Pub Date : 2024-09-03DOI: 10.1016/j.bioorg.2024.107789
Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant PfDHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue LA1 bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. In vitro log D7.4 and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to P218. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates.
{"title":"Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors","authors":"","doi":"10.1016/j.bioorg.2024.107789","DOIUrl":"10.1016/j.bioorg.2024.107789","url":null,"abstract":"<div><p>Recently, <strong>P218</strong>, a new flexible antifolate targeting <em>Plasmodium falciparum</em> dihydrofolate reductase (<em>Pf</em>DHFR), has entered its clinical trial with good safety profile and effective <em>Pf</em> infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of <strong>P218</strong> analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant <em>Pf</em>DHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue <strong>LA1</strong> bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. <em>In vitro</em> log D<sub>7.4</sub> and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to <strong>P218</strong>. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158185","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}
Pub Date : 2024-09-03DOI: 10.1016/j.bioorg.2024.107780
Pyrimidine-based heterocyclic compounds are garnering substantial interest due to their essential role as a class of natural and synthetic molecules. These compounds show a diverse array of biologically relevant activities, making them highly prospective candidates for clinical translation as therapeutic agents in combating various diseases. Pyrimidine derivatives and their fused analogues, such as thienopyrimidines, pyrazolopyrimidines, pyridopyrimidines, and pyrimidopyrimidines, hold immense possibility in both anticancer and antibacterial research. These compounds exhibit notable efficacy by targeting protein kinases, which are crucial enzymes regulating fundamental cellular processes like metabolism, migration, division, and growth. Through enzyme inhibition, these derivatives disrupt key cellular signaling pathways, thereby affecting critical cellular functions and viability. The advantage lies in the ubiquity of the pyrimidine structure across various natural compounds, enabling interactions with enzymes, genetic material, and cellular components pivotal for chemical and biological processes. This interaction plays a central role in modulating vital biological activities, making pyrimidine-containing compounds indispensable in drug discovery. In the realm of anticancer therapy, these compounds strategically target key proteins like EGFR, important for aberrant cell growth. Fused pyrimidine motifs, exemplified by various drugs, are designed to inhibit EGFR, thereby impeding tumor progression. Moreover, these compounds influence potent antibacterial activity, interfering with microbial growth through mechanisms ranging from DNA replication inhibition to other vital cellular functions. This dual activity, targeting both cancer cells and microbial pathogens, underscores the versatility and potential of pyrimidine derivatives in medical applications. This review provides insights into the structural characteristics, synthesis methods, and significant medicinal applications of fused pyrimidine derivatives, highlighting their double role in combating cancer and bacterial infections.
嘧啶类杂环化合物作为一类重要的天然和合成分子,正在引起人们的极大兴趣。这些化合物显示出多种多样的生物相关活性,使它们极有可能被临床转化为治疗各种疾病的药物。嘧啶衍生物及其融合类似物,如噻吩嘧啶类、吡唑嘧啶类、吡啶嘧啶类和嘧啶嘧啶类,在抗癌和抗菌研究中都具有巨大的潜力。蛋白激酶是调节新陈代谢、迁移、分裂和生长等基本细胞过程的关键酶,这些化合物通过靶向蛋白激酶发挥显著疗效。通过酶抑制作用,这些衍生物可以破坏关键的细胞信号传导途径,从而影响关键的细胞功能和活力。其优势在于嘧啶结构在各种天然化合物中无处不在,能够与酶、遗传物质以及化学和生物过程中至关重要的细胞成分相互作用。这种相互作用在调节重要的生物活性方面发挥着核心作用,因此含嘧啶化合物在药物研发中不可或缺。在抗癌治疗领域,这些化合物以表皮生长因子受体(EGFR)等关键蛋白为战略目标,这些蛋白对细胞的异常生长非常重要。以各种药物为例,融合的嘧啶基团可抑制表皮生长因子受体,从而阻碍肿瘤的发展。此外,这些化合物还具有强大的抗菌活性,可通过 DNA 复制抑制和其他重要细胞功能等机制干扰微生物的生长。这种同时针对癌细胞和微生物病原体的双重活性凸显了嘧啶衍生物在医学应用中的多样性和潜力。本综述深入探讨了融合嘧啶衍生物的结构特征、合成方法和重要的医药应用,重点介绍了它们在抗击癌症和细菌感染方面的双重作用。
{"title":"Anticancer and Antibacterial Activeness of Fused Pyrimidines: Newfangled Updates","authors":"","doi":"10.1016/j.bioorg.2024.107780","DOIUrl":"10.1016/j.bioorg.2024.107780","url":null,"abstract":"<div><p>Pyrimidine-based heterocyclic compounds are garnering substantial interest due to their essential role as a class of natural and synthetic molecules. These compounds show a diverse array of biologically relevant activities, making them highly prospective candidates for clinical translation as therapeutic agents in combating various diseases. Pyrimidine derivatives and their fused analogues, such as thienopyrimidines, pyrazolopyrimidines, pyridopyrimidines, and pyrimidopyrimidines, hold immense possibility in both anticancer and antibacterial research. These compounds exhibit notable efficacy by targeting protein kinases, which are crucial enzymes regulating fundamental cellular processes like