Bioorganic & Medicinal Chemistry最新文献

{"title":"An overview of GPX4-targeting TPDs for cancer therapy.","authors":"Xiaojuan Yang, Liqiang Wu, Shaohong Xu","doi":"10.1016/j.bmc.2024.118046","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.118046","url":null,"abstract":"<p><p>Ferroptosis is a newly identified form of regulated, non-apoptotic cell death caused by iron-dependent phospholipid peroxidation. Glutathione peroxidase 4 (GPX4) inactivation-induced ferroptosis is an efficient antitumor treatment. Currently, several GPX4 inhibitors have been identified. However, these inhibitors exhibit low selectivity and poor pharmacokinetic properties that preclude their clinical use. Targeted protein degradation (TPD) is an efficient strategy for discovering drugs and has unique advantages over target protein inhibition. Given GPX4's antitumor effects and the potential of TPD, researchers have explored GPX4-targeting TPDs, which outperform conventional inhibitors in several aspects, such as increased selectivity, strong anti-proliferative effects, overcoming drug resistance, and enhancing drug-like properties. In this review, we comprehensively summarize the progress in GPX4-targeting TPDs. In addition, we reviewed the changes and challenges related to the development of GPX4-targeting TPDs for cancer therapy.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118046"},"PeriodicalIF":3.3,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 biological evaluation of new SIRT3 activators for the treatment of triple-negative breast cancer.","authors":"Guichan Huang, Hailing Wang, Xi Zhao, Chen Wang, Jin Zhang, Dahong Yao, Chenyang Li","doi":"10.1016/j.bmc.2024.118040","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.118040","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) represents a highly malignant subtype of breast cancer with limited therapeutic options. In this study, we designed and synthesized a series of 1,4-DHP derivatives by structure-based strategy, 43 was documented to be a potent SIRT3 activator and exhibited profound anti-proliferative activity in BT-549 and MDA-MB-231 cells with low toxicity over normal cells. Additionally, 43 displayed the ability of direct binding to SIRT3 with a K_d value of 51.51 μM in BLI assay, and the potential bonding mode was elucidated through molecular docking. 43 could inhibit the proliferation, migration, and glycolysis, induced mitochondrial membrane potential decreased and apoptosis in BT-549 and MDA-MB-231 cells. Collectively, these results demonstrate that 43 is a potent SIRT3 activator with the potential to anti-TNBC through signaling pathways regulated by SIRT3.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118040"},"PeriodicalIF":3.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential COX-2 inhibitors modulating NF-κB/MAPK signaling pathways: Design, synthesis and evaluation of anti-inflammatory activity of Pterostilbene-carboxylic acid derivatives with an oxime ether moiety.","authors":"Peng Luo, Taotao Chen, Shaoling Huang, Feng Peng, Yunhou Huang, Weigao Pan","doi":"10.1016/j.bmc.2024.118022","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.118022","url":null,"abstract":"<p><p>In this work, a series of novel Pterostilbene-oxime ether-carboxylic acid (POC) derivatives (d1-d10, e1-e10 and 1-13) were designed, synthesized, and characterized by spectroscopic techniques. In order to further determine the absolute configuration of these compounds, one of them, compound d3, was investigated by X-ray single crystal diffraction method. d3 had a triclinic crystal with P-1 space group, and its CHCH and CHN was confirmed as E configuration. A strong hydrogen bond was formed between the hydrogen atom in CHCH moiety and the nitrogen atom in CHN moiety, which was a vital factor in the formation and stability of E configuration in the CHCH and CHN. The safety and anti-inflammatory activities of compounds (d1-d10, e1-e10 and 1-13) in vitro were evaluated. At 20 μM, compounds (d1-d10, e1-e10 and 1-13 were non-toxic and exhibited weak to strong inhibitory effects on the LPS-induced NO release. Among them, five compounds (1, 2, 7, 8 and 9) showed excellent anti-inflammatory effects with IC₅₀ (NO) values ranging from 9.87 to 19.78 μM, as well as strong COX-2 inhibitory abilities with IC₅₀ (COX-2) values ranging from 85.44 to 140.88 