Bioorganic & Medicinal Chemistry最新文献

{"title":"Recent advancement in developing small molecular inhibitors targeting key kinase pathways against triple-negative breast cancer","authors":"Rajibul Islam ,&nbsp;Khor Poh Yen ,&nbsp;Nur Najihah ’Izzati Mat Rani ,&nbsp;Md. Selim Hossain","doi":"10.1016/j.bmc.2024.117877","DOIUrl":"10.1016/j.bmc.2024.117877","url":null,"abstract":"<div><p>Triple-negative breast cancer (TNBC) stands out as the most formidable variant of breast cancer, predominantly affecting younger women and characterized by a bleak outlook and a high likelihood of spreading. The absence of safe and effective targeted treatments leaves standard cytotoxic chemotherapy as the primary option. The role of protein kinases, frequently altered in many cancers, is significant in the advancement and drug resistance of TNBC, making them a logical target for creating new, potent therapies against TNBC. Recently, an array of promising small molecules aimed at various kinases have been developed specifically for TNBC, with combination studies showing a synergistic improvement in combatting this condition. This review underscores the effectiveness of small molecule kinase inhibitors in battling the most lethal form of breast cancer and sheds light on prospective pathways for crafting novel treatments.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117877"},"PeriodicalIF":3.3,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002918/pdfft?md5=3dcdbf35cec2596294dfc94c9e8243b8&pid=1-s2.0-S0968089624002918-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142002365","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}

{"title":"Current development and structure–activity relationship study of berberine derivatives","authors":"Xiong-Fei Luo ,&nbsp;Han Zhou ,&nbsp;Peng Deng ,&nbsp;Shao-Yong Zhang ,&nbsp;Yi-Rong Wang ,&nbsp;Yan-Yan Ding ,&nbsp;Guang-Han Wang ,&nbsp;Zhi-Jun Zhang ,&nbsp;Zheng-Rong Wu ,&nbsp;Ying-Qian Liu","doi":"10.1016/j.bmc.2024.117880","DOIUrl":"10.1016/j.bmc.2024.117880","url":null,"abstract":"<div><p>Berberine is a quaternary ammonium isoquinoline alkaloid derived from traditional Chinese medicines <em>Coptis chinensis</em> and <em>Phellodendron chinense</em>. It has many pharmacological activities such as hypoglycemic, hypolipidemic, anti-tumor, antimicrobial and anti-inflammatory. Through structural modifications at various sites of berberine, the introduction of different groups can change berberine’s physical and chemical properties, thereby improving the biological activity and clinical efficacy, and expanding the scope of application. This paper reviews the research progress and structure–activity relationships of berberine in recent years, aiming to provide valuable insights for the exploration of novel berberine derivatives.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117880"},"PeriodicalIF":3.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099189","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 novel 7-phenoxy-benzimidazole derivative as a potent and orally available BRD4 inhibitor for the treatment of melanoma","authors":"Yuhei Horai,&nbsp;Naoki Suda,&nbsp;Shinsuke Uchihashi,&nbsp;Mayako Katakuse,&nbsp;Tomomi Shigeno,&nbsp;Takashige Hirano,&nbsp;Junichi Takahara,&nbsp;Tomoyuki Fujita,&nbsp;Yohei Mukoyama,&nbsp;Yuji Haga","doi":"10.1016/j.bmc.2024.117882","DOIUrl":"10.1016/j.bmc.2024.117882","url":null,"abstract":"<div><p>The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative <strong>12</strong>, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative <strong>1</strong>. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate <strong>1</strong> exhibit mutagenicity, which was confirmed by the positive Ames test results. Based on our hypothesis that the cause of the Ames test positivity is the metabolic intermediates generated from those chemical series, we implemented a scaffold hopping strategy to avoid the <em>N-</em>benzyl moiety by relocating the substituent groups to preserve the essential interaction. Based on this strategy, we successfully obtained compound <strong>12</strong>; the Ames test results of this compound were negative. Notably, compound <strong>12</strong> not only exhibited a favorable pharmacokinetic (PK) profile but also significant tumor growth inhibition in a mouse melanoma xenograft model, indicating its potential as a therapeutic agent for the treatment of melanoma.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117882"},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002967/pdfft?md5=b14155c98da7035044b41fce144ea726&pid=1-s2.0-S0968089624002967-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012127","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}