metabolism, migration, division, and growth. Through enzyme inhibition, these derivatives disrupt key cellular signaling pathways, thereby affecting critical cellular functions and viability. The advantage lies in the ubiquity of the pyrimidine structure across various natural compounds, enabling interactions with enzymes, genetic material, and cellular components pivotal for chemical and biological processes. This interaction plays a central role in modulating vital biological activities, making pyrimidine-containing compounds indispensable in drug discovery. In the realm of anticancer therapy, these compounds strategically target key proteins like EGFR, important for aberrant cell growth. Fused pyrimidine motifs, exemplified by various drugs, are designed to inhibit EGFR, thereby impeding tumor progression. Moreover, these compounds influence potent antibacterial activity, interfering with microbial growth through mechanisms ranging from DNA replication inhibition to other vital cellular functions. This dual activity, targeting both cancer cells and microbial pathogens, underscores the versatility and potential of pyrimidine derivatives in medical applications. This review provides insights into the structural characteristics, synthesis methods, and significant medicinal applications of fused pyrimidine derivatives, highlighting their double role in combating cancer and bacterial infections.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163810","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107772
Targeted protein degradation (TPD) has emerged as a powerful approach for eliminating cancer-causing proteins through an “event-driven” pharmacological mode. Proteolysis-targeting chimeras (PROTACs), molecular glues (MGs), and hydrophobic tagging (HyTing) have evolved into three major classes of TPD technologies. Natural products (NPs) are a primary source of anticancer drugs and have played important roles in the development of TPD technology. NPs potentially expand the toolbox of TPD by providing a variety of E3 ligase ligands, protein of interest (POI) warheads, and hydrophobic tags (HyTs). As a promising direction in the TPD field, NP-based degraders have shown great potential for anticancer therapy. In this review, we summarize recent advances in the development of NP-based degraders (PROTACs, MGs and HyTing) with anticancer applications. Moreover, we put forward the challenges while presenting potential opportunities for the advancement of future targeted protein degraders derived from NPs.
{"title":"Development of natural product-based targeted protein degraders as anticancer agents","authors":"","doi":"10.1016/j.bioorg.2024.107772","DOIUrl":"10.1016/j.bioorg.2024.107772","url":null,"abstract":"<div><p>Targeted protein degradation (TPD) has emerged as a powerful approach for eliminating cancer-causing proteins through an “event-driven” pharmacological mode. Proteolysis-targeting chimeras (PROTACs), molecular glues (MGs), and hydrophobic tagging (HyTing) have evolved into three major classes of TPD technologies. Natural products (NPs) are a primary source of anticancer drugs and have played important roles in the development of TPD technology. NPs potentially expand the toolbox of TPD by providing a variety of E3 ligase ligands, protein of interest (POI) warheads, and hydrophobic tags (HyTs). As a promising direction in the TPD field, NP-based degraders have shown great potential for anticancer therapy. In this review, we summarize recent advances in the development of NP-based degraders (PROTACs, MGs and HyTing) with anticancer applications. Moreover, we put forward the challenges while presenting potential opportunities for the advancement of future targeted protein degraders derived from NPs.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144570","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107787
(±)-Elodeoidileons A-L (1–12), 12 pairs of previously undescribed filicinic acid based meroterpenoids were isolated from Hypericum elodeoides with unique linear or angular 6/6/6 ring core. Modern spectroscopic techniques, modified Mosher’s method and quantum chemical calculations were used to identify the planner structures and configurations of 1–12. Additionally, the potential biosynthetic pathways for 1–12 were anticipated. Moreover, biological activity assessments suggested that 1a, 5a, and 11b could activate Retinoid X receptor-α (RXRα) transcription and enhance the ATP-binding cassette transporter A1 (ABCA1) protein’s expression. Fluorescence titration assay suggested that 1a might have a direct interaction with the RXRα-LBD protein, with an estimated Kd value of 5.85 μM. Moreover, molecular docking study confirmed the binding of 1a to RXRα and further validated by cellular thermal shift assay (CETSA). Thus, compound 1a may promote β-amyloid (Aβ) clearance by targeting RXRα and upregulating the expression of the ABCA1 protein, showing promise as anti-Alzheimer’s agent.
