RSC medicinal chemistry最新文献

{"title":"Recent advancements in the structural exploration of TGR5 agonists for diabetes treatment","authors":"Rachana S. Bhimanwar, Amit Mittal, Snehal Chaudhari and Vikas Sharma","doi":"10.1039/D4MD00473F","DOIUrl":"10.1039/D4MD00473F","url":null,"abstract":"<p >TGR5, a receptor that interacts with bile acids on cell surfaces, has become a promising therapeutic target for type II diabetes due to its ability to regulate energy expenditure and blood sugar levels. While several TGR5 agonists have been identified, only a few are currently in clinical trials. This article reviews the promising TGR5 agonists discovered in recent years, highlighting the chemical structure and pharmacological profile of the most effective compounds. With the limited number of effective drugs available for treating type II diabetes, the search for a potent TGR5 agonist with high efficacy and fewer side effects continues. The goal of this article is to provide an overview of the latest advancements in TGR5 agonists and offer insights for the future development of novel, potent TGR5 agonists for diabetes treatment. A noteworthy aspect addressed in the discussion is the common side effect associated with TGR5 agonist treatment – gallbladder filling. The review also explores potential strategies to mitigate this side effect, with the goal of improving the overall safety and tolerability of TGR5-targeted therapies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3026-3037"},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semisynthetic phytochemicals in cancer treatment: a medicinal chemistry perspective","authors":"Meghna Arora, Ankit Kumar Singh, Adarsh Kumar, Harshwardhan Singh, Prateek Pathak, Maria Grishina, Jagat Pal Yadav, Amita Verma and Pradeep Kumar","doi":"10.1039/D4MD00317A","DOIUrl":"10.1039/D4MD00317A","url":null,"abstract":"<p >Cancer is the uncontrolled proliferation of abnormal cells that invade other areas, spread to other organs, and cause metastases, which is the most common cause of death. A review of all FDA-approved new molecular entities (NMEs) shows that natural products and derivatives account for over one-third of all NMEs. Before 1940, unmodified products and derivatives accounted for 43% and 14% of NME registrations, respectively. Since then, the share of unmodified products has decreased to 9.5% of all approved NMEs, while the share of derivatives has increased to 28%. Since the 1940s, semi-synthetic and synthetic derivatives of natural substances have gained importance, and this trend continues to date. In this study, we have discussed in detail isolated phytoconstituents with chemical modifications that are either FDA-approved or under clinical trials, such as podophyllotoxin, Taxol (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastine), camptothecin, genistein, cephalotaxine, rohitukine, and many more, which may act as essential leads to the development of novel anticancer agents. Furthermore, we have also discussed recent developments in the most potent semisynthetic phytoconstituents, their unique properties, and their importance in cancer treatment.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 3345-3370"},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based virtual screening discovers novel PKMYT1 inhibitors†","authors":"Haoyu Zhang, Jinyu Yu, Ziheng Yang, Zhiqiang Guo, Rui Liu, Qiaohua Qin, Yixiang Sun, Nian Liu, Zixuan Gao, Dongmei Zhao and Maosheng Cheng","doi":"10.1039/D4MD00389F","DOIUrl":"10.1039/D4MD00389F","url":null,"abstract":"<p >PKMYT1, a member of the WEE family, plays a crucial role in the cell cycle by specifically phosphorylating CDK1-CyclinB at Tyr15 and Thr14. Recent investigations have revealed that the amplification of CCNE1 and the inhibition of PKMYT1 kinase collectively result in synthetic lethality, further indicating that PKMYT1 is promising as an effective target for tumor therapy. Existing PKMYT1 inhibitors are mostly derivatives of RP-6306 or pan-inhibitors, limiting their further development. Herein, we conducted virtual screening of a natural product library, and <em>in vitro</em> enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC<small>₅₀</small> values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3114-3124"},"PeriodicalIF":4.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141944949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Rosavin improves insulin resistance and alleviates hepatic and kidney damage via modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals","authors":"Hebatallah S. Ali, Hiba S. Al-Amodi, Shaimaa Hamady, Marian M. S. Roushdy, Amany Helmy Hasanin, Ghada Ellithy, Rasha A. Elmansy, Hagir H. T. Ahmed, Enshrah M. E. Ahmed, Doaa M. A. Elzoghby, Hala F. M. Kamel, Ghida Hassan, Hind A. ELsawi, Laila M. Farid, Mariam B. Abouelkhair, Eman K. Habib, Mohamed Esawie, Heba Fikry, Lobna A. Saleh and Marwa Matboli","doi":"10.1039/D4MD90030H","DOIUrl":"10.1039/D4MD90030H","url":null,"abstract":"<p >Correction for ‘Rosavin improves insulin resistance and alleviates hepatic and kidney damage <em>via</em> modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals’ by Hebatallah S. Ali <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, <strong>15</strong>, 2098–2113, https://doi.org/10.1039/D4MD00023D.