{"title":"Synthesis, SAR, and application of JQ1 analogs as PROTACs for cancer therapy","authors":"Soumik De ,&nbsp;Raghaba Sahu ,&nbsp;Shubhendu Palei ,&nbsp;Laxmi Narayan Nanda","doi":"10.1016/j.bmc.2024.117875","DOIUrl":"10.1016/j.bmc.2024.117875","url":null,"abstract":"<div><p>JQ1 is a wonder therapeutic molecule that selectively inhibits the BRD4 signaling pathway and is thus widely used in the anticancer drug discovery program. Due to its unique selective BRD4 binding property, its applications are further extended in the design and synthesis of bi-functional PROTAC molecules. This BRD4 targeting PROTAC molecule selectively degrades the protein by proteolysis. There are several modifications of JQ1 known to date and extensively explored for their applications in PROTAC technology by several research groups in academia as well as industry for targeting oncogenic genes. In this review, we have covered the discovery and synthesis of the JQ1 molecule. The SAR of the JQ1 analogs will help researchers develop potent JQ1 compounds with improved inhibitory properties against malignant cells. Furthermore, we explored the potential application of JQ1 analogs in PROTAC technology. The brief history of the bromodomain family of proteins, as well as the obstacles connected with PROTAC technology, can help comprehend the context of the current research, which has the potential to improve the drug development process. Overall, this review comprehensively appraises JQ1 molecules and their prior implementation in PROTAC technology and cancer therapy.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117875"},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045071","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":"Enhanced control of RNA modification and CRISPR-Cas activity through redox-triggered disulfide cleavage","authors":"Huajun Lei ,&nbsp;Wei Xiong ,&nbsp;Ming Li ,&nbsp;Qianqian Qi,&nbsp;Xingyu Liu,&nbsp;Shaoru Wang,&nbsp;Tian Tian,&nbsp;Xiang Zhou","doi":"10.1016/j.bmc.2024.117878","DOIUrl":"10.1016/j.bmc.2024.117878","url":null,"abstract":"<div><p>Chemical RNA modification has emerged as a flexible approach for post-synthetic modifications in chemical biology research. Guide RNA (gRNA) plays a crucial role in the clustered regularly interspaced short palindromic repeats and associated protein system (CRISPR-Cas). Several toolkits have been developed to regulate gene expression and editing through modifications of gRNA. However, conditional regulation strategies to control gene editing in cells as required are still lacking. In this context, we introduce a strategy employing a cyclic disulfide-substituted acylating agent to randomly acylate the 2′-OH group on the gRNA strand. The CRISPR-Cas systems demonstrate off–on transformation activity driven by redox-triggered disulfide cleavage and undergo intramolecular cyclization, which releases the functionalized gRNA. Dithiothreitol (DTT) exhibits superior reductive capabilities in cleaving disulfides compared to glutathione (GSH), requiring fewer reductants. This acylation method with cyclic disulfides enables conditional control of CRISPR-Cas9, CRISPR-Cas13a, RNA hybridization, and aptamer folding. Our strategy facilitates precise in vivo control of gene editing, making it particularly valuable for targeted applications.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117878"},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012128","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":"Recent advances in the treatment of gout with NLRP3 inflammasome inhibitors","authors":"Ye Tian ,&nbsp;Xiaofang He ,&nbsp;Ruping Li ,&nbsp;Yanxin Wu ,&nbsp;Qiang Ren ,&nbsp;Yusen Hou","doi":"10.1016/j.bmc.2024.117874","DOIUrl":"10.1016/j.bmc.2024.117874","url":null,"abstract":"<div><p>Gout is an autoinflammatory disorder characterized by the accumulation of monosodium urate crystals in joints and other tissues, representing the predominant type of inflammatory arthritis with a notable prevalence and propensity for severe outcomes. The NLRP3 inflammasome, a member of the pyrin domain-containing NOD-like receptor family, exerts a substantial impact on both innate and adaptive immune responses and serves as a pivotal factor in the pathogenesis of gout. In recent years, there has been significant academic and industrial interest in the development of NLRP3-targeted small molecule inhibitors as a promising therapeutic approach for gout. To assess the advancements in NLRP3 inflammasome inhibitors for gout treatment, this review offers a comprehensive analysis and evaluation of current clinical candidates and other inhibitors targeting NLRP3 inflammasome from a chemical structure standpoint, with the goal of identifying more efficacious options for clinical management of gout.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117874"},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012126","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":"Advancing drug discovery: Thiadiazole derivatives as multifaceted agents in medicinal chemistry and pharmacology","authors":"Benjamin Ayodipupo Babalola ,&nbsp;Lekhnath Sharma ,&nbsp;Olanike Olowokere ,&nbsp;Monika Malik ,&nbsp;Oreoluwa Folajimi","doi":"10.1016/j.bmc.2024.117876","DOIUrl":"10.1016/j.bmc.2024.117876","url":null,"abstract":"<div><p>In this dispensation of rapid scientific and technological advancements, significant efforts are being made to curb health-related diseases. Research discoveries have highlighted the value of heterocyclic compounds, particularly thiadiazole derivatives, due to their diverse pharmacological activities. These compounds play a crucial role in therapeutic medicine and the development of effective drugs. Thiadiazoles are five-membered heterocyclic compounds consisting of one sulfur and two nitrogen atoms. This review explores advanced synthesis techniques, including the use of heterogeneous catalysts, microwave-assisted methods, ultrasound-assisted synthesis, solvent-free processes, multicomponent reactions, copper-catalyzed aerobic oxidative annulation, intramolecular cyclization, click-chemistry supported synthesis, and alkali-promoted, transition-metal-free mediated synthesis. These methods enhance the diversity and potential applications of thiadiazole compounds. Furthermore, this study provides up-to-date information on the key pharmacological activities of thiadiazole derivatives, highlighting their potential in therapeutic medicine for drug development. The structure–activity relationship (SAR) is also discussed to better understand their interactions and safety in biological systems. This work aims to expand on the reported chemistry and pharmacological potential of the thiadiazole moiety to validate their efficacy as promising pharmacophores in drug design and development.