{"title":"Filicinic acid based meroterpenoids from Hypericum elodeoides and their anti-Alzheimer’s disease effects","authors":"","doi":"10.1016/j.bioorg.2024.107787","DOIUrl":"10.1016/j.bioorg.2024.107787","url":null,"abstract":"<div><p>(±)-Elodeoidileons A-L (<strong>1</strong>–<strong>12</strong>), 12 pairs of previously undescribed filicinic acid based meroterpenoids were isolated from <em>Hypericum elodeoides</em> with unique linear or angular 6/6/6 ring core. Modern spectroscopic techniques, modified Mosher’s method and quantum chemical calculations were used to identify the planner structures and configurations of <strong>1</strong>–<strong>12</strong>. Additionally, the potential biosynthetic pathways for <strong>1</strong>–<strong>12</strong> were anticipated. Moreover, biological activity assessments suggested that <strong>1a</strong>, <strong>5a</strong>, and <strong>11b</strong> could activate Retinoid X receptor-α (RXRα) transcription and enhance the ATP-binding cassette transporter A1 (ABCA1) protein’s expression. Fluorescence titration assay suggested that <strong>1a</strong> might have a direct interaction with the RXRα-LBD protein, with an estimated K<sub>d</sub> value of 5.85 μM. Moreover, molecular docking study confirmed the binding of <strong>1a</strong> to RXRα and further validated by cellular thermal shift assay (CETSA). Thus, compound <strong>1a</strong> may promote β-amyloid (Aβ) clearance by targeting RXRα and upregulating the expression of the ABCA1 protein, showing promise as anti-Alzheimer’s agent.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144574","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107790
Commelina communis L., a functional food and herbal plant in Asia, has been used against obesity, diabetes, and infections for centuries. A growing body of studies has demonstrated that indigestible polysaccharides are significant in obesity management. However, the structures and bioactivities of homogeneous polysaccharides from C. communis remain unclear. This study presented the structural characterization, simulated digestion, and human gut Bacteroides proliferation promotion activity of a novel homogeneous polysaccharide (CCB-3) from C. communis. The results showed that CCB-3 was an arabinoglucuronoxylan, primarily composed of arabinose, galactose, xylose, glucuronic acid (GlcA), and 4-O-methyl GlcA with a molecular weight (Mw) of 58.8 kDa. Following a 6-hour exposure to simulated gastrointestinal fluid, the Mw of CCB-3 remained unchanged, revealing that CCB-3 was an indigestible polysaccharide. Notably, CCB-3 could promote the proliferation of B. thetaiotaomicron, B. ovatus, and B. cellulosilyticus and produce short-chain fatty acids (SCFAs) and 1,2-propanediol. These findings might shed light on the discovery of polysaccharide-based leading compounds from C. communis against obesity.
