JACS Au最新文献

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Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Photoexcited Palladium Catalysis 通过光激发钯催化三氟甲基烯的去氟多组分级联反应
IF 8.5
JACS Au Pub Date : 2024-11-06 DOI: 10.1021/jacsau.4c0089910.1021/jacsau.4c00899
Zhibin Li, Lei Bao, Kaihang Wei, Beibei Zhan, Ping Lu and Xiaheng Zhang*, 
{"title":"Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Photoexcited Palladium Catalysis","authors":"Zhibin Li,&nbsp;Lei Bao,&nbsp;Kaihang Wei,&nbsp;Beibei Zhan,&nbsp;Ping Lu and Xiaheng Zhang*,&nbsp;","doi":"10.1021/jacsau.4c0089910.1021/jacsau.4c00899","DOIUrl":"https://doi.org/10.1021/jacsau.4c00899https://doi.org/10.1021/jacsau.4c00899","url":null,"abstract":"<p >The incorporation of aromatic difluoromethyl motifs has proven to be a fruitful strategy for enhancing the therapeutic profiles of modern pharmaceutical candidates. While the defluorofunctionalization of trifluoromethylarenes offers a promising pathway toward diverse aromatic difluoromethyl compounds, current methods are predominantly limited to two-component reactions. Multicomponent cascade reactions (MCRs) involving a transient aromatic difluoromethyl radical are still uncommon and highly sought after, owing to their capacity to rapidly generate challenging molecular structures. In this study, we present a photocatalytic manifold that combines commercially available trifluoromethylarenes, feedstock dienes, and various nucleophiles to achieve a modular defluorinative MCR. This method features mild reaction conditions and a broad substrate scope with excellent functional group compatibility. Furthermore, this protocol enables a previously unreported process of defluorinative editing for the resulting MCR aromatic difluoromethyl adducts. Preliminary mechanistic studies support the proposed photoexcited palladium catalytic cycle.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4223–4233 4223–4233"},"PeriodicalIF":8.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00899","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Iridium-Catalyzed Enantioselective Vinylogous and Bisvinylogous Allenylic Substitution 铱催化的对映选择性乙烯基和双乙烯基烯丙基取代反应
IF 8.5
JACS Au Pub Date : 2024-11-05 DOI: 10.1021/jacsau.4c0064010.1021/jacsau.4c00640
Sankash Mitra,  and , Santanu Mukherjee*, 
{"title":"Iridium-Catalyzed Enantioselective Vinylogous and Bisvinylogous Allenylic Substitution","authors":"Sankash Mitra,&nbsp; and ,&nbsp;Santanu Mukherjee*,&nbsp;","doi":"10.1021/jacsau.4c0064010.1021/jacsau.4c00640","DOIUrl":"https://doi.org/10.1021/jacsau.4c00640https://doi.org/10.1021/jacsau.4c00640","url":null,"abstract":"<p >Compared to the widely explored enol silanes, the applicability of their extended variants especially as bisvinylogous nucleophiles in enantioselective catalysis has been sparse. Herein, we describe the first enantioselective vinylogous and bisvinylogous allenylic substitution using silyl dienol and trienol ethers, respectively, as a nucleophile. With racemic allenylic alcohols as the electrophile, these enantioconvergent reactions are cooperatively catalyzed by an Ir(I)/(phosphoramidite,olefin) complex and Lewis acidic La(OTf)<sub>3</sub> and display remarkable regio- and diastereoselectivity in most cases. The ability of such extended silyl enol ethers in distant functionalization and creation of remote stereocenters is evident from the resulting γ- and ε-allenylic unsaturated ketones, bearing δ- and ζ-stereocenters, respectively, which are obtained in moderate to high yields with good to excellent enantioselectivity. The synthetic utility of these unsaturated carbonyls bearing an allene moiety is demonstrated with several transformations, including controlled reductions and stereoselective olefinations, which lead to products with desired degrees of unsaturation.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4285–4294 4285–4294"},"PeriodicalIF":8.5,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00640","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Controllable Enzymatic Synthesis of Natural Asymmetric Human Milk Oligosaccharides 天然不对称人乳低聚糖的可控酶法合成
IF 8.5
JACS Au Pub Date : 2024-11-02 DOI: 10.1021/jacsau.4c0083010.1021/jacsau.4c00830
Hsien-Wei Tseng, Hsin-Kai Tseng, Kai-Eng Ooi, Cheng-En You, Hung-Kai Wang, Wen-Hua Kuo, Chi-Kung Ni, Yoshiyuki Manabe and Chun-Cheng Lin*, 
{"title":"Controllable Enzymatic Synthesis of Natural Asymmetric Human Milk Oligosaccharides","authors":"Hsien-Wei Tseng,&nbsp;Hsin-Kai Tseng,&nbsp;Kai-Eng Ooi,&nbsp;Cheng-En You,&nbsp;Hung-Kai Wang,&nbsp;Wen-Hua Kuo,&nbsp;Chi-Kung Ni,&nbsp;Yoshiyuki Manabe and Chun-Cheng Lin*,&nbsp;","doi":"10.1021/jacsau.4c0083010.1021/jacsau.4c00830","DOIUrl":"https://doi.org/10.1021/jacsau.4c00830https://doi.org/10.1021/jacsau.4c00830","url":null,"abstract":"<p >Among human milk oligosaccharides (HMOs), linear HMOs are synthesized through mature but varied routes. Although branched HMOs can be synthesized by chemical, enzymatic, or chemoenzymatic methods, these methods cannot be easily applied to the synthesis of asymmetric multiantennary oligosaccharides. Herein, we developed a controllable method to synthesize asymmetric biantennary HMOs. In our synthetic route, GlcNAcβ1,3(GlcN3β1,6)Glaβ1,4Glc was first chemically synthesized as the core tetrasaccharide, which contains β1,6GlcN3 as the “stop” sugar in transferase-catalyzed glycosylation. The desired sugars at the GlcNAcβ1–3Gal arm can be assembled using galactosyltransferase, <i>N</i>-acetylglucosaminyltransferase, and fucosyltransferase. Then, the Staudinger reduction and acetylation were used to transform GlcN3 to GlcNAc and assemble sugars by initiating the “go” process. By manipulating transferase-catalyzed glycosylations, 22 natural asymmetric biantennary oligosaccharides were synthesized.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4496–4506 4496–4506"},"PeriodicalIF":8.5,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00830","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Precise Regulations at the Subcellular Level through Intracellular Polymerization, Assembly, and Transformation 通过胞内聚合、组装和转化实现亚细胞水平的精确调节