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117876"},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142006703","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":"Exploring novel A2AAR antagonists: Design, synthesis, and evaluation of 2,6,9-trisubstituted purine derivatives as promising antifibrotic agents","authors":"Jingyang Sun ,&nbsp;Seojeong Kim ,&nbsp;Seojeong Park,&nbsp;Seohui Hwang,&nbsp;Naeun Sheen,&nbsp;Soobin Kim,&nbsp;Youngjoo Kwon,&nbsp;Jae-Sang Ryu","doi":"10.1016/j.bmc.2024.117881","DOIUrl":"10.1016/j.bmc.2024.117881","url":null,"abstract":"<div><p>A series of 2,6,9-trisubstituted purine derivatives were designed and synthesized with diverse chemical moieties. Through a comprehensive biological evaluation, we identified 4-(6-(methylamino)-2-(phenylethynyl)-9<em>H</em>-purin-9-yl)phenol (<strong>6a</strong>) as a promising A_2AAR antagonist with potent antifibrotic properties. Compound <strong>6a</strong> demonstrated significant efficacy in inhibiting CRE promoter activity and in reducing the expression of fibrogenic marker proteins and downstream effectors of A_2AAR activation, surpassing the A_2AAR antagonist ZM241385 and initial screening hits, 9-benzyl-<em>N</em>-methyl-2-(phenylethynyl)-9<em>H</em>-purin-6-amine (<strong>5a</strong>) and 9-((benzyloxy)methyl)-<em>N</em>-methyl-2-(phenylethynyl)-9<em>H</em>-purin-6-amine (<strong>5j</strong>). Further validation revealed that compound <strong>6a</strong> effectively inhibited fibrogenic marker proteins induced by A_2AAR overexpression or TGF-β1 treatment in hepatic stellate cells, alongside reducing PKA and CREB phosphorylation. These findings suggest that compound <strong>6a</strong> exerts its antifibrotic action by modulating the cAMP/PKA/CREB pathway through A_2AAR inhibition. Overall, our study provides valuable insights for the development of novel therapeutics that target hepatic fibrosis through A_2AAR antagonism.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117881"},"PeriodicalIF":3.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142040230","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":"Let’s get biophysical – How to get your favorite protein’s digits","authors":"Marcus J.C. Long ,&nbsp;Yimon Aye","doi":"10.1016/j.bmc.2024.117873","DOIUrl":"10.1016/j.bmc.2024.117873","url":null,"abstract":"<div><p>In these days of information overload and high-throughput analysis, it is easy to lose focus on the study of individual proteins. It is our conjecture that such investigations are still crucially important and offer uniquely penetrative insights. We thus present a discussion of biophysical methods to allow readers to get to know their protein of interest better. Although this perspective is not written with the expert in mind, we hope that for interdisciplinary scientists, or researchers who do not routinely perform biophysical analyses, the content will be helpful and inspiring.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117873"},"PeriodicalIF":3.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002876/pdfft?md5=0cc1439955f5fa195e31a0c3cdd101f1&pid=1-s2.0-S0968089624002876-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047781","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}

{"title":"Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents","authors":"Samuele Maramai ,&nbsp;Mario Saletti ,&nbsp;Marco Paolino ,&nbsp;Germano Giuliani ,&nbsp;Jessica Cazzola ,&nbsp;Paolo Spaiardi ,&nbsp;Francesca Talpo ,&nbsp;Maria Frosini ,&nbsp;Alice Pifferi ,&nbsp;Marco Ballarotto ,&nbsp;Andrea Carotti ,&nbsp;Federica Poggialini ,&nbsp;Chiara Vagaggini ,&nbsp;Elena Dreassi ,&nbsp;Gianluca Giorgi ,&nbsp;Giulio Dondio ,&nbsp;Andrea Cappelli ,&nbsp;Gerardo Rosario Biella ,&nbsp;Maurizio Anzini","doi":"10.1016/j.bmc.2024.117872","DOIUrl":"10.1016/j.bmc.2024.117872","url":null,"abstract":"<div><p>Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (<strong>2a-c</strong>), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[<em>b</em>][1,4]thiazepines <strong>3a-c</strong> and expanded intermediates <em>N</em>-cyano-benzo[<em>b</em>][1,4]thiazepines <strong>4a-c</strong>, which were fully characterized. The newly obtained structures <strong>3a-c</strong>, bearing riluzole key elements, were initially tested in an <em>in vitro</em> ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound <strong>3b</strong> as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative <strong>3b</strong> completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound <strong>3b</strong> was then selected to assess its effects on voltage-dependent Na⁺ and K⁺ currents. The results indicated that derivative <strong>3b</strong> induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for <strong>3b</strong>, as it represents an elegant example of a MTDL and opens the way to further <em>ex-vivo</em> and/or <em>in-vivo</em> characterization.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117872"},"PeriodicalIF":3.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994852","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}