{"title":"Structural characterization and Bacteroides proliferation promotion activity of a novel homogeneous arabinoglucuronoxylan from Commelina communis L.","authors":"","doi":"10.1016/j.bioorg.2024.107790","DOIUrl":"10.1016/j.bioorg.2024.107790","url":null,"abstract":"<div><p><em>Commelina communis</em> L., a functional food and herbal plant in Asia, has been used against obesity, diabetes, and infections for centuries. A growing body of studies has demonstrated that indigestible polysaccharides are significant in obesity management. However, the structures and bioactivities of homogeneous polysaccharides from <em>C. communis</em> remain unclear. This study presented the structural characterization, simulated digestion, and human gut <em>Bacteroides</em> proliferation promotion activity of a novel homogeneous polysaccharide (CCB-3) from <em>C. communis</em>. The results showed that CCB-3 was an arabinoglucuronoxylan, primarily composed of arabinose, galactose, xylose, glucuronic acid (GlcA), and 4-<em>O</em>-methyl GlcA with a molecular weight (<em>Mw</em>) of 58.8 kDa. Following a 6-hour exposure to simulated gastrointestinal fluid, the <em>Mw</em> of CCB-3 remained unchanged, revealing that CCB-3 was an indigestible polysaccharide. Notably, CCB-3 could promote the proliferation of <em>B. thetaiotaomicron, B</em>. <em>ovatus</em>, and <em>B</em>. <em>cellulosilyticus</em> and produce short-chain fatty acids (SCFAs) and 1,2-propanediol. These findings might shed light on the discovery of polysaccharide-based leading compounds from <em>C. communis</em> against obesity.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144576","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107773
Antimicrobial resistance poses a global health concern and develops a need to discover novel antimicrobial agents or targets to tackle this problem. Fluoroquinolone (FN), a DNA gyrase and topoisomerase IV inhibitor, has helped to conquer antimicrobial resistance as it provides flexibility to researchers to rationally modify its structure to increase potency and efficacy. This review provides insights into the rational modification of FNs, the causes of resistance to FNs, and the mechanism of action of FNs. Herein, we have explored the latest advancements in antimicrobial activities of FN analogues and the effect of various substitutions with a focus on utilizing the FN nucleus to search for novel potential antimicrobial candidates. Moreover, this review also provides a comparative analysis of two widely prescribed FNs that are ciprofloxacin and norfloxacin, explaining their rationale for their design, structure–activity relationships (SAR), causes of resistance, and mechanistic studies. These insights will prove advantageous for new researchers by aiding them in designing novel and effective FN-based compounds to combat antimicrobial resistance.
抗菌药耐药性是一个全球健康问题,因此需要发现新型抗菌剂或靶点来解决这一问题。氟喹诺酮(FN)是一种 DNA 回旋酶和拓扑异构酶 IV 抑制剂,它为研究人员合理改造其结构以提高效力和疗效提供了灵活性,因而有助于克服抗菌药耐药性。本综述深入探讨了 FNs 的合理改造、FNs 产生抗药性的原因以及 FNs 的作用机制。在此,我们探讨了 FN 类似物抗菌活性的最新进展以及各种取代的效果,重点是利用 FN 核寻找新的潜在抗菌候选物。此外,本综述还对两种广泛使用的 FN(环丙沙星和诺氟沙星)进行了比较分析,解释了它们的设计原理、结构-活性关系(SAR)、耐药性原因和机理研究。这些见解将有助于新研究人员设计新颖、有效的 FN 类化合物来对抗抗菌药耐药性。
{"title":"Fluoroquinolones tackling antimicrobial resistance: Rational design, mechanistic insights and comparative analysis of norfloxacin vs ciprofloxacin derivatives","authors":"","doi":"10.1016/j.bioorg.2024.107773","DOIUrl":"10.1016/j.bioorg.2024.107773","url":null,"abstract":"<div><p>Antimicrobial resistance poses a global health concern and develops a need to discover novel antimicrobial agents or targets to tackle this problem. Fluoroquinolone (FN), a DNA gyrase and topoisomerase IV inhibitor, has helped to conquer antimicrobial resistance as it provides flexibility to researchers to rationally modify its structure to increase potency and efficacy. This review provides insights into the rational modification of FNs, the causes of resistance to FNs, and the mechanism of action of FNs. Herein, we have explored the latest advancements in antimicrobial activities of FN analogues and the effect of various substitutions with a focus on utilizing the FN nucleus to search for novel potential antimicrobial candidates. Moreover, this review also provides a comparative analysis of two widely prescribed FNs that are ciprofloxacin and norfloxacin, explaining their rationale for their design, structure–activity relationships (SAR), causes of resistance, and mechanistic studies. These insights will prove advantageous for new researchers by aiding them in designing novel and effective FN-based compounds to combat antimicrobial resistance.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144575","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107791
Resveratrol (Res) has long been discovered to have antioxidant effects to prevent such as oxidation, inflammation, neurodegeneration and age-related diseases. However, its poor water solubility, low bioavailability and instability have become a barrier to its pharmaceutical application. In order to improve the neuroprotective effects and develop more potential usage of Res, three Res derivatives containing one or two glucose groups, i.e., Res-Glu1, Res-Glu2 and Res-Glu3, were designed and synthesized through click reaction. Res-Glu1, Res-Glu2 and Res-Glu3 were tested being better water solubility and stability compared to Res. Res derivatives reduced •OH radicals-induced DNA damage. PC12 assays indicated that glucosylated Res derivatives could alleviate H2O2-induced neurotoxicity and reduce intracellular ROS generation, demonstrating their neuroprotective effects. In addition, Res derivatives enhanced the protective effects on cerebral ischemia–reperfusion injury in rats. Res-Glu3 displayed the best neuroprotective effects among the three derivatives.