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 8","pages":" 2959-2959"},"PeriodicalIF":4.1,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md90030h?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141886139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116†","authors":"Zhong-Ying Ma, Xiao-Jing Ding, Zhen-Zhen Zhu, Qian Chen, Dong-Bo Wang, Xin Qiao and Jing-Yuan Xu","doi":"10.1039/D4MD00327F","DOIUrl":"10.1039/D4MD00327F","url":null,"abstract":"<p >Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(<small>IV</small>) conjugates derived from Pt(<small>II</small>) drug (cisplatin or oxaliplatin) and niflumic acid, complexes <strong>1</strong> and <strong>2</strong>, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex <strong>2</strong> afforded higher cytotoxicity than <strong>1</strong> and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, <strong>2</strong> was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of <strong>2</strong> is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that <strong>2</strong> inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3239-3247"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides†‡","authors":"Hugo Kocek, Dominika Chalupská, Milan Dejmek, Alexandra Dvořáková, Michala Zgarbová, Michal Šála, Karel Chalupský, Petra Krafčíková, Tomáš Otava, Matúš Drexler, Eliška Procházková, Blanka Klepetářová, Milan Štefek, Ján Kozic, Helena Mertlíková-Kaiserová, Evzen Boura, Jan Weber and Radim Nencka","doi":"10.1039/D4MD00422A","DOIUrl":"10.1039/D4MD00422A","url":null,"abstract":"<p >The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA capping, offers a promising approach for the development of small-molecule inhibitors. We designed and synthesized a series of adenosine 5′-carboxamide derivatives as potential nsp14 inhibitors and identified coumarin analogs to be particularly effective. Structural modifications revealed the importance of the 5′-carboxyl moiety for the inhibitory activity, showing superior efficacy compared to other modifications. Notably, compound <strong>18l</strong> (<strong>HK370</strong>) demonstrated high selectivity and favorable <em>in vitro</em> pharmacokinetic properties and exhibited moderate antiviral activity in cell-based assays. These findings provide a robust foundation for developing targeted nsp14 inhibitors as a potential treatment for COVID-19 and related diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 3469-3476"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142111559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical synthetic approaches to mimic the TRAIL: promising cancer therapeutics","authors":"Abdullah-Al Masum, Shin Aoki, Md. Mahbubur Rahman and Yosuke Hisamatsu","doi":"10.1039/D4MD00183D","DOIUrl":"10.1039/D4MD00183D","url":null,"abstract":"<p >Apoptosis is programmed cell death that eliminates undesired cells to maintain homeostasis in metazoan. Aberration of this process may lead to cancer genesis. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in cancer cells after ligation with death receptors (DR4/DR5) while sparing most normal cells. Therefore, strategies to induce apoptosis in cancer cells by mimicking the TRAIL emerge as a promising therapeutic tool. Hence, approaches are taken to develop TRAIL/DR-based cancer therapeutics. The recombinant soluble TRAIL (rhTRAIL) and death receptor agonistic antibodies were produced and tested pre-clinically and clinically. Pre-clinical and clinical trial data demonstrate that these therapeutics are safe and relatively well tolerated. But some of these therapeutics failed to exert adequate efficacy in clinical settings. Besides these biotechnologically derived therapeutics, a few chemically synthesized therapeutics are reported. Some of these therapeutics exert considerable efficacy <em>in vitro</em> and <em>in vivo</em>. In this review, we will discuss chemically synthesized TRAIL/DR-based therapeutics, their chemical and biological behaviour, design concepts and strategies that may contribute to further improvement of TRAIL/DR-based therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 11","pages":" 3639-3651"},"PeriodicalIF":4.1,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and evaluation of 3-(2-isocyanobenzyl)-1H-indole derivatives as potential quorum sensing inhibitors for the control of Pseudomonas aeruginosa infections in vitro†","authors":"Jiang Wang, Jing-Yi Yang, Pradeepraj Durairaj, Wei-Huan Wen, Nadana Sabapathi, Liang Yang, Bo Wang and Ai-Qun Jia","doi":"10.1039/D4MD00354C","DOIUrl":"10.1039/D4MD00354C","url":null,"abstract":"<p >Quorum sensing (QS) inhibition stands out as an innovative therapeutic strategy for combating infections caused by drug-resistant pathogens. In this study, we assessed the potential of 3-(2-isocyanobenzyl)-1<em>H</em>-indole derivatives as novel quorum sensing inhibitors (QSIs). Initial screenings of their QS inhibitory activities were conducted against <em>Pseudomonas aeruginosa</em> PAO1 and <em>Chromobacterium violaceum</em> CV026. Notably, six 3-(2-isocyanobenzyl)-1<em>H</em>-indole derivatives (4, 12, 25, 28, 32, and 33) exhibited promising QS, biofilms, and pyocyanin