nM. Moreover, there was a rough positive correlation between their anti-inflammatory properties and the COX-2 inhibitory abilities. Compounds (1, 2, 7, 8 and 9) smoothly docked with COX-2 protein (PDB ID: 5KIR) to form stable complexes with strong hydrogen bonds, with an affinity range of -8.3 to -9.9 kcal/mol. SAR indicated that the amidation of POC at R₂ position was more favorable for enhancing the compound's biological actives than esterification. In addition, the 4-fluobenzyl substitution at R₂ position of the oxime ether moiety can obviously enhance the activity of above amide derivates. Introducing acyl groups (CO(CH₂)_nCH₃, n = 2, 4 and 6) into NH(CH₂)₃OH group to form ester chain is disadvantageous for activity enhancing, moreover, the longer the carbon chain, the poorer the activity. The strongest COX-2 inhibitor (IC₅₀ (COX-2) = 85.44 ± 3.88 nM), compound 7, exerted as anti-inflammatory activities (IC₅₀ (NO) = 9.87 ± 1.38 μM) by down-regulating the expression of COX-2 and iNOS, and modulating NF-κB/MAPK signaling pathways.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118022"},"PeriodicalIF":3.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural toxicity relationship (STR) of linezolid to mitigate myelosuppression and serotonergic toxicity","authors":"Matin Shaikh ,&nbsp;Harun Patel","doi":"10.1016/j.bmc.2024.118025","DOIUrl":"10.1016/j.bmc.2024.118025","url":null,"abstract":"<div><div>Tuberculosis (TB) remains a significant global health challenge, with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains posing severe threats to treatment efficacy. Linezolid, a key component of the BPaL (Bedaquiline, Pretomanid and Linezolid) regimen, has demonstrated substantial efficacy against MDR-TB and XDR-TB. However, its clinical utility is often limited by side effects such as myelosuppression and monoamine oxidase (MAO) inhibition, linked to its mechanism of action. This perspective centres on the structural toxicity relationship (STR) of Linezolid and its analogues, exploring modifications to the C-ring and C-5 position that aim to reduce these toxicities while maintaining or enhancing antibacterial activity. Several promising analogues have been identified that exhibit reduced myelosuppression and MAO inhibition, highlighting the potential for developing safer Linezolid derivatives. The findings underscore the importance of continued research into the structure toxicity relationships of oxazolidinones to improve the therapeutic profiles of these essential drugs in combating drug-resistant TB.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118025"},"PeriodicalIF":3.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3-Halo-3-nitro-aza/thioflavanones: DNMT inhibitors with a two-site binding mode in the hDNMT3A catalytic pocket.","authors":"Alexandra Serhouni, Francesco Calzaferri, Yannick Bessina, Arie van der Lee, Paola B Arimondo, Maxime Louet, Jean-Yves Winum, Marie Lopez","doi":"10.1016/j.bmc.2024.117988","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.117988","url":null,"abstract":"<p><p>Flavonoid derivatives are natural product analogues that have shown great interest for therapeutic applications as modulators of DNA methylation. In this article we report new synthesis pathways to access ten novel flavonoid derivatives (i.e. 3-halo-3-nitro-aza/thioflavanones) to be used as potential DNA methyltransferase inhibitors. These compounds have a micromolar inhibition against human DNA methyltransferase 3A in our in vitro fluorescence-based assay. Importantly, a docking study of representative compounds of this series in the enzyme pocket highlights a mode of interaction in the catalytic pocket of hDNMT3A that has never been described.