RSC medicinal chemistry最新文献

Probing structural requirements for thiazole-based mimetics of sunitinib as potent VEGFR-2 inhibitors.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-22 DOI: 10.1039/d4md00754a

Alaa A Abd Elhameed, Ahmed R Ali, Hazem A Ghabbour, Said M Bayomi, Nadia S El-Gohary

{"title":"Probing structural requirements for thiazole-based mimetics of sunitinib as potent VEGFR-2 inhibitors.","authors":"Alaa A Abd Elhameed, Ahmed R Ali, Hazem A Ghabbour, Said M Bayomi, Nadia S El-Gohary","doi":"10.1039/d4md00754a","DOIUrl":"10.1039/d4md00754a","url":null,"abstract":"Novel thiazole analogs 3a, 3b, 4, 5, 6a-g, 8a, 8b, 9a-c, 10a-d and 11 were designed and synthesized as molecular mimetics of sunitinib. In vitro antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds 3b and 10c are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds 3a, 3b, 6g, 8a and 10c were assessed for their in vitro VEGFR-2 inhibitory activity. Results proved that compound 10c exhibited outstanding VEGFR-2 inhibition (IC50 = 0.104 μM) compared to sunitinib. Compound 10c paused the G0-G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound 10c elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death via apoptosis. Furthermore, compound 10c showed a significant reduction in tumor volume in Swiss albino female mice as an in vivo breast cancer model. Docking results confirmed the tight binding interactions of compound 10c with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. In silico PK studies predicted compound 10c to have good oral bioavailability and a good drug score with low human toxicity risks.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028891","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}

引用次数: 0

Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-20 DOI: 10.1039/d4md00876f

Cláudia Braga, Margarida Ferreira-Silva, M Luísa Corvo, Rui Moreira, Alexandra R Fernandes, João Vaz, Maria J Perry

{"title":"Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma.","authors":"Cláudia Braga, Margarida Ferreira-Silva, M Luísa Corvo, Rui Moreira, Alexandra R Fernandes, João Vaz, Maria J Perry","doi":"10.1039/d4md00876f","DOIUrl":"10.1039/d4md00876f","url":null,"abstract":"Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion via a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs 1b, 1d and 1e elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs 1d and 1e, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028875","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}

引用次数: 0

Prodrugs and their activation mechanisms for brain drug delivery. 前药及其脑给药激活机制。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-17 DOI: 10.1039/d4md00788c

Ida Aaberg Lillethorup, Andreas Victor Hemmingsen, Katrine Qvortrup

引用次数: 0

Breaking the energy chain: importance of ATP synthase in Mycobacterium tuberculosis and its potential as a drug target. 打破能量链：ATP合酶在结核分枝杆菌中的重要性及其作为药物靶点的潜力。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-08 DOI: 10.1039/d4md00829d

Summaya Perveen, Sunny Pal, Rashmi Sharma

{"title":"Breaking the energy chain: importance of ATP synthase in Mycobacterium tuberculosis and its potential as a drug target.","authors":"Summaya Perveen, Sunny Pal, Rashmi Sharma","doi":"10.1039/d4md00829d","DOIUrl":"10.1039/d4md00829d","url":null,"abstract":"Unveiling novel pathways for drug discovery forms the foundation of a new era in the combat against tuberculosis. The discovery of a novel drug, bedaquiline, targeting mycobacterial ATP synthase highlighted the targetability of the energy metabolism pathway. The significant potency of bedaquiline against heterogeneous population of Mycobacterium tuberculosis marks ATP synthase as an important complex of the electron transport chain. This review focuses on the importance and unique characteristics of mycobacterial ATP synthase. Understanding these distinctions enables the targeting of ATP synthase subunits for drug discovery, without aiming at the mammalian counterpart. Furthermore, a brief comparison of the structural differences between mycobacterial and mitochondrial ATP synthase is discussed. Being a complex multi-subunit protein, ATP synthase offers multiple sites for potential inhibitors, including the a, c, ε, γ, and δ subunits. Inhibitors targeting these subunits are critically reviewed, providing insight into the design of better and more potent chemical entities with the potential for effective treatment regimens.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954202","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}

引用次数: 0

Saponin components exhibit antiviral properties against porcine epidemic diarrhea virus in vitro. 皂苷成分对猪流行性腹泻病毒具有体外抗病毒作用。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-08 DOI: 10.1039/d4md00894d

Yiyi Hu, Yunchuan Li, Haodan Zhu, Dandan Wang, Junming Zhou, Bin Li

{"title":"Saponin components exhibit antiviral properties against porcine epidemic diarrhea virus in vitro.","authors":"Yiyi Hu, Yunchuan Li, Haodan Zhu, Dandan Wang, Junming Zhou, Bin Li","doi":"10.1039/d4md00894d","DOIUrl":"10.1039/d4md00894d","url":null,"abstract":"Piglets afflicted with porcine epidemic diarrhea virus (PEDV) experience severe diarrhea and elevated death rates, leading to substantial financial losses in the pig farming sector. The objective of this study is to investigate the impact of saponins on PEDV within Vero cells by utilizing different methodologies to evaluate their anti-PEDV effect. By producing 40 saponins, we have discovered that No. 29, No. 31, No. 35, and No. 38 exhibit properties that make them effective against PEDV, serving as potential drugs. The findings showed that in a clear dose-dependent manner, the mRNA levels of PEDV were significantly inhibited in the high, middle, and low-dose groups of No. 29, No. 31, No. 35, and No. 38, when compared to the PEDV control. The four tested saponins significantly inhibited the levels of PEDV N contents and viral titers. Furthermore, concentration of cytotoxicity 50% (CC50) values for No. 29, No. 31, No. 35, and No. 38 saponins were 37.13 μM, 52.86 μM, 44.98 μM, and 43.81 μM, respectively, demonstrating the safety of these medications in clinical environments. Collectively, these findings indicate that the four examined saponins could efficiently modulate the immune response against PEDV and hold promise for utilization in antiviral treatments.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954220","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}