inhibitory activities under minimum inhibitory concentrations (MICs) against <em>P. aeruginosa</em> PAO1. Among them, 3-(2-isocyano-6-methylbenzyl)-1<em>H</em>-indole (IMBI, 32) emerged as the most promising candidate, demonstrating superior biofilm and pyocyanin inhibition. Further comprehensive studies revealed that derivative 32 at 25 μg mL<small>⁻¹</small> inhibited biofilm formation by 70% against <em>P. aeruginosa</em> PAO1, as confirmed by scanning electron microscopy (SEM). Additionally, derivative 32 substantially increased the susceptibility of mature biofilms, leading to a 57% destruction of biofilm architecture. In terms of interfering with virulence factors in <em>P. aeruginosa</em> PAO1, derivative 32 (25 μg mL<small>⁻¹</small>) displayed remarkable inhibitory effects on pyocyanin, protease, and extracellular polysaccharides (EPS) by 73%, 51%, and 37%, respectively, exceeding the positive control resveratrol (RSV). Derivative 32 at 25 μg mL<small>⁻¹</small> also exhibited effective inhibition of swimming and swarming motilities. Moreover, it downregulated the expressions of QS-related genes, including <em>lasI</em>, <em>lasR</em>, <em>rhlI</em>, <em>rhlR</em>, <em>pqsR</em>, <em>sdhB</em>, <em>sucD</em>, <em>sodB</em>, and <em>PA5439</em>, by 1.82- to 10.87-fold. Molecular docking, molecular dynamics simulations (MD), and energy calculations further supported the stable binding of 32 to LasR, RhlI, RhlR, EsaL, and PqsR antagonizing the expression of QS-linked traits. Evaluation of the toxicity of derivative 32 on HEK293T cells <em>via</em> CCK-8 assay demonstrated low cytotoxicity. Overall, this study underscores the efficacy of derivative 32 in inhibiting virulence factors in <em>P. aeruginosa</em>. Derivative 32 emerges as a potential QSI for controlling <em>P. aeruginosa</em> PAO1 infections <em>in vitro</em> and an anti-biofilm agent for restoring or enhancing drug sensitivity in drug-resistant pathogens.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3256-3271"},"PeriodicalIF":4.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated radiosynthesis and preclinical imaging of a novel [18F]fluorolidocaine analogue via sequential C–H radiolabelling†","authors":"Madison Frazier, Jay S. Wright, David M. Raffel, Jenelle Stauff, Wade P. Winton, Peter J. H. Scott and Allen F. Brooks","doi":"10.1039/D4MD00293H","DOIUrl":"10.1039/D4MD00293H","url":null,"abstract":"<p >The most prominent myocardial voltage-gated sodium channel, Na<small>_V</small>1.5, is a major drug target for treating cardiovascular disease. However, treatment determination and therapeutic development are complicated partly by an inadequate understanding of how the density of SCN5A, the gene that encodes Na<small>_V</small>1.5, relates to treatment response and disease prognosis. To address these challenges, imaging agents derived from Na<small>_V</small>1.5 blocking therapeutics have been employed in positron emission tomography (PET) imaging to infer how SCN5A expression relates to human disease <em>in vivo</em>. Herein, we describe the preparation of a novel fluorine-18 labelled analogue of lidocaine, a known Na<small>_V</small>1.5 inhibitor, and compare this agent to a previously described analogue. Evidence from rodent and non-human primate PET imaging experiments suggests that the imaging utility of these agents may be limited by rapid metabolism and clearance.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3223-3227"},"PeriodicalIF":4.1,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11339636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of naphthalimide hydrazide derivatives as potent antibacterial agents against carbapenem-resistant A. baumannii†","authors":"Preeti Rana, Rahul Maitra, Deepanshi Saxena, Abdul Akhir, Manasa Vadakattu, Abdul Kalam, Swanand Vinayak Joshi, Ramulu Parupalli, Vasundhra Bhandari, Y. V. Madhavi, Arunava Dasgupta, Sidharth Chopra and Srinivas Nanduri","doi":"10.1039/D4MD00368C","DOIUrl":"10.1039/D4MD00368C","url":null,"abstract":"<p >In this work, a novel series of naphthalimide hydrazide derivatives were designed, synthesized and evaluated against a bacterial pathogen panel. Most of the compounds were found to exhibit potent antibacterial activity against carbapenem-resistant <em>A. baumannii</em> BAA 1605, with MIC ranging from 0.5 to 16 μg mL<small>⁻¹</small>. Compounds <strong>5b</strong>, <strong>5c</strong>, <strong>5d</strong> and <strong>5e</strong> showed the most potent antibacterial activity, with an MIC range of 0.5–1 μg mL<small>⁻¹</small>. These compounds were also found to be non-toxic to Vero cells with a high selectivity index. Further, they were active against 24 clinical isolates of MDR-AB with potent antibacterial activity. In addition, synergistic studies revealed that compound <strong>5d</strong> exhibited synergism with FDA-approved drugs, as further validated through time-kill kinetic studies. These results highlight the potential of the synthesized compounds as promising leads for the development of novel and selective agents against carbapenem-resistant <em>A. baumannii</em>.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4011-4017"},"PeriodicalIF":4.1,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}