白藜芦醇(Res)很早就被发现具有抗氧化作用,可预防氧化、炎症、神经退化和与年龄有关的疾病。然而,白藜芦醇的水溶性差、生物利用率低和不稳定性成为其制药应用的障碍。为了提高 Res 的神经保护作用并开发其更多潜在用途,研究人员通过点击反应设计并合成了三种含有一个或两个葡萄糖基团的 Res 衍生物,即 Res-Glu1、Res-Glu2 和 Res-Glu3。经测试,与 Res 相比,Res-Glu1、Res-Glu2 和 Res-Glu3 具有更好的水溶性和稳定性。Res 衍生物可减少-OH 自由基诱导的 DNA 损伤。PC12 试验表明,葡萄糖基化的 Res 衍生物可减轻 H2O2 诱导的神经毒性并减少细胞内 ROS 的生成,这证明了它们的神经保护作用。此外,Res 衍生物还能增强对大鼠脑缺血再灌注损伤的保护作用。在三种衍生物中,Res-Glu3 的神经保护效果最好。
{"title":"Synthesis and bioactivity evaluation of glycosylated resveratrol derivatives as antioxidative neuroprotection agents against cerebral Ischemia-Reperfusion injury","authors":"","doi":"10.1016/j.bioorg.2024.107791","DOIUrl":"10.1016/j.bioorg.2024.107791","url":null,"abstract":"<div><p>Resveratrol (Res) has long been discovered to have antioxidant effects to prevent such as oxidation, inflammation, neurodegeneration and age-related diseases. However, its poor water solubility, low bioavailability and instability have become a barrier to its pharmaceutical application. In order to improve the neuroprotective effects and develop more potential usage of Res, three Res derivatives containing one or two glucose groups, i.e., Res-Glu1, Res-Glu2 and Res-Glu3, were designed and synthesized through click reaction. Res-Glu1, Res-Glu2 and Res-Glu3 were tested being better water solubility and stability compared to Res. Res derivatives reduced •OH radicals-induced DNA damage. PC12 assays indicated that glucosylated Res derivatives could alleviate H<sub>2</sub>O<sub>2</sub>-induced neurotoxicity and reduce intracellular ROS generation, demonstrating their neuroprotective effects. In addition, Res derivatives enhanced the protective effects on cerebral ischemia–reperfusion injury in rats. Res-Glu3 displayed the best neuroprotective effects among the three derivatives.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142149739","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107776
Among members of the mitogen-activated protein kinase (MAPK) family, c-Jun N-terminal kinases (JNKs) are vital for cellular responses to stress, inflammation, and apoptosis. Recent advances have highlighted their important implications in cancer biology, where dysregulated JNK signalling plays a role in the growth, progression, and metastasis of tumors. The present understanding of JNK kinase and its function in the etiology of cancer is summarized in this review. By modifying a number of downstream targets, such as transcription factors, apoptotic regulators, and cell cycle proteins, JNKs exert diverse effects on cancer cells. Apoptosis avoidance, cell survival, and proliferation are all promoted by abnormal JNK activation in many types of cancer, which leads to tumor growth and resistance to treatment. JNKs also affect the tumour microenvironment by controlling the generation of inflammatory cytokines, angiogenesis, and immune cell activity. However, challenges remain in deciphering the context-specific roles of JNK isoforms and their intricate crosstalk with other signalling pathways within the complex tumor environment. Further research is warranted to delineate the precise mechanisms underlying JNK-mediated tumorigenesis and to develop tailored therapeutic strategies targeting JNK signalling to improve cancer management. The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.
