AK-4 sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under ex vivo conditions. We further investigated the ability of AK-4 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 (AK-4) 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 in silico revealed optimal properties of AK-4 for oral administration without potential side effects.

糖尿病是与高血糖相关的最常见代谢性疾病之一。虽然抗糖尿病药物能降低高血糖，但糖尿病患者的血糖水平会出现异常波动，导致长期并发症的发生。醛糖还原酶抑制剂被认为是调节糖尿病特异性并发症发生的一种有前途的策略。迄今为止，依帕司他是亚洲国家唯一获批的药物。在本文中，我们的研究立足于发现新型依帕司他类似物，以预防慢性并发症并使高血糖正常化。在本文中，我们介绍了四种新型 4-噻唑烷酮乙酸衍生物（AK-1-4）的合理设计与合成，并评估了它们对大鼠镜片中醛糖还原酶的疗效及其对大鼠肾脏中同源酶的特异性。AK-1-4 还针对人重组蛋白酪氨酸磷酸酶 1B 进行了测试，该酶是胰岛素增敏作用的关键靶点，AK-1-4 还针对与之密切相关的 T 细胞衍生酶进行了测试。对接分析表明了与所研究靶点的可能结合模式。AK-4 具有良好的抑制作用，这激发了我们探索其对胰岛素受体信号通路的影响及其在体内外条件下刺激葡萄糖摄取的能力的兴趣。我们进一步研究了 AK-4 作为解偶联剂靶向线粒体和损害线粒体膜电位的能力。在此，我们首次报道了一种新型降糖药物（AK-4），它通过控制线粒体解偶联活性，既能缓解慢性糖尿病并发症，又不会产生脱靶不良反应，同时还具有降血糖功效。硅学药代动力学和毒性研究显示，AK-4 具有最佳口服特性，且无潜在副作用。

{"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 , Paolo Paoli , Lucia Kovacikova , Massimo Genovese , Alice Santi , Milan Stefek , Anthi Petrou , 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}

引用次数: 0

Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors 一系列强效、选择性和药物样 G 蛋白偶联受体激酶 5 抑制剂的设计、合成和 X 射线结构研究

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-08 DOI: 10.1016/j.ejmech.2024.117024

Arun K. Ghosh , Yueyi Chen , Ranjith Kumar Gadi , Amol Sonawane , Sandali Piladuwa Gamage , JohnJ.G. Tesmer

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.

G蛋白偶联受体激酶5（GRK5）已成为治疗心力衰竭和癌症的潜在药物开发靶点。GRK6的同源物是多发性骨髓瘤的治疗靶点。我们合理地设计了一系列高选择性、强效、非共价和类药物 GRK5 抑制剂。几种抑制剂对 GRK5 的抑制作用低至纳摩尔，对 GRK2 有高选择性，令人惊讶的是，有些抑制剂对 GRK6 也有选择性。我们测定了几种抑制剂与 GRK5 复合物的高分辨率 X 射线晶体结构，从而从分子角度揭示了导致 GRK5 选择性和效力的配体-结合位点相互作用。

引用次数: 0

Synthesis and pharmacodynamic evaluation of 2-aminoindole derivatives against influenza A virus in vitro/vivo 针对甲型流感病毒的 2-氨基吲哚衍生物的体外/体内合成和药效学评价

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-08 DOI: 10.1016/j.ejmech.2024.117044

Zhongmou Zhang , Nanfang Wang , Jiejie Lu , Ying Qu , Yihui Song , Xinyu Yang , Zhanyong Wei , Qi Zhang , Piet Herdewijn , Junbiao Chang , Xiao-Na Wang , Zhenya Wang

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 N-arylynamides with sulfilimines and evaluated for their anti-influenza virus activity. The experimental results showed that 2-aminoindole 3h had significant antiviral activity (EC₅₀ = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC₅₀ = 669.26 ± 11.42 μM) in vitro. 2-Aminoindole 3h 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 3h 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.

