Chinese Chemical Letters最新文献_第5页

Advancements in nanophotonics and smart nanomaterials integrated with artificial intelligence-driven gene editing: A paradigm shift in cancer diagnosis and therapeutic 纳米光子学和智能纳米材料的进展与人工智能驱动的基因编辑：癌症诊断和治疗的范式转变

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-14 DOI: 10.1016/j.cclet.2025.111955

Bakr Ahmed Taha , Ali J. Addie , Luai Farhan Zghair Kolie , Saba Talib Wahhab , Sinan Adnan Abdulateef , Adawiya J. Haider , Khalid Ibnaouf , Norhana Arsad

Traditional cancer therapies are limited by side effects and damage to healthy tissues, while modern targeted treatments face challenges such as drug resistance and restricted applicability across cancer types. Early diagnosis also remains difficult, as many methods lack the sensitivity and specificity needed to reliably detect small, early-stage tumors. This review explores hybrid nanomaterial-based delivery systems, such as lipid–gold nanoparticle composites combined with polymeric nanocarriers, to improve the precision and efficacy of gene therapy. Advances in nanotechnology are highlighted for their ability to augment gene-editing tools including RNA interference and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), supported by techniques like optical tweezers, plasmonics, fluorescence imaging, and metamaterials. Nanophotonics in particular offers ultra-sensitive molecular imaging and real-time biomarker detection, underscoring its value for early cancer diagnosis. Artificial intelligence further strengthens these approaches by optimizing nanocarrier design, predicting therapeutic outcomes, and guiding personalized treatment strategies. Machine learning and deep learning platforms enable efficient analysis of complex genomic and clinical datasets, improving predictive accuracy and therapeutic customization. The review also outlines molecular mechanisms of gene therapy, from editing to expression, and addresses barriers to clinical translation, such as data integration, model validation, and regulatory considerations. Combining nanotechnology, artificial intelligence (AI), and gene-editing advances holds promise for more effective, targeted, and minimally invasive cancer treatments. These integrated strategies support earlier detection, enhance therapeutic precision, and provide a framework for translating experimental breakthroughs into clinical applications that better align with the goals of personalized medicine.

传统的癌症治疗受到副作用和对健康组织的损害的限制，而现代靶向治疗面临着诸如耐药性和对癌症类型的适用性限制等挑战。早期诊断仍然很困难，因为许多方法缺乏可靠检测早期小肿瘤所需的敏感性和特异性。本文综述了基于混合纳米材料的递送系统，如脂质-金纳米颗粒复合材料与聚合物纳米载体的结合，以提高基因治疗的准确性和有效性。在光学镊子、等离子体、荧光成像和超材料等技术的支持下，纳米技术的进步突出了它们增强基因编辑工具的能力，包括RNA干扰和聚集规律间隔短回文重复序列/CRISPR相关蛋白9 （CRISPR/Cas9）。特别是纳米光子学提供了超灵敏的分子成像和实时生物标志物检测，强调了其在早期癌症诊断中的价值。人工智能通过优化纳米载体设计、预测治疗结果和指导个性化治疗策略进一步加强了这些方法。机器学习和深度学习平台能够有效分析复杂的基因组和临床数据集，提高预测准确性和治疗定制。该综述还概述了基因治疗的分子机制，从编辑到表达，并解决了临床翻译的障碍，如数据整合、模型验证和监管考虑。结合纳米技术、人工智能（AI）和基因编辑技术的进步，有望实现更有效、更有针对性和更微创的癌症治疗。这些综合策略支持早期发现，提高治疗精度，并为将实验突破转化为临床应用提供框架，从而更好地符合个性化医疗的目标。

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引用次数: 0

Mediating electron delocalization of surface palladium atoms by diethylamine ligand for efficient CO2 electroreduction 二乙胺配体介导表面钯原子的电子离域，实现高效的CO2电还原

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-14 DOI: 10.1016/j.cclet.2025.111958

Mulin Yu , Shuo Liu , Yufeng Tang , Guoqiang Lu , Linbo Liu , Pengfei Sui , Xianzhu Fu , Subiao Liu , Yifei Sun , Jingli Luo

