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Development of small-molecule fluorescent probes targeting neutrophils via N-formyl peptide receptors.
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-14 DOI: 10.1039/d4md00849a
Qi Xu, Kalwant S Authi, Liliya N Kirpotina, Igor A Schepetkin, Mark T Quinn, Agostino Cilibrizzi

N-Formyl peptide receptors (FPRs) are membrane receptors that are abundantly expressed in innate immune cells, including neutrophils and platelets, demonstrating potential new targets for immune system regulation and the treatment of inflammatory conditions. We report here the development and bio-physical validation of new FPR imaging agents as effective tools to track FPR distribution, localisation and functions, ultimately helping to establish FPR exact roles and functions in pathological and physiological conditions. The new series of probes feature a small molecule-based FPR address system conjugated to suitable fluorophores, resulting in highly specific FPR agents, including a partial agonist endowed with high affinity (i.e. low/sub-nanomolar potency) on FPR-transfected cells and human neutrophils. Preliminary imaging studies via multiphoton microscopy demonstrate that the probes enable the visualisation of FPRs in live cells, thus representing valid bio-imaging tools for the analysis of FPR-mediated signalling, such as the activation of neutrophils in inflammatory events.

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引用次数: 0
Development of benzofuran-derived sulfamates as dual aromatase-steroid sulfatase inhibitors (DASIs): design, synthesis and biological evaluation.
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.1039/d4md00795f
Ahmed G Eissa, Francesca Gozzi, Oqab Aloqab, Charlotte E Parrish, Nadira Mohamed, Irene Shiali, Harith Al-Baldawi, Paul A Foster, Claire Simons

Resistance of oestrogen receptor-positive (ER+) breast cancer, the most prevalent type of breast cancer accounting for ∼70% of all cases, to current therapies necessitates the study of alternative strategies. One promising strategy is the multi-targeting approach using dual aromatase-steroid sulfatase inhibitors (DASIs). Herein, we describe the development of DASIs using a common benzofuran pharmacophore. Triazole benzofuran sulfamates were found to have low nM aromatase (Arom) inhibitory activity but no steroid sulfatase (STS) inhibitory activity (IC50 > 10 μM); by contrast, benzofuran ketone sulfamates demonstrated low nM STS inhibitory activity but no Arom inhibitory activity (IC50 > 1 μM). The addition of a methyl group at the 3rd position of the benzofuran ring in the benzofuran ketone sulfamate 19 (R1 = CH3) had a notable effect, resulting in dual aromatase and STS inhibitory activities with the 4-chloro derivative 19b (Arom IC50 = 137 nM, STS IC50 = 48 nM) and 4-methoxy derivative 19e (Arom IC50 = 35 nM, STS IC50 = 164 nM) optimal for dual inhibition. Arom/STS inhibition results combined with molecular dynamics studies provided a clear rationale for the activity observed.

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.1039/d4md00829d
Summaya Perveen, Sunny Pal, Rashmi Sharma

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.

揭示药物发现的新途径构成了抗击结核病新时代的基础。一种靶向分枝杆菌ATP合成酶的新药贝达喹啉的发现突出了能量代谢途径的靶向性。贝达喹啉对结核分枝杆菌异种群体的显著效力表明ATP合酶是电子传递链的重要复合物。本文就分枝杆菌ATP合酶的重要性及其独特的特性作一综述。了解这些区别可以使ATP合酶亚基成为药物发现的靶标,而无需针对哺乳动物。此外,简要比较了分枝杆菌和线粒体ATP合酶的结构差异进行了讨论。作为一种复杂的多亚基蛋白,ATP合酶为潜在的抑制剂提供了多个位点,包括a, c, ε, γ和δ亚基。针对这些亚基的抑制剂进行了严格的审查,为设计更好,更有效的化学实体提供了见解,具有有效治疗方案的潜力。
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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.1039/d4md00894d
Yiyi Hu, Yunchuan Li, Haodan Zhu, Dandan Wang, Junming Zhou, Bin Li

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.

感染猪流行性腹泻病毒(PEDV)的仔猪会出现严重腹泻和死亡率升高,导致养猪业遭受重大经济损失。本研究的目的是通过使用不同的方法来评估皂苷对Vero细胞内PEDV的影响。通过生产40种皂苷,我们发现29号、31号、35号和38号表现出对PEDV有效的特性,可以作为潜在的药物。结果显示,与PEDV对照组相比,No. 29、No. 31、No. 35、No. 38高、中、低剂量组PEDV mRNA水平均明显受到抑制,且呈明显的剂量依赖性。4种皂苷均能显著抑制PEDV N含量和病毒滴度。29号、31号、35号和38号皂苷的细胞毒性50% (CC50)浓度分别为37.13 μM、52.86 μM、44.98 μM和43.81 μM,表明其在临床环境下是安全的。总的来说,这些发现表明,四种被检测的皂苷可以有效地调节对PEDV的免疫反应,并有望用于抗病毒治疗。
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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY 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

In continuation of our efforts to develop new anticancer compounds, a new series of imidazo[1,5-a]pyridine-chalcone derivatives was designed, synthesized, characterized, and evaluated for its cytotoxicity against five human cancer cell lines, i.e., breast (MDA-MB-231), colon (RKO), bone (Mg-63), prostate (PC-3), and liver (HepG2) cell lines, as well as a normal cell line (HEK). Among the synthesized compounds, two exhibited promising cytotoxicity against the MDA-MB-231 cell line with IC50 values of 4.23 ± 0.25 μM and 3.26 ± 0.56 μM. We also studied apoptotic induction of the compounds using annexin V-FITC/PI staining, and ROS-mediated mitochondrial damage was elucidated using DCFDA, followed by JC-1 staining. The potential activity of the compounds was further confirmed by immuno-fluorescence and molecular docking studies, which revealed the anticancer activity of active compounds through binding and microtubule disruption.

为了继续开发新的抗癌化合物,我们设计、合成、表征了一系列新的咪唑[1,5-a]吡啶查尔酮衍生物,并评估了其对五种人类癌细胞系的细胞毒性,即乳腺癌(MDA-MB-231)、结肠癌(RKO)、骨(Mg-63)、前列腺(PC-3)、肝脏(HepG2)细胞系以及正常细胞系(HEK)。其中2个化合物对MDA-MB-231细胞株具有良好的细胞毒性,IC50值分别为4.23±0.25 μM和3.26±0.56 μM。我们还通过annexin V-FITC/PI染色研究了化合物对细胞凋亡的诱导作用,并通过DCFDA和JC-1染色研究了ros介导的线粒体损伤。通过免疫荧光和分子对接研究进一步证实了化合物的潜在活性,揭示了活性化合物通过结合和微管破坏的抗癌活性。
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引用次数: 0
Novel multipotent conjugate bearing tacrine and donepezil motifs with dual cholinergic inhibition and neuroprotective properties targeting Alzheimer's disease.
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-07 DOI: 10.1039/d4md00804a
Andrés F Yepes, Wilson Cardona-Galeano, Angie Herrera-Ramírez, Marlyn S Rada, Edison Osorio, Luis Alfonso Gonzalez-Molina, Yaneth Miranda-Brand, Rafael Posada-Duque

In this work, we developed potential multifunctional agents to combat Alzheimer's disease. According to our strategy, fragments of tacrine and donepezil were merged in a unique hybrid structure. After successfully synthesizing the compounds, they were evaluated for their dual AChE/BuChE inhibitor potential and neuroprotector response using a glutamate-induced excitotoxicity model. Most of the compounds showed promising activity. Among them, the hybrid with 2,5-dimetoxysubstitution (3b) was the most potent analogue, triggering dual potent AChE/BuChE inhibition with low nanomolar affinity (IC50 ∼ 300 nM) and low toxicity to human liver cancer cells (HepG2). This analogue prevented the glutamate excitotoxic stimulus during pre/post treatment testing, maintained ATP levels, possessed an astrocytic protective response, and abolished the glutamate-induced excitotoxicity. Besides, the hit compound 3b exhibited suitable permeability in the blood-brain barrier (BBB) and low degradability in human blood-plasma. In addition, the docking studies suggested that the neuroprotectant response exhibited by 3b can be related to the direct blockage of the NMDA channel pore. Finally, an ideal neuropharmacokinetic profile was estimated for 3b. Overall, the designed conjugates provide a novel multifunctional molecular scaffold that can be used as a prototype drug in further investigations toward novel multipotent therapeutics for treating AD.

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引用次数: 0
Lazertinib: breaking the mold of third-generation EGFR inhibitors.
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-07 DOI: 10.1039/d4md00800f
Kishan B Patel, David E Heppner

Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.

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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY 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

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.

鞘氨醇-1-磷酸-5 (S1P5)受体是五个膜G蛋白偶联受体之一,被溶血磷脂激活,鞘氨醇-1-磷酸,导致许多细胞过程的调节。S1P5受体位于少突胶质细胞上,被认为影响少突胶质细胞生理。了解S1P5在髓鞘再生过程中的调节可能对脱髓鞘性中枢神经系统疾病如多发性硬化症(MS)有潜在的应用。本文报道了一系列氟化6-芳基氨基苯酰胺作为S1P5正电子发射断层扫描(PET)配体的合成和初步评价。采用[35S]GTPγS法进行药代动力学筛选和结合评价,发现了选择性高亲和力的S1P5激动剂TEFM78。放射性合成[18F]TEFM78在动物模型中进行了先导PET成像研究,结果表明[18F]TEFM78可以穿过血脑屏障,在大鼠脑和脊髓中摄取良好。
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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1039/d4md00781f
Kehan Chen, Hui Yang, Guo Xu, Yunhan Hu, Xue Tian, Song Qin, Tianyue Jiang

Topical delivery of therapeutics on the skin can effectively alleviate skin symptoms of psoriasis and reduce systemic toxicity. However, the low delivery efficiency caused by the stratum corneum barrier limits the therapeutic impact. Here, we reported an oligopeptide hydrogel that encapsulates cell-penetrating-peptide (CPP)-decorated curcumin-loaded nanoemulsions (Cur-CNEs) to enhance the skin penetration of curcumin for topical treatment of psoriasis. After being applied to the skin of psoriatic mice, the Cur-CNE embedded oligopeptide hydrogel (Cur-CNEs/Gel) provided a prolonged residue time of Cur-CNEs on the skin lesion. The fluidic and elastic properties of the nanoemulsions enabled them to effectively pass through the interstitial spaces of the stratum corneum, while the CPP decoration further enhanced skin penetration and cellular uptake of Cur-CNEs. The Cur-CNEs/Gel exhibits effective alleviation of the symptoms of psoriasis in mice and provides a promising strategy for topical treatment of psoriasis.

在皮肤上局部给药可有效缓解银屑病的皮肤症状,并降低全身毒性。然而,角质层屏障导致的低给药效率限制了治疗效果。在此,我们报道了一种包裹了细胞穿透肽(CPP)装饰的姜黄素负载纳米乳液(Cur-CNEs)的寡肽水凝胶,以增强姜黄素的皮肤渗透性,用于银屑病的局部治疗。将 Cur-CNE 嵌入寡肽水凝胶(Cur-CNEs/Gel)涂抹在银屑病小鼠皮肤上后,Cur-CNEs 在皮损处的残留时间延长了。纳米乳液的流动性和弹性使其能够有效穿过角质层的间隙,而CPP装饰则进一步增强了Cur-CNEs的皮肤渗透和细胞吸收。Cur-CNEs/凝胶能有效缓解小鼠的银屑病症状,为银屑病的局部治疗提供了一种前景广阔的策略。
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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 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-02 DOI: 10.1039/d4md00855c
Diana McDonough, Christian A Sanchez, William M Wuest, Kevin P C Minbiole

The development and characterization of quaternary phosphonium compounds (QPCs) have long benefitted from their incorporation into a cornerstone reaction in organic synthesis - the Wittig reaction. These structures have, more recently, been developed into a wide variety of novel applications, ranging from phase transfer catalysis to mitochondrial targeting. Importantly, their antimicrobial action has demonstrated great promise against a wide variety of bacteria. This review aims to provide an overview of recent development in non-polymeric biocidal QPC structures, highlighting their synthetic preparation, and comparing their antimicrobial performance. Discussions of similarities and dissimilarities to QACs are included, both in bioactivity as well as likely mechanism(s) of action. The observed potential of QPCs to eradicate Gram-negative pathogens via a novel mechanism is highlighted, as there is an urgent need to address the declining biocide arsenal in modern infection control.

季磷化合物(QPCs)的开发和表征一直受益于将其纳入有机合成的基础反应- Wittig反应。最近,这些结构被开发成各种各样的新应用,从相转移催化到线粒体靶向。重要的是,它们的抗菌作用已经显示出对多种细菌的巨大希望。本文综述了近年来非高分子杀菌剂QPC结构的研究进展,重点介绍了它们的合成方法,并比较了它们的抗菌性能。讨论了与QACs的异同,包括生物活性和可能的作用机制。由于迫切需要解决现代感染控制中不断减少的杀菌剂库,QPCs通过一种新机制根除革兰氏阴性病原体的潜力得到了强调。
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引用次数: 0
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RSC medicinal chemistry
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