流感病毒是一种发病率和死亡率极高的呼吸道病原体，至今仍威胁着人类的健康。现有的抗流感药物存在各种局限性，如无法减轻身体损伤和副作用。目前仍急需开发一种新型抗病毒药物，在有效抑制病毒感染的同时避免对机体的伤害。研究人员通过 TMSOTf 催化 N-arylynamides 与亚磺酰亚胺的反应合成了一系列 2-氨基吲哚衍生物，并对其抗流感病毒活性进行了评估。实验结果表明，2-氨基吲哚 3h 在体外具有显著的抗病毒活性（EC50 = 8.37 ± 0.65 μM）和最低的细胞毒性（CC50 = 669.26 ± 11.42 μM）。2-Aminoindole 3h 可与 RNA 依赖性 RNA 聚合酶（RdRp）有效结合，从而抑制病毒复制，还可直接靶向宿主细胞，抑制病毒感染引起的细胞因子风暴和细胞凋亡，从而提高宿主细胞存活率。此外，2-氨基吲哚 3h 还能有效降低感染小鼠肺组织中的病毒载量和器官损伤，生物安全性令人满意。这些研究结果凸显了2-氨基吲哚作为抗流感病毒感染的治疗药物的潜力，同时也为该领域的进一步研究和开发奠定了基础。

{"title":"Synthesis and pharmacodynamic evaluation of 2-aminoindole derivatives against influenza A virus in vitro/vivo","authors":"Zhongmou Zhang , Nanfang Wang , Jiejie Lu , Ying Qu , Yihui Song , Xinyu Yang , Zhanyong Wei , Qi Zhang , Piet Herdewijn , Junbiao Chang , Xiao-Na Wang , 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 (EC<sub>50</sub> = 8.37 ± 0.65 μM) and the lowest cytotoxicity (CC<sub>50</sub> = 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}

引用次数: 0

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. 优化一系列新型 ENaC 抑制剂，最终选定长效吸入式临床候选药物 ETD001，这是一种治疗囊性纤维化的潜在新疗法。

IF 6.7 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-08 DOI: 10.1016/j.ejmech.2024.117040

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

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.

囊性纤维化（CF）是由于囊性纤维化跨膜传导调节器（CFTR）功能丧失造成的，CFTR 是气道上皮中的一个重要离子通道。CFTR 有助于控制气道的最佳水合状态，这是肺部健康的关键要求。CFTR 调节剂最近已被批准作为治疗多种 CF 遗传变异的有效方法。上皮钠通道（ENaC）与具有分泌功能的 CFTR 不同，它是一种吸收途径，因此抑制ENaC 是帮助呼吸道水合的另一种可能的补充方法。由于 ENaC 抑制剂会对肾脏产生不良影响，我们和其他一些人一样，致力于设计和合成新型 ENaC 抑制剂，以便通过吸入直接输送到气道。本文介绍了一系列新型 ENaC 抑制剂，其中第一代抑制剂的吡嗪核心已被吡咯并嗪取代。为了实现吸入后在肺部表面的高保留率，该模板的优化重点是显著增加极性，以最大限度地降低被动细胞渗透性。优化后的临床候选药物 ETD001 对 ENaC 有强效抑制作用（59 nM），气管内给药后在大鼠气道中保留时间长（6 小时后保留了 13% 的给药剂量），吸入后在绵羊粘膜清除模型中具有强效和长效作用（ED100 (4-6h) = 9 μg/kg）。2024 年 7 月，ETD001 进入 CF 患者的 II 期研究。

{"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 (ED<sub>100</sub> (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}

引用次数: 0

Novel frontiers through nitrogen substitution at 6th, 10th and 11th position of artemisinin: Synthetic approaches and antimalarial activity 青蒿素第 6、10 和 11 位氮取代的新前沿：合成方法和抗疟活性

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-07 DOI: 10.1016/j.ejmech.2024.117032

Priyanka Yadav , Varun Rawat , Shalini Kaushik Love , Ved Prakash Verma

Malaria pertains to an array of catastrophic illnesses spurred on by the Plasmodium 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 in vivo 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.

疟疾是由疟原虫引起的一系列灾难性疾病。目前，青蒿素（ART）与另一种药物联合使用，作为急性疟疾治疗方案的一部分。即使在缺乏所需的热代谢稳定性之后，这些目前的处方药已经存在了一段时间，同时还出现了关于抗药性和与连续服用此类联合疗法相关的神经毒性的新说法。多年来，抗逆转录病毒疗法似乎因能加速减少寄生虫血症而广受欢迎，因此需要使用具有不同稳定性的抗逆转录病毒疗法衍生物，通过联合或单独使用来控制疟疾的扩散。抗逆转录病毒疗法药理结构中的内过氧化物桥在对寄生虫生命周期的多个阶段起着不可忽视的作用。然而，较短的半衰期和有限的生物利用度往往为另一类内过氧化物打开了大门。ART 第 6、第 10 和第 11 位的氮替代物因其不同的稳定性和无法在体内水解分解为 DHA 而成为最佳替代物。过去 30 年中报道的此类杂青蒿素类和氨基青蒿素类药物，由于其合成方法和抗疟药效，引起了人们的强烈关注，目的是为未来的候选药物确定有价值的分子。