Functionalizing ligands on surface metal atoms has been implemented to tune the adsorption behaviors of intermediates in electrochemical CO₂ reduction reaction (CO₂RR). However, it is always bound within an unfavorable linear scaling relationship of the synchronously changed adsorption energies of intermediates. To break it, a win-win diethylamine (DEA)-mediated strategy was proposed to functionalize surface Pd atoms by exchanging the residual oleylamine (OAm) on ultrafine Pd nanoparticles (Pd NPs) with DEA. The molecular dynamics simulations, coupled with in situ Fourier transform infrared spectroscopy results, revealed that DEA hindered less toward CO₂ than H₂O on Pd NPs surface, and induced more CO linear configuration intermediate (*CO_L), indicative of ease CO₂ transport and CO desorption. Additionally, computational calculations implied that -NH- in DEA delocalized more electrons to surface Pd atoms and formed H-bond with *COOH, asynchronously changing the adsorption energies of *COOH and *CO, which enabled a CO Faraday efficiency (FE_CO) close to 100 % in an ultrawide potential window and a stability of over 50 h with a FE_CO over 90 %. This study dexterously addresses the residual issue of end-blocking agents on metal nanostructures from synthesis, and synchronously realizes the surface molecular functionalization, paving a smart avenue to design high-performance electrocatalysts.

在电化学CO2还原反应（CO2RR）中，利用表面金属原子上的功能化配体调节中间体的吸附行为。然而，中间体吸附能的同步变化总是束缚在不利的线性标度关系中。为了打破这一局面，研究人员提出了一种双赢的二乙胺（DEA）介导策略，通过与DEA交换超细Pd纳米颗粒（Pd NPs）上残留的油胺（OAm）来实现表面Pd原子的功能化。分子动力学模拟和原位傅里叶变换红外光谱结果表明，DEA在Pd NPs表面对CO2的阻碍小于H2O，并诱导出更多的CO线性构型中间体（*COL），表明DEA有利于CO2的运输和CO的解吸。此外，计算表明，DEA中的- nh -使更多的电子离域到表面Pd原子上，并与*COOH形成氢键，异步改变*COOH和*CO的吸附能，使CO的法拉第效率（FECO）在超宽电位窗口内接近100% %，FECO在90% %以上的情况下稳定性超过50 h。该研究巧妙地解决了末端阻断剂在金属纳米结构合成过程中的残留问题，并同步实现了表面分子功能化，为高性能电催化剂的设计开辟了一条智能途径。

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引用次数: 0

Lewis acid catalyzed enantioselective dearomative (3+2) cycloaddition of aromatic N-heterocycles with bicyclobutanes 路易斯酸催化芳香n -杂环与双环丁烷对映选择性脱芳（3+2）环加成反应

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-14 DOI: 10.1016/j.cclet.2025.111963

Feng Wu , Yuanjiu Xiao , Mengran Wei , Guoqiang Wang , Jian-Jun Feng

Given the emerging demand to “escape from flatland” for modern medicinal chemistry, both the catalytic construction of complex three-dimensional molecular architectures from planar aromatics and the bioisosteric substitution of aromatic ring with bicyclo[2.1.1]hexanes (BCHs) become increasingly valuable. Despite notable advancements in the cycloaddition reactions involving bicyclo[1.1.0]butanes (BCBs) and 2π-components, the application of easily accessible aromatic compounds in these transformations, particularly in an asymmetric manner, is still relatively unexplored. Herein, we report a nickel-catalyzed enantioselective polar dearomative (3 + 2) cycloaddition of BCBs with benzazoles and indoles. This protocol offers an efficient route for the synthesis of N,S- or N,N-heterocycles decorated fused aza-BCHs bearing two quaternary carbon centers. This approach stands out for its practicality and appeal due to the utilization of easily accessible starting materials and catalysts, broad substrate scope, easy scalability, and the employment of mild reaction conditions. Density functional theory (DFT) calculations offer crucial insights into the reaction mechanism and elucidate the factors governing the enantioselectivity within the dearomative cycloaddition process.