{"title":"Targeting JNK kinase inhibitors via molecular docking: A promising strategy to address tumorigenesis and drug resistance","authors":"","doi":"10.1016/j.bioorg.2024.107776","DOIUrl":"10.1016/j.bioorg.2024.107776","url":null,"abstract":"<div><p>Among members of the mitogen-activated protein kinase (MAPK) family, c-Jun <em>N</em>-terminal kinases (JNKs) are vital for cellular responses to stress, inflammation, and apoptosis. Recent advances have highlighted their important implications in cancer biology, where dysregulated JNK signalling plays a role in the growth, progression, and metastasis of tumors. The present understanding of JNK kinase and its function in the etiology of cancer is summarized in this review. By modifying a number of downstream targets, such as transcription factors, apoptotic regulators, and cell cycle proteins, JNKs exert diverse effects on cancer cells. Apoptosis avoidance, cell survival, and proliferation are all promoted by abnormal JNK activation in many types of cancer, which leads to tumor growth and resistance to treatment. JNKs also affect the tumour microenvironment by controlling the generation of inflammatory cytokines, angiogenesis, and immune cell activity. However, challenges remain in deciphering the context-specific roles of JNK isoforms and their intricate crosstalk with other signalling pathways within the complex tumor environment. Further research is warranted to delineate the precise mechanisms underlying JNK-mediated tumorigenesis and to develop tailored therapeutic strategies targeting JNK signalling to improve cancer management. The review emphasizes the role of JNK kinases in cancer biology, as well as their potential as pharmaceutical targets for precision oncology therapy and cancer resistance. Also, this review summarizes all the available promising JNK inhibitors that are suggested to promote the responsiveness of cancer cells to cancer treatment.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227987","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}
Pub Date : 2024-09-02DOI: 10.1016/j.bioorg.2024.107775
Cannabinoid receptors CB1 and CB2 play critical roles in regulating numerous central and peripheral physiological activities. While efforts have been made to develop ligands for both CB1 and CB2 receptors, CB1 receptor ligands often have restricted use due to undesirable psychotropic side effects. Consequently, recent cannabis research has increasingly focused on CB2-specific ligands. Pharmacological agonists of CB2 receptors have shown potential in managing pain, inflammation, arthritis, neuroprotection, cancer, and other disorders. Despite several CB2 receptor ligands entering clinical trials, none have achieved market approval except natural cannabinoids and their derivatives, primarily due to insufficient CB2/CB1 receptor selectivity. However, new-generation ligands developed in recent years have demonstrated improved selectivity. This review covers patent literature on CB2 modulators from 2016 to 2024, highlighting the major advances in the field. During this period, the majority of research has concentrated on using CB2 modulators to alleviate inflammation and pain. Additionally, patents have explored CB2 modulators for a range of specific diseases, including: psychiatric and neuropsychiatric disorders, schizophrenia, multiple myeloma and osteoporosis, ocular inflammation and neuropathic Pain, cancer anorexia and weight loss, antioxidant and anti-aging agents, lymphocytopenia, hearing loss, Alzheimer’s disease, cancer and non-malignant tumors. Notably, recent years have seen increased interest in CB2 antagonists/inverse agonists, with few candidates advancing to clinical studies. Significant progress has been made in the synthesis and modulation of selective CB2 agonists and antagonists, paving the way for future developments in CB2 modulators. This review provides insights and prospects for the continued evolution of CB2-targeted therapies.