{"title":"Novel frontiers through nitrogen substitution at 6th, 10th and 11th position of artemisinin: Synthetic approaches and antimalarial activity","authors":"Priyanka Yadav , Varun Rawat , Shalini Kaushik Love , 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}

引用次数: 0

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile 发现新型融合terocycle-bearing Diarypyrimidine Derivatives 作为 HIV-1 强效 NNRTIs，靶向耐受区 I 以增强抗病毒活性和耐药性特征

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-07 DOI: 10.1016/j.ejmech.2024.117033

Jiaojiao Dai , Xiangyi Jiang , Heng Gao , Boshi Huang , Erik De Clercq , Christophe Pannecouque , Shaoqing Du , Xinyong Liu , Peng Zhan

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 XJ-18b1 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 3k 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 3k demonstrated antiviral activity against HIV-2 with EC₅₀ value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k 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-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.

作为抗艾滋病疗法的重要组成部分，HIV-1 非核苷类逆转录酶抑制剂饱受耐药性和毒性问题的困扰。我们以已报道的 XJ-18b1 为先导化合物，采用支架跳转策略设计了一系列新型二芳基嘧啶衍生物，发现了具有更强抗药性和类药物特征的强效 NNRTIs。活性最强的化合物 3k 对野生型 HIV-1（EC50 = 0.0019 μM）和常见突变株（包括 K103N（EC50 = 0.0019 μM）、L100I（EC50 = 0.0087 μM）、E138K（EC50 = 0.011 μM））具有显著的抑制活性，同时还具有低细胞毒性和高选择性指数（CC50 = 21.95 μM，SI = 11478）。此外，化合物 3k 对 HIV-2 具有抗病毒活性，EC50 值为 6.14 μM。酶联免疫吸附试验验证了 3k 能显著抑制 HIV-1 逆转录酶的活性（IC50 = 0.025 μM）。此外，还进行了分子动力学模拟研究，以说明 RT-3k 复合物的潜在结合模式和结合自由能。总之，3k 被证明是一种很有希望的先导化合物，可进一步优化以获得抗 HIV 候选药物。

{"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 , Xiangyi Jiang , Heng Gao , Boshi Huang , Erik De Clercq , Christophe Pannecouque , Shaoqing Du , Xinyong Liu , 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 (EC<sub>50</sub> = 0.0019 μM) and common mutant strains including K103 N (EC<sub>50</sub> = 0.0019 μM), L100I (EC<sub>50</sub> = 0.0087 μM), E138K (EC<sub>50</sub> = 0.011 μM), along with low cytotoxicity and high selectivity index (CC<sub>50</sub> = 21.95 μM, SI = 11478). Additionally, compound <strong>3k</strong> demonstrated antiviral activity against HIV-2 with EC<sub>50</sub> 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 (IC<sub>50</sub> = 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}

引用次数: 0

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 发现具有抗氧化、金属络合和神经保护能力的新型硫代氨基羰基吖啶丁酰胆碱酯酶，作为阿尔茨海默病的潜在治疗药物：体外、体内和硅学研究。

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-07 DOI: 10.1016/j.ejmech.2024.117030

Gleyton Leonel Silva Sousa , Nathalia Fonseca Nadur , Larissa de Almeida Peixoto Ferreira , Thiago da Silva Honório , Alice Simon , Lucio Mendes Cabral , Maria Luiza Móra Santos , Bruna Andrade , Emanuelle V. de Lima , Julia R. Clarke , Rosane Nora Castro , Ricardo Olímpio de Moura , Arthur Eugen Kümmerle

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 in vitro 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.