鉴于现代药物化学“逃离平原”的新需求，从平面芳烃催化构建复杂的三维分子结构，以及用双环[2.1.1]己烷（BCHs）取代芳烃环的生物等构反应都变得越来越有价值。尽管在涉及双环[1.1.0]丁烷（BCBs）和2π组分的环加成反应方面取得了显著进展，但在这些转化中，特别是以不对称方式，容易获得的芳香族化合物的应用仍然相对未被探索。在此，我们报道了镍催化bcb与苯唑和吲哚的对映选择性极性脱芳（3 + 2）环加成反应。该工艺为合成带有两个季碳中心的N，S-或N，N-杂环修饰的杂氮杂环杂氮杂环化合物提供了一条有效途径。该方法因其实用性和吸引力而脱颖而出，因为它使用了容易获得的起始材料和催化剂，广泛的底物范围，易于扩展，以及使用温和的反应条件。密度泛函理论（DFT）的计算提供了对反应机理的重要见解，并阐明了在脱芳环加成过程中控制对映选择性的因素。

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引用次数: 0

Recent advances in carbon dots imaging at the subcellular level: Synthesis strategies, properties, and organelle imaging 亚细胞水平碳点成像的最新进展：合成策略、性质和细胞器成像

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-14 DOI: 10.1016/j.cclet.2025.111957

Xinjuan He , Zishuo Wang , Boyang Wang , Yongqiang Zhang , Xiaokai Xu , Huijuan Cai , Siyu Lu

Carbon dots (CDs), a class of emerging fluorescent nanomaterials, have garnered notable attention in the biomedical field owing to their outstanding photoluminescence properties, excellent biocompatibility, and ease of synthesis and functionalization. Recently, numerous CDs have been developed that allow precise subcellular localization through surface modifications or covalent conjugation with targeting ligands such as peptides, small molecules, Golgi-specific agents, and cell membrane-specific agents. This review begins with an overview of the synthesis strategies of CDs, highlighting their exceptional optical properties, stability, biocompatibility, and significance for subcellular imaging. The mechanisms by which CDs target specific organelles, including the nucleus, mitochondrion, lysosomes, Golgi apparatus, and cell membrane, are discussed. These mechanisms include specific targeting molecules, pH-sensitive targeting, charge-driven interactions, and hydrophobic and hydrophilic dynamics. Furthermore, we summarize their applications in subcellular imaging, such as the long-term dynamic monitoring of organelles, sensing, reactive oxygen species scavenging, and therapy. By presenting a comprehensive review of CDs in subcellular imaging, we aim to pave the way for further development of CDs in bioimaging and related biomedical applications.

碳点（CDs）是一类新兴的荧光纳米材料，因其优异的光致发光性能、良好的生物相容性以及易于合成和功能化而在生物医学领域受到广泛关注。最近，已经开发了许多cd，通过表面修饰或与靶向配体（如肽、小分子、高尔基特异性药物和细胞膜特异性药物）的共价偶联，可以实现精确的亚细胞定位。本文首先综述了CDs的合成策略，重点介绍了它们卓越的光学特性、稳定性、生物相容性和对亚细胞成像的意义。讨论了CDs靶向特定细胞器的机制，包括细胞核、线粒体、溶酶体、高尔基体和细胞膜。这些机制包括特异性靶向分子、ph敏感靶向、电荷驱动相互作用以及疏水和亲水动力学。此外，我们总结了它们在亚细胞成像中的应用，如细胞器的长期动态监测、传感、活性氧清除和治疗。通过对亚细胞成像中cd的全面综述，我们旨在为cd在生物成像和相关生物医学应用中的进一步发展铺平道路。

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引用次数: 0

Host-guest interaction mediated low-shrinkage photosensitive positioning adhesive 主客体相互作用介导的低收缩光敏定位胶

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-13 DOI: 10.1016/j.cclet.2025.111949

Zhao Liu , Junjian Xie , Xiaoming Ren , Muhammad Tahir , Shixin Fa , Qiuyu Zhang

As a common electronic adhesive, ultraviolet (UV) curing polyurethane acrylate adhesive has both flexibility and wear resistance of polyurethane, excellent weather resistance and optical properties of acrylate. Despite the extensive applications, it is still difficult to solve the problems caused by the shrinkage of adhesive. Here, a new type of photosensitive adhesive for bonding electronic components based on supramolecular interaction was designed and synthesized. The supramolecular interaction of cyclodextrin and adamantane moieties introduced into the adhesive polymer entitles the viscosity of the adhesive to rise rapidly during use, thereby preventing adhesive loss and dislocation of electronic components. UV light could further cure the adhesive and position the electronic components. The adhesive shrunk <2 % when cured by UV light, so it can be used for electronic packaging and high-resolution, defect-free lithography.