引用次数: 0

Exploration of the cytotoxic and microtubule disruption potential of novel imidazo[1,5-a]pyridine-based chalcones. 新型咪唑[1,5-a]吡啶查尔酮的细胞毒性和微管破坏潜力的探索。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-08 DOI: 10.1039/d4md00838c

Ramu Gopathi, Mommuleti Pradeep Kumar, Gangasani Jagadeesh Kumar, Syamprasad N P, Bheeshma Geetanjali Kodiripaka, V G M Naidu, Bathini Nagendra Babu

引用次数: 0

Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor. 6-芳基氨基苯酰胺作为鞘氨醇-1-磷酸-5受体正电子发射断层成像配体的合成与评价。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-03 DOI: 10.1039/d4md00929k

Timaeus E F Morgan, Emma K Grant, Robert C Shaw, Lachlan J N Waddell, Martyn C Henry, Holly McErlain, Carlos J Alcaide-Corral, Sally L Pimlott, Adriana A S Tavares, Andrew Sutherland

{"title":"Synthesis and evaluation of 6-arylaminobenzamides as positron emission tomography imaging ligands for the sphingosine-1-phosphate-5 receptor.","authors":"Timaeus E F Morgan, Emma K Grant, Robert C Shaw, Lachlan J N Waddell, Martyn C Henry, Holly McErlain, Carlos J Alcaide-Corral, Sally L Pimlott, Adriana A S Tavares, Andrew Sutherland","doi":"10.1039/d4md00929k","DOIUrl":"https://doi.org/10.1039/d4md00929k","url":null,"abstract":"The sphingosine-1-phosphate-5 (S1P5) receptor is one of the five membrane G protein-coupled receptors that are activated by the lysophospholipid, sphingosine-1-phosphate, resulting in regulation of many cellular processes. S1P5 receptors are located on oligodendrocytes and are proposed to influence oligodendrocyte physiology. Understanding S1P5 modulation during processes such as remyelination could have potential applications for demyelinating CNS disorders such as multiple sclerosis (MS). Herein, we report the synthesis and preliminary evaluation of a series of fluorinated 6-arylaminobenzamides as positron emission tomography (PET) ligands of S1P5. Pharmacokinetic screening and binding evaluation using a [35S]GTPγS assay led to the discovery of TEFM78, a selective and high affinity agonist of S1P5. Radiosynthesis of [18F]TEFM78 allowed pilot PET imaging studies in an animal model, which showed that [18F]TEFM78 can cross the blood brain barrier with good uptake in rat brain and spinal cord.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010733","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}

引用次数: 0

Enhanced skin penetration of curcumin by a nanoemulsion-embedded oligopeptide hydrogel for psoriasis topical therapy. 纳米乳液包埋寡肽水凝胶对银屑病局部治疗的姜黄素皮肤渗透增强作用。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-02 DOI: 10.1039/d4md00781f

Kehan Chen, Hui Yang, Guo Xu, Yunhan Hu, Xue Tian, Song Qin, Tianyue Jiang

引用次数: 0

Recent developments in antimicrobial small molecule quaternary phosphonium compounds (QPCs) - synthesis and biological insights. 抗菌小分子季磷化合物（QPCs）的合成及生物学研究进展。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-02 DOI: 10.1039/d4md00855c

Diana McDonough, Christian A Sanchez, William M Wuest, Kevin P C Minbiole

引用次数: 0

Structure-activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors. 抗增殖性磷脂酰胆碱特异性磷脂酶C抑制剂2- morpholinobzoic acid scaffold的构效关系扩展和微粒体稳定性评估。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-01 DOI: 10.1039/d4md00831f

Shaun W P Rees, Tayla A Rees, Emily K Paulin, Olivia R Arnerich, Euphemia Leung, Christopher S Walker, David Barker, Lisa I Pilkington

{"title":"Structure-activity relationship expansion and microsomal stability assessment of the 2-morpholinobenzoic acid scaffold as antiproliferative phosphatidylcholine-specific phospholipase C inhibitors.","authors":"Shaun W P Rees, Tayla A Rees, Emily K Paulin, Olivia R Arnerich, Euphemia Leung, Christopher S Walker, David Barker, Lisa I Pilkington","doi":"10.1039/d4md00831f","DOIUrl":"https://doi.org/10.1039/d4md00831f","url":null,"abstract":"Dysregulation of choline phospholipid metabolism and overexpression of phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in various cancers. Current known enzyme inhibitors include compounds based on a 2-morpholino-5-N-benzylamino benzoic acid, or hydroxamic acid, scaffold. In this work, 81 compounds were made by modifying this core structure to explore the pharmacophore. Specifically, these novel compounds result from changes to the central ring substitution pattern, alkyl heterocycle and methylation of the N-benzyl bridge. The anti-proliferative activity of the synthesised compounds was assessed against cancer cell lines MDA-MB-231 and HCT116. PC-PLCBC enzyme inhibition was also assessed, and the development of a pharmacokinetic profile was initiated using a microsomal stability assay. The findings confirmed the optimal pharmacophore as a 2-morpholino-5-N-benzylamino benzoic acid, or acid derivative, scaffold, and that this family of molecules demonstrate a high degree of stability following treatment with rat microsomes. Additionally, benzylic N-methylated compounds were the most biologically active compounds, encouraging further investigation into this region of the pharmacophore.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010728","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}

引用次数: 0