抑制胆碱酯酶与抗氧化活性、金属螯合能力和神经保护相结合，被认为是治疗阿尔茨海默病（AD）的有效多靶点疗法。基于我们内部的硫代氨基脲-吖啶化合物，本研究将这些衍生物视为可能的多靶点配体（MTDL）。对胆碱酯酶的初步筛选确定了 CL-01，它对丁酰胆碱酯酶（BChE）的 IC50 值为 0.71 μM，前景看好。在 CL-01 的基础上设计了 12 种新的衍生物，旨在保留 BChE 抑制活性的同时融入 MTDL 特性，包括抗氧化特性和金属络合能力。在这些新衍生物中，CL-13 保持了良好的 BChE 抑制作用（IC50 = 1.15 μM），并提高了对乙酰胆碱酯酶的选择性指数（SI = 9.2）。吖啶核对其活性非常重要，因为其饱和四氢吖啶类似物（TA-01）显示出胆碱酯酶抑制效力下降，并改变了抑制模式，首次揭示了两个核的不同功能作用。此外，CL-13 还是一种很有前途的先导化合物，它具有有趣的抗氧化活性（DPPH EC50 = 47.01 μM），对参与 Aβ 聚集和/或氧化应激的生物金属具有螯合能力，并且在 SH-SY5Y 细胞中 50 μM 的浓度下没有神经毒性。在 H2O2 诱导的体外氧化应激模型中，它还表现出神经保护作用。最后，体内实验证实，CL-13 能有效逆转东莨菪碱诱导的小鼠认知障碍，且不影响小鼠的运动活动。

{"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 , Nathalia Fonseca Nadur , Larissa de Almeida Peixoto Ferreira , Thiago da Silva Honório , Alice Simon , Lucio Mendes Cabral , Maria Luiza Móra Santos , Bruna Andrade , Emanuelle V. de Lima , Julia R. Clarke , Rosane Nora Castro , Ricardo Olímpio de Moura , 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 IC<sub>50</sub> 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 (IC<sub>50</sub> = 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 EC<sub>50</sub> = 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 H<sub>2</sub>O<sub>2</sub>. 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}

引用次数: 0

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 发现 4-(4-(3-(1-(2-(哌啶-1-基)乙基)-1H-苯并[d]咪唑-2-基)异恶唑-5-基)苯基)吗啉作为一种新型 c-Myc 体外和体内肺癌抑制剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-07 DOI: 10.1016/j.ejmech.2024.117023

Jian Gao , Jiacheng Yin , Shihao Li , Pingting Jia, Renjie Hong, Jiahui Chen, Xinxin Qu, Zihui Zhang, Mengting Li, Hui Zhao

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 D347–2761, 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 A1 displayed IC₅₀ values of 6.32 μM and 11.39 μM against the A549 and NCI–H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC₅₀ values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 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 A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 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 A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.

c-Myc在肺癌的发生和发展过程中起着关键的驱动作用，这使它成为抗肺癌治疗研究的关键靶点。在之前的研究中，我们报道了一种新型小分子抑制剂 D347-2761的发现，它能特异性地靶向 c-Myc 的不稳定结构域并破坏 c-Myc/Max 异二聚体。为了进一步提高靶向治疗的效果，我们进行了广泛的结构分析，并设计出一系列创新的苯并咪唑衍生物。利用 CCK-8 试验评估了这些化合物的细胞毒性活性，结果显示化合物 A1 对 A549 和 NCI-H1299 肺癌细胞株的 IC50 值分别为 6.32 μM 和 11.39 μM，而化合物 A5 对相同细胞株的 IC50 值分别为 4.08 μM 和 7.86 μM。我们的研究结果表明，化合物 A1 和 A5 通过破坏 c-Myc 和 Max 蛋白之间的相互作用，导致 c-Myc 蛋白水平下调，并通过细胞凋亡途径诱导细胞凋亡，从而显示出强大的抗癌活性。值得注意的是，与其他测试化合物相比，化合物 A5 表现出更强的抑制能力。此外，在合成肿瘤模型中，化合物 A5 表现出卓越的疗效，肿瘤生长抑制率高达 76.4%，同时 c-Myc 蛋白表达水平显著降低。因此，化合物 A5有望成为抗肺癌治疗中靶向 c-Myc 的潜在药物。

{"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 , Jiacheng Yin , Shihao Li , Pingting Jia, Renjie Hong, Jiahui Chen, Xinxin Qu, Zihui Zhang, Mengting Li, 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 IC<sub>50</sub> 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 IC<sub>50</sub> 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}

引用次数: 0

Discovery of novel phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects 发现具有抗结肠癌和潜在免疫调节作用的新型苯基尿素 SHP2 抑制剂

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-06 DOI: 10.1016/j.ejmech.2024.117036

Kaizhen Wang , Xiangyu Zhang , Yingxin Hu, Jiazheng Guo, Guoqing Shen, Kuojun Zhang, Sheng Jiang, Tianyu Wang

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 SHP099 and TNO155. Herein, we reported our discovery and optimization of phenyl urea as novel SHP2 inhibitors. A8, the most potential SHP2 inhibitor, exhibited great antiproliferative activities against SHP099/TNO155-insensitive tumor cell lines, and rescued PD-L1-mediated immunosuppression. A8 significantly suppressed in vivo tumor growth in a CT26 mouse model and activated immunomodulatory effects in tumor microenvironment. Our work demonstrated that A8 has the potential to be a lead compound for the further development of SHP2 inhibitor and the treatment of CRC.

Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2（SHP2）是一种非受体型蛋白酪氨酸磷酸酶（PTP），被认为是潜在的、有吸引力的癌症治疗靶点。目前，还没有SHP2抑制剂被批准用于临床，而且结直肠癌（CRC）细胞对已报道的SHP2抑制剂（如SHP099和TNO155）经常表现出耐药性。在此，我们报告了苯脲作为新型 SHP2 抑制剂的发现和优化。A8是最有潜力的SHP2抑制剂，它对SHP099/TNO155不敏感的肿瘤细胞株具有很强的抗增殖活性，并能挽救PD-L1介导的免疫抑制。在 CT26 小鼠模型中，A8 能明显抑制体内肿瘤生长，并激活肿瘤微环境中的免疫调节作用。我们的研究表明，A8 有潜力成为进一步开发 SHP2 抑制剂和治疗 CRC 的先导化合物。

{"title":"Discovery of novel phenyl urea SHP2 inhibitors with anti-colon cancer and potential immunomodulatory effects","authors":"Kaizhen Wang , Xiangyu Zhang , Yingxin Hu, Jiazheng Guo, Guoqing Shen, Kuojun Zhang, Sheng Jiang, 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}

引用次数: 0

Design and synthesis of glycofullerene derivatives as novel photosensitizer for potential application in PDT to treat cancer 设计和合成作为新型光敏剂的 Glycofullerene 衍生物，有望应用于治疗癌症的光导疗法

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2024-11-06 DOI: 10.1016/j.ejmech.2024.117009

Xue Bai , Tian Yang , Xinle Shao , Bobo Jia , Huifang Hao , Faiz-Ur Rahman , Yongmin Zhang

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 12 and 13. 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 13 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.

癌症是人类已知的最具侵袭性的疾病之一，其特点是存活率低、预后差。目前，铂类抗癌药物和光动力疗法（PDT）中使用的传统光敏剂是最广泛使用的治疗方式。然而，铂类药物，尤其是最常用的顺铂，存在一些缺点。这些缺点可能包括全身毒性，在治疗过程中可能表现为肾毒性、神经毒性、耳毒性或呕吐。这些副作用会严重损害患者的身体，大大降低治疗干预的整体效果。相比之下，光动力疗法没有这些缺点。光动力疗法有许多优点，包括降低长期发病率、全身毒性极小、低侵入性、耐药性可忽略不计以及时间和地域选择性，所有这些都能提高患者的生活质量。因此，寻找新型、有效和实用的光敏剂至关重要。富勒烯具有独特的物理化学特性，非常适合作为光敏剂。在这项研究中，我们开发了一种全面而简单的方法来合成两种水溶性糖富勒烯衍生物，分别命名为 12 和 13。多种分析技术，包括 1H NMR、13C NMR、高分辨率质谱（HRMS）、傅立叶变换红外光谱（FT-IR）和紫外可见光谱（UV-Vis），共同证实了这些衍生物的化学结构，并验证了它们的成功合成。在强度为 2.5J/cm2 的白光照射下，化合物 13 对三种不同的肿瘤细胞株具有显著的生物活性：其 IC50 值分别为 5.65μM、2.43μM 和 1.82μM。这项研究为开发创新型临床光敏剂奠定了基础。

{"title":"Design and synthesis of glycofullerene derivatives as novel photosensitizer for potential application in PDT to treat cancer","authors":"Xue Bai , Tian Yang , Xinle Shao , Bobo Jia , Huifang Hao , Faiz-Ur Rahman , 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 <sup>1</sup>H NMR, <sup>13</sup>C 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/cm<sup>2</sup>, compound <strong>13</strong> demonstrated significant biological activity against three distinct tumor cell lines: HepG2, MKN45, and RPMI 4788, with IC<sub>50</sub> 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}

引用次数: 0