紫外线固化聚氨酯丙烯酸酯胶粘剂是一种常用的电子胶粘剂，它既具有聚氨酯的柔韧性和耐磨性，又具有丙烯酸酯优异的耐候性和光学性能。尽管得到了广泛的应用，但由于胶粘剂的收缩引起的问题仍然难以解决。本文设计并合成了一种基于超分子相互作用的新型电子元件光敏胶粘剂。在胶粘剂聚合物中引入环糊精和金刚烷基团的超分子相互作用，使胶粘剂的粘度在使用过程中迅速上升，从而防止了胶粘剂的损失和电子元件的错位。紫外线可以进一步固化胶粘剂和定位电子元件。该胶粘剂经紫外光固化后可收缩<；2 %，因此可用于电子封装和高分辨率，无缺陷光刻。

引用次数: 0

Enhanced structural coloration and thermal management via hydrophobic force-driven colloidal photonic crystals 通过疏水性力驱动的胶体光子晶体增强结构着色和热管理

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-12 DOI: 10.1016/j.cclet.2025.111947

Xiaoqing Yu , Jie Ren , Nianxiang Zhang , Zirong Li , Kebing Chen , Jiazhuang Guo , Su Chen , Guoxing Li , Chang Liu

Developing passive cooling materials with dual functionality of high-performance thermal management and aesthetic appeal remains a critical challenge for sustainable development. Here, we present a hydrophobic force-driven assembly strategy to construct crack-free colloidal photonic crystals (CPCs) for colored passive daytime cooling (PDC) textiles. Monodispersed poly(styrene-hydroxypropyl acrylate-hexafluorobutyl methacrylate) (P(St-HPA-HFBMA)) colloidal particles with low surface energy (9 mN/m) and high monodispersity (PDI < 0.05) are synthesized via soap-free emulsion polymerization. The hexafluorobutyl terminal groups (C₃F₆) enable robust hydrophobicity (water contact angle: 124°), facilitating crack-free CPC assembly through hydrophobic driving force. By integrating the CPCs with SiO₂ aerogel-embedded polyethylene oxide (PEO/SiO₂ aerogel) fiber scaffold based on microfluidic spinning technology, a colored hybrid composite film is fabricated, achieving 0.76 solar reflectance and 0.84 thermal emissivity in the atmospheric window (8-13 μm). Outdoor evaluations demonstrate a sub-ambient cooling temperature of 4.1 °C under 732 W/m² solar intensity, reaching the desirable level of PDC materials. The hybrid composite film also exhibits angle-independent structural colors, mechanical robustness (tensile strength: 1.86 MPa), and scalable manufacturability. This work provides a paradigm for multifunctional PDC systems combining aesthetic versatility with sustainable cooling performance.

开发具有高性能热管理和美观双重功能的被动冷却材料仍然是可持续发展的关键挑战。在这里，我们提出了一种疏水力驱动的组装策略，以构建用于彩色被动日间冷却（PDC）纺织品的无裂纹胶体光子晶体（cpc）。采用无皂乳液聚合法制备了低表面能（9 mN/m）、高单分散性（PDI < 0.05）的单分散聚（苯乙烯-丙烯酸羟丙基-甲基丙烯酸六氟丁酯）(P（St-HPA-HFBMA）胶体颗粒。六氟丁基末端基团（C3F6）具有强大的疏水性（水接触角：124°），通过疏水驱动力促进无裂纹CPC组装。基于微流控纺丝技术，将聚苯乙烯与SiO2气凝胶包埋聚乙烯氧化物（PEO/SiO2气凝胶）纤维支架相结合，制备了彩色杂化复合膜，在大气窗口（8 ~ 13 μm）内太阳反射率为0.76，热发射率为0.84。室外评估表明，在732 W/m²太阳强度下，亚环境冷却温度为4.1°C，达到了PDC材料的理想水平。混合复合薄膜还具有与角度无关的结构颜色、机械坚固性（抗拉强度：1.86 MPa）和可扩展制造性。这项工作为多功能PDC系统提供了一个范例，将美观的多功能性与可持续的冷却性能相结合。