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"117988"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and anti-tumor activity of menthylamine derivatives: Focusing on the potent inhibitory effect of compound W8 on glioma growth","authors":"Xiaoran Wu ,&nbsp;Yanhang Zhuo ,&nbsp;Jiangjian Liu ,&nbsp;Ziming He ,&nbsp;Meiling Wang ,&nbsp;Wenjun Lei ,&nbsp;Qiong Liang ,&nbsp;Aidong Wang ,&nbsp;Zhiyi Shen ,&nbsp;Sunhui Chen ,&nbsp;Shihao Zheng ,&nbsp;Huihui Huang","doi":"10.1016/j.bmc.2024.118024","DOIUrl":"10.1016/j.bmc.2024.118024","url":null,"abstract":"<div><div>In this work, we successfully synthesized eight distinct compounds, comprising four chiral menthylamines and related derivatives. We evaluated their cytotoxic potential against a panel of human cancer cell lines, including human colon cancer HCT-116 cells, human esophageal squamous KYSE-150 cells, human breast cancer MCF-7 cells, and human glioma U87 cells. The U87 cells were chosen for a more in-depth investigation of their anti-tumor efficacy. Further exploration of the cytotoxicity mechanisms was conducted, complemented by in vivo studies using mice bearing tumors. These analyses unveiled the possible mechanisms by which menthylamide derivatives exert their anti-tumor effects. Notably, compound W8 demonstrated a potent inhibitory action against the proliferation of brain glioma cells. The findings from this research provide valuable insights that pave the way for the future application of menthylamides in cancer therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118024"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142757395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a potent and selective TRPC3 antagonist with neuroprotective effects","authors":"Jiaxing Wang ,&nbsp;Sicheng Zhang ,&nbsp;Vijay K. Boda ,&nbsp;Hao Chen ,&nbsp;Hyunseo Park ,&nbsp;Keyur Parmar ,&nbsp;Dejian Ma ,&nbsp;Duane D. Miller ,&nbsp;Bernd Meibohm ,&nbsp;Jianyang Du ,&nbsp;Francesca-Fang Liao ,&nbsp;Zhongzhi Wu ,&nbsp;Wei Li","doi":"10.1016/j.bmc.2024.118021","DOIUrl":"10.1016/j.bmc.2024.118021","url":null,"abstract":"<div><div>The TRPC3 protein plays a pivotal role in calcium signaling, influencing cell function. Aberrant TRPC3 expression is implicated in various pathologies, including cardiovascular diseases, tumors, and neurodegeneration. Despite its functional similarities with TRPC6 and TRPC7, TRPC3 exhibits distinct roles in disease contexts. Therefore, it is of paramount importance to develop a potent and selective TRPC3 antagonist with favorable drug-like properties. We employed extensive medicinal chemistry synthesis and structure–activity relationships (SARs) study. Thirty-one novel TRPC3 antagonists were designed and synthesized using the lead compound <strong>JW-65</strong> as the scaffold. Compound <strong>60a</strong> exhibits a 4-fold improvement in potency and displays exceptional selectivity. With favorable drug-like properties, this compound shows a heightened <em>in vitro</em> neuronal protective effect. Molecular modeling suggests possible modes of action between the TRPC3 protein and its antagonists. In summary, <strong>60a</strong> holds significant promise for clinical development in conditions associated with TRPC3 dysregulation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118021"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of aromatic glycoconjugates as anti-fungal agents against Candida spp. and assessment of their covalent crosslinking capabilities","authors":"Kyle Doherty ,&nbsp;Keela Kessie ,&nbsp;Harlei Martin ,&nbsp;Jordan Loughlin ,&nbsp;Oliwier Dulawa ,&nbsp;Kaja Kasements ,&nbsp;Trinidad Velasco-Torrijos","doi":"10.1016/j.bmc.2024.118020","DOIUrl":"10.1016/j.bmc.2024.118020","url":null,"abstract":"<div><div>Covalent drugs are becoming increasingly attractive in drug discovery, as they can enhance potency and selectivity for their molecular targets. Covalent inhibitors have been investigated for several therapeutic applications, including anti-cancer and anti-infection agents. However, there are only a few examples of covalent inhibitors targeting fungal pathogens. We have previously reported aromatic glycoconjugates (AGCs) capable of inhibiting the adhesion of <em>Candida albicans</em> to buccal epithelial cells. In this work, we synthesize novel derivatives of the AGCs to which we have added reactive functional groups, such as acryloyl and vinyl sulfones, and investigated their antifungal efficacy against <em>Candida</em> spp<em>.</em> Although the compounds were ineffective at clinically relevant concentrations, we found that some of the galactose derivatives featuring reactive groups were amongst the most active, so their ability to crosslink nucleophilic side chains was assessed in model reactions.