IF 8.5
JACS Au Pub Date : 2024-11-01 DOI: 10.1021/jacsau.4c0084910.1021/jacsau.4c00849
Le He, Fanying Meng, Ran Chen, Jinlong Qin, Min Sun*, Zhen Fan* and Jianzhong Du*, 
{"title":"Precise Regulations at the Subcellular Level through Intracellular Polymerization, Assembly, and Transformation","authors":"Le He,&nbsp;Fanying Meng,&nbsp;Ran Chen,&nbsp;Jinlong Qin,&nbsp;Min Sun*,&nbsp;Zhen Fan* and Jianzhong Du*,&nbsp;","doi":"10.1021/jacsau.4c0084910.1021/jacsau.4c00849","DOIUrl":"https://doi.org/10.1021/jacsau.4c00849https://doi.org/10.1021/jacsau.4c00849","url":null,"abstract":"<p >A living cell is an intricate machine that creates subregions to operate cell functions effectively. Subcellular dysfunction has been identified as a potential druggable target for successful drug design and therapy. The treatments based on intracellular polymerization, self-assembly, or transformation offer various advantages, including enhanced blood circulation of monomers, long-term drug delivery pharmacokinetics, low drug resistance, and the ability to target deep tissues and organelles. In this review, we discuss the latest developments of intracellular synthesis applied to precisely control cellular functions. First, we discuss the design and applications of endogenous and exogenous stimuli-triggered intracellular polymerization, self-assembly, and dynamic morphology transformation of biomolecules at the subcellular level. Second, we highlight the benefits of these strategies applied in cancer diagnosis and treatment and modulating cellular states or cell metabolism of living systems. Finally, we conclude the recent progress in this field, discuss future perspectives, analyze the challenges of the intracellular functional reactions for regulation, and find future opportunities.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4162–4186 4162–4186"},"PeriodicalIF":8.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00849","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Water-Microdroplet-Driven Interface-Charged Chemistries 水微滴驱动的界面充注化学工艺
IF 8.5
JACS Au Pub Date : 2024-10-31 DOI: 10.1021/jacsau.4c0080410.1021/jacsau.4c00804
Xiuquan Jia, Jianhan Wu and Feng Wang*, 
{"title":"Water-Microdroplet-Driven Interface-Charged Chemistries","authors":"Xiuquan Jia,&nbsp;Jianhan Wu and Feng Wang*,&nbsp;","doi":"10.1021/jacsau.4c0080410.1021/jacsau.4c00804","DOIUrl":"https://doi.org/10.1021/jacsau.4c00804https://doi.org/10.1021/jacsau.4c00804","url":null,"abstract":"<p >Water has made Earth a habitable planet by electrifying the troposphere. For example, the lightning caused by the electrification and discharge of cloudwater microdroplets is closely related to atmospheric chemistry. Recent work has revealed that a high electric field exists at the interface of water microdroplets, which is ∼3 orders of magnitude higher than the electric field that accounts for lightning. A surge of exotic redox reactions that were recently found over water microdroplets can be contributed by such an interfacial electric field. However, the role of net charge in microdroplet redox chemistry should not be ignored. In this Perspective, we show how redox reactions can be driven by electron transfer pathways in the electrification and discharge process of water microdroplets. Understanding and harnessing the origin and evolution of charged microdroplets are likely to lead to a paradigm shift of electrochemistry, which may play an overlooked role in geological and environmental chemistry.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4141–4147 4141–4147"},"PeriodicalIF":8.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00804","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Slow-Binding and Covalent HDAC Inhibition: A New Paradigm? 慢结合和共价 HDAC 抑制:新范例?
IF 8.5
JACS Au Pub Date : 2024-10-31 DOI: 10.1021/jacsau.4c0082810.1021/jacsau.4c00828
Yasir S. Raouf*,  and , Carlos Moreno-Yruela*, 
{"title":"Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?","authors":"Yasir S. Raouf*,&nbsp; and ,&nbsp;Carlos Moreno-Yruela*,&nbsp;","doi":"10.1021/jacsau.4c0082810.1021/jacsau.4c00828","DOIUrl":"https://doi.org/10.1021/jacsau.4c00828https://doi.org/10.1021/jacsau.4c00828","url":null,"abstract":"<p >The dysregulated post-translational modification of proteins is an established hallmark of human disease. Through Zn<sup>2+</sup>-dependent hydrolysis of acyl-lysine modifications, histone deacetylases (HDACs) are key regulators of disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting of this family of 11 enzymes (HDAC1–11) afforded a first generation of broadly acting inhibitors with medicinal applications in oncology, specifically in