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引用次数: 0

Ion-cluster-optimized microphase separation in shape-memory polydisulfides for enhanced mechanical performance 形状记忆聚二硫化物中离子簇优化微相分离增强机械性能

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-12 DOI: 10.1016/j.cclet.2025.111946

Chengyuan Yu , Huiyao Lin , Le Li , Ruirui Gu , Qi Zhang , Chenyu Shi , Chenchen Zhang , Fei Tong

Developing advanced polymeric materials with enhanced mechanical properties and functionalities has been a long-standing goal in materials science. Recently, supramolecular polymeric materials (SPMs) have drawn increased attention due to their unique properties and potential applications in self-healing, shape memory, sensors, and flexible electronics. Here, we develop an ionic cluster-optimized microphase separation strategy to enhance the toughening and energy dissipation capabilities of polydisulfide-based supramolecular polymers. The mechanical properties, including Young's modulus and toughness, are significantly improved by integrating the quadruple H-bonding 2-ureido-4-pyrimidone (UPy) induced microphase separation with iron(III)-to-carboxylate ionic clusters. By combining established chemical approaches with adjustable polymer phase ratios, it is revealed that the synergistic effect of these factors expands the interchain spacing, facilitates the formation of microphase domains, and enhances the tolerance of polythioctic acid-based polymers to external mechanical and thermal stimuli, meeting the practical requirements for industrial plastic applications. Moreover, the UPy-functionalized polymers incorporating iron carboxylate clusters exhibit good one-way shape memory behavior with practical applicability at a relatively low recovery temperature. Our work demonstrates a novel strategy for constructing industrially viable shape memory dynamic SPMs and paves the way for future innovations in developing SPMs.

开发具有增强机械性能和功能的先进聚合物材料一直是材料科学的长期目标。近年来，超分子高分子材料（SPMs）因其独特的性能和在自修复、形状记忆、传感器和柔性电子等领域的潜在应用而受到越来越多的关注。在这里，我们开发了一种离子簇优化的微相分离策略，以增强聚二硫基超分子聚合物的增韧和能量耗散能力。通过与铁(III)-羧酸离子团簇整合四氢键2-脲-4-嘧啶（UPy）诱导的微相分离，显著提高了材料的杨氏模量和韧性等力学性能。通过将已建立的化学方法与可调节的聚合物相比相结合，揭示了这些因素的协同效应扩大了链间间距，促进了微相域的形成，增强了聚硫辛酸基聚合物对外部机械和热刺激的耐受性，满足了工业塑料应用的实际要求。此外，含有羧酸铁簇的upy功能化聚合物具有良好的单向形状记忆行为，在相对较低的恢复温度下具有实际适用性。我们的工作展示了构建工业上可行的形状记忆动态spm的新策略，并为未来发展spm的创新铺平了道路。

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引用次数: 0

Polymer modification effects in nanocarrier-loaded dissolving microneedles: Implications for transdermal drug delivery 载纳米载体溶解微针中的聚合物修饰效应：对经皮给药的影响

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-11 DOI: 10.1016/j.cclet.2025.111944

Yuhuan Wu , Hoiian Ieong , Wenhao Wang , Chuanbin Wu , Anqi Lu , Xin Pan , Zhengwei Huang

Polymer surface modification constitutes a pivotal strategy for enhancing the efficacy of nanomedicine delivery, where intentional modifications (e.g., PEGylation, hyaluronic acid coating) are designed to optimize nanocarrier performance. However, conventional approaches remain constrained by the impermeable stratum corneum in transdermal applications. Dissolving microneedles (DMNs) circumvent this barrier by creating transient microchannels, thereby offering an innovative route for cutaneous nanocarriers administration. Nevertheless, the DMN polymeric matrix may unintentionally alter the physicochemical attributes of loaded nanocarriers via non-covalent interactions, giving rise to a distinct “polymer modification effect” (PME) that differs from purposeful surface engineering. Such unintended interfacial phenomena can modulate nanocarrier characteristics and, consequently, dictate their in vivo fate, including release kinetics, biodistribution, clearance, cellular uptake, and other interactions with the biological system. Herein, we review documented cases of DMN polymer-nanocarrier modifications, elucidate the underlying mechanisms and implications of PME, and propose rational strategies for its precise regulation. This conceptual framework is expected to guide the rational design of next-generation nanocarrier-loaded DMN delivery systems.

聚合物表面修饰是提高纳米药物递送效率的关键策略，其中有意修饰（例如聚乙二醇化，透明质酸涂层）旨在优化纳米载体的性能。然而，在透皮应用中，传统的方法仍然受到不渗透角质层的限制。溶解微针（DMNs）通过创建瞬时微通道绕过这一屏障，从而为皮肤纳米载体的给药提供了一种创新途径。然而，DMN聚合物基质可能会通过非共价相互作用无意中改变负载纳米载体的物理化学属性，从而产生不同于有目的的表面工程的独特的“聚合物修饰效应”（PME）。这种意想不到的界面现象可以调节纳米载体的特性，从而决定它们在体内的命运，包括释放动力学、生物分布、清除、细胞摄取以及与生物系统的其他相互作用。在此，我们回顾了DMN聚合物-纳米载体修饰的文献案例，阐明了PME的潜在机制和意义，并提出了精确调控的合理策略。这一概念框架有望指导下一代纳米载流子DMN递送系统的合理设计。

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引用次数: 0

Batch and continuous-flow asymmetric synthesis of d-pantothenic acid precursor enabled by immobilized ketoreductase mutant 固定化酮还原酶突变体批量连续不对称合成d-泛酸前体

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-11 DOI: 10.1016/j.cclet.2025.111945

Pan Hu , Xiaofan Wu , Yi An , Xianjing Zheng , Liang Gao , Yuan Tao , Yajiao Zhang , Zedu Huang , Fener Chen

We report an immobilized enzyme-catalyzed batch and continuous-flow synthesis of optically pure ethyl (R)-pantothenate ((R)-PaOEt), the direct precursor of d-pantothenic acid. Firstly, a ketoreductase mutant designated as M2, carrying two-point mutations of F97L and M242F relative to the wild-type SSCR, was constructed by site-directed mutagenesis, exhibited simultaneously improved activity toward ethyl 2′-ketopantothenate (K-PaOEt) and isopropanol, and could effectively catalyze the stereoselective reduction of K-PaOEt to (R)-PaOEt by using isopropanol as the sacrificial co-substrate to regenerate NADPH. After screening six commercially available carriers, an amino resin LXTE-700 was identified as the best solid support for the immobilization of M2 via the glutaraldehyde activation method. Upon optimization of the immobilization process and reaction conditions, the fabricated immobilized enzyme M2@amino resin demonstrated excellent recyclability and reusability, with the complete conversion of K-PaOEt to (R)-PaOEt being still realized after 12 cycles of reuse. Finally, M2@amino resin-catalyzed synthesis of (R)-PaOEt was successfully implemented in continuous-flow, accomplishing a 6.3 times higher space-time yield than that with the batch synthesis (529.2 versus 84 g L^-1 d^-1). Our developed flow biocatalysis system also features an outstanding operational stability, as evidenced by the 100 % conversion rate achieved after 15 consecutive days of operation.

我们报道了固定化酶催化分批和连续流合成光纯乙基(R)-泛酸酯（(R)-PaOEt）， d-泛酸的直接前体。首先，通过定点诱变构建了一个携带F97L和M242F位点突变的酮还原酶突变体M2，该突变体对2′-酮酸乙酯（K-PaOEt）和异丙醇的活性同时提高，并能通过异丙醇作为牺牲共底物再生NADPH，有效地催化K-PaOEt立体选择性还原为(R)-PaOEt。在筛选了6种市售载体后，通过戊二醛活化法确定了LXTE-700为固定M2的最佳固体载体。通过对固定化工艺和反应条件的优化，制备的固定化酶M2@amino树脂具有良好的可回收性和可重复使用性，在重复使用12次后仍可实现K-PaOEt完全转化为(R)-PaOEt。最终，M2@amino树脂催化合成(R)-PaOEt在连续流中成功实现，实现了比间歇合成高6.3倍的时空产率（529.2 vs 84 g L-1 d-1）。我们开发的流动生物催化系统还具有出色的运行稳定性，连续15天运行后转化率达到100% %。

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引用次数: 0

Discovery of pyrethalkalines A and B as potent analgesics with unprecedented chemical skeletons dual targeting TRPM8 and Kv1.2 ion channels 发现邻苯二甲酸A和B作为强效镇痛药，具有前所未有的化学骨架双重靶向TRPM8和Kv1.2离子通道

IF 8.9 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Chinese Chemical Letters

Pub Date : 2025-10-10 DOI: 10.1016/j.cclet.2025.111938

Hui Chen , Xieraili Tuerxun , Amina Abula , Yenan Sun , Hanqi Zhang , Guangmin Yao , Haji Akber Aisa

Two pairs of potent analgesic alkaloid enantiomers with unprecedented chemical architectures, named pyrethalkalines A (1) and B (2), were isolated from the roots of Anacyclus pyrethrum. Pyrethalkaline A (1) is an unprecedented 6/6/6/6/5-fused pentacyclic triamino alkaloid featuring a unique 8,15-diaza-pentacyclo[12.3.1.1^1,9.0^5,19.0^10,14]nonadecane core, and pyrethalkaline B (2) is a novel 6/6/6/6/5/6-fused hexacyclic triamino alkaloid possessing an unprecedented 8,13,19-triazahexacyclo[16.3.1.1^1,9.0^5,23.0^10,18.0^11,16]tricosane motif. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum ¹³C nuclear magnetic resonance (NMR) DP4+ and electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis, and their plausible biosynthetic pathways were proposed. Alkaloids (±)-1 and (−)-1 at three lower doses of 1, 0.2, and 0.04 mg/kg, and (+)-2 at two lower doses of 1 and 0.2 mg/kg showed more potent analgesic activity than the positive control morphine. Further investigation revealed that (+)-1 and (−)-1 are dual transient receptor potential melastatin 8 (TRPM8) (half-maximal inhibitory concentration (IC₅₀) = 1.90 ± 0.09 and 1.40 ± 0.17 µmol/L, respectively) and Kv1.2 inhibitors. Molecular dockings of 1 provide a novel structural model to develop potent analgesics dual targeting TRPM8 and Kv1.2 ion channels, and (±)-1 have the potential for the development of a non-opioid potent analgesic to treat neurogenic pains.

从拟除虫菊根中分离出两对化学结构前所未有的强效镇痛生物碱对映体，分别命名为pyrethalkalines A(1)和B(2)。邻苯二甲酸乙酯A(1)是一种史无前例的6/6/6/6/5融合的五环三氨基生物碱，具有独特的8,15-二氮杂-五环[12.3.1.11,9.05,19.010,14]壬烷核心；邻苯二甲酸乙酯B(2)是一种新颖的6/6/6/6/5- 6融合的六环三氨基生物碱，具有前所未有的8,13,19-三氮杂-五环[16.3.1.11,9.05,23.010,18.011,16]三烷基序。通过综合光谱数据分析、量子13C核磁共振（NMR） DP4+和电子圆二色性（ECD）计算以及单晶x射线衍射分析对其结构进行了解析，并提出了可能的生物合成途径。生物碱（±）-1和(−)-1在1、0.2和0.04 mg/kg三个较低剂量下，(+)-2在1和0.2 mg/kg两个较低剂量下表现出比阳性对照吗啡更强的镇痛活性。进一步研究发现(+)-1和(−)-1是双瞬时受体电位美拉他汀8 (TRPM8)（半最大抑制浓度（IC50） = 分别为1.90±0.09和1.40±0.17 µmol/L）和Kv1.2抑制剂。1的分子对接为开发双靶向TRPM8和Kv1.2离子通道的强效镇痛药提供了一种新的结构模型，（±）-1具有开发非阿片类强效镇痛药治疗神经源性疼痛的潜力。

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