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118020"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A bleomycin-mimicking manganese-porphyrin-conjugated mitochondria-targeting peptoid for cancer therapy","authors":"Minjae Jun ,&nbsp;Veena Vijayan ,&nbsp;Seungheon Shin ,&nbsp;Ho Yeon Nam ,&nbsp;Dasom Song ,&nbsp;Jieun Choi ,&nbsp;Shyam Vasvani ,&nbsp;Steve K. Cho ,&nbsp;In-Kyu Park ,&nbsp;Jiwon Seo","doi":"10.1016/j.bmc.2024.118023","DOIUrl":"10.1016/j.bmc.2024.118023","url":null,"abstract":"<div><div>Bleomycin (BLM) is a natural product with established anticancer activity, attributed to its ability to cleave intracellular DNA. BLM complexes with iron (BLM-Fe³⁺) exhibit peroxidase-like activity, generate reactive oxygen species (ROS), and cause DNA cleavage. Inspired by the mechanism of BLM, we synthesized a novel conjugate of manganese tetraphenylporphyrin (MnTPP) with a biomimetic peptoid (i.e., oligo-<em>N</em>-substituted glycines); this conjugate harnesses the oxidative capabilities of manganese porphyrins combined with the cell-penetrating ability of a previously reported mitochondria-targeting peptoid (MTP). UV–vis spectroscopy showed the formation of Mn(V)-oxo porphyrin, a potent oxidative species, in the presence of hydrogen peroxide, simulating metallobleomycin reactivity. Biological assays demonstrated that MnTPP-MTP significantly boosted ROS production and induced cytotoxicity toward cancer cells, while sparing normal fibroblasts. Tetramethylrhodamine ethyl ester (TMRE) assay revealed reversible, dose-dependent impairment of the mitochondrial membrane potential by MnTPP-MTP treatment. DNA cleavage assays showed that MnTPP-MTP, specifically in the presence of hydrogen peroxide, could elicit substantial DNA damage, in a similar way to BLM. In vivo studies using liposome-encapsulated MnTPP-MTP (lipo-peptoid) indicated superior tumor suppression, without systemic toxicity, when administered locally. Immunofluorescence staining for Ki67 and TUNEL confirmed reduced cell proliferation and increased apoptosis, respectively, validating the anticancer efficacy of lipo-peptoid. These results suggest that MnTPP-MTP, particularly in a liposomal formulation, is a promising new chemotherapeutic agent with robust oxidative mechanisms, poised for further development and application against diverse cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118023"},"PeriodicalIF":3.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereoisomers of cannabidiols and their pharmacological activities – A potentially novel direction for cannabinoids","authors":"Vajja Krishna Rao ,&nbsp;Melissa M. Lewis-Bakker ,&nbsp;Ewa Wasilewski ,&nbsp;Hance A. Clarke ,&nbsp;Lakshmi P. Kotra","doi":"10.1016/j.bmc.2024.118019","DOIUrl":"10.1016/j.bmc.2024.118019","url":null,"abstract":"<div><div>Cannabidiol (CBD), a bicyclic non-psychoactive cannabinoid biosynthesized by <em>Cannabis</em> spp. of plants, has attracted significant interest in the past decade due to its therapeutic properties. In 2018, the US FDA approved Epidiolex®, a CBD<strong>-</strong>based drug for the treatment of two rare epileptic seizure disorders.</div><div>CBD possesses two chiral centers at C3 and C4 on its terpenoid moiety and exhibits <em>cis</em>–<em>trans</em> stereoisomerism along the C3–C4 bond axis. (−)<strong>-</strong><em>trans</em><strong>-</strong>(3<em>R</em>,4<em>R</em>)<strong>-</strong>CBD, the natural CBD, is biosynthesized by the cannabis plant, while the unnatural (+)<strong>-</strong><em>trans</em><strong>-</strong>(3<em>S</em>,4<em>S</em>)<strong>-</strong>CBD is obtained <em>via</em> chemical synthesis. Both <em>trans</em> isomers exhibit broad <em>in vitro</em> and <em>in vivo</em> biological activities; typically, the unnatural stereoisomer (+)<strong>-</strong><em>trans</em>-CBD and its derivatives exhibited more potent activities in comparison to the corresponding (−)<strong>-</strong><em>trans</em> isomers. On the other hand, <em>cis</em><strong>-</strong>CBD isomers have only been reported recently and can undergo epimerization into <em>trans</em> isomers.</div><div>There is a significant opportunity to explore unique synthetic methods and biological activities of stereoisomers of CBD that may pave the path for the development of novel therapeutics. Herein, as a novel direction in cannabinoids, we review the chemistry of CBD stereoisomers, their structure–activity relationships, target selectivity and efficacy in animal models.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118019"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}