{"title":"Cannabinoid receptor 2 (CB2) modulators: A patent review (2016–2024)","authors":"","doi":"10.1016/j.bioorg.2024.107775","DOIUrl":"10.1016/j.bioorg.2024.107775","url":null,"abstract":"<div><p>Cannabinoid receptors CB1 and CB2 play critical roles in regulating numerous central and peripheral physiological activities. While efforts have been made to develop ligands for both CB1 and CB2 receptors, CB1 receptor ligands often have restricted use due to undesirable psychotropic side effects. Consequently, recent cannabis research has increasingly focused on CB2-specific ligands. Pharmacological agonists of CB2 receptors have shown potential in managing pain, inflammation, arthritis, neuroprotection, cancer, and other disorders. Despite several CB2 receptor ligands entering clinical trials, none have achieved market approval except natural cannabinoids and their derivatives, primarily due to insufficient CB2/CB1 receptor selectivity. However, new-generation ligands developed in recent years have demonstrated improved selectivity. This review covers patent literature on CB2 modulators from 2016 to 2024, highlighting the major advances in the field. During this period, the majority of research has concentrated on using CB2 modulators to alleviate inflammation and pain. Additionally, patents have explored CB2 modulators for a range of specific diseases, including: psychiatric and neuropsychiatric disorders, schizophrenia, multiple myeloma and osteoporosis, ocular inflammation and neuropathic Pain, cancer anorexia and weight loss, antioxidant and anti-aging agents, lymphocytopenia, hearing loss, Alzheimer’s disease, cancer and non-malignant tumors. Notably, recent years have seen increased interest in CB2 antagonists/inverse agonists, with few candidates advancing to clinical studies. Significant progress has been made in the synthesis and modulation of selective CB2 agonists and antagonists, paving the way for future developments in CB2 modulators. This review provides insights and prospects for the continued evolution of CB2-targeted therapies.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240144","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}
Pub Date : 2024-09-01DOI: 10.1016/j.bioorg.2024.107777
Inhibiting cyclin-dependent kinases (CDK) offers an important arsenal for cancer treatments by interfering with apoptotic proteins related to cancer. Novel selective cyclin-dependent kinases inhibitors using the Quinazoline as the cap with multiple electronic donating (EDG) and/or electron withdrawing group (EWG) substituted Aniline chain at the C-2 position were designed, synthesized, and evaluated for activity against liver cancer. Among the tested compounds, compounds B34 and B35 emerged as potent candidates in the series, with IC50 values of 0.102 ± 0.04 µM and 0.058 ± 0.003 µM, respectively. They also suppressed the enzymatic activity of CDK2/cyclinA2 selectively. Further biological studies revealed that compounds B34 and B35 arrested the cell cycle, and induced apoptosis in HepG-2 cancer cells through a Caspase-mediated mechanism, facilitating the release of Cyt-c through modulation of Caspase-3 expression. More importantly, compounds B34 and B35 suppressed the xenografted tumor growth in mice in a dose-dependent manner. Finally, through a molecular docking study, it was confirmed that compounds B34 and B35 retained crucial hydrogen bonding and hydrophobic interactions with CDK receptor, rationalizing their higher efficacy compared to other compounds in the series. Taken together, the Quinazoline derivatives B34 and B35 may serve as novel chemotherapeutic agents through inhibition of CDK.
{"title":"Design, synthesis, molecular docking, and evaluation of sulfonyl quinazoline analogues as promising liver cancer drugs","authors":"","doi":"10.1016/j.bioorg.2024.107777","DOIUrl":"10.1016/j.bioorg.2024.107777","url":null,"abstract":"<div><p>Inhibiting cyclin-dependent kinases (CDK) offers an important arsenal for cancer treatments by interfering with apoptotic proteins related to cancer. Novel selective cyclin-dependent kinases inhibitors using the Quinazoline as the cap with multiple electronic donating (EDG) and/or electron withdrawing group (EWG) substituted Aniline chain at the C-2 position were designed, synthesized, and evaluated for activity against liver cancer. Among the tested compounds, compounds B34 and B35 emerged as potent candidates in the series, with IC<sub>50</sub> values of 0.102 ± 0.04 µM and 0.058 ± 0.003 µM, respectively. They also suppressed the enzymatic activity of CDK2/cyclinA2 selectively. Further biological studies revealed that compounds B34 and B35 arrested the cell cycle, and induced apoptosis in HepG-2 cancer cells through a Caspase-mediated mechanism, facilitating the release of Cyt-c through modulation of Caspase-3 expression. More importantly, compounds B34 and B35 suppressed the xenografted tumor growth in mice in a dose-dependent manner. Finally, through a molecular docking study, it was confirmed that compounds<!--> <!-->B34 and<!--> <!-->B35 retained crucial hydrogen bonding and hydrophobic interactions with CDK receptor, rationalizing their higher efficacy compared to other compounds in the series. Taken together, the Quinazoline derivatives B34 and B35 may serve as novel chemotherapeutic agents through inhibition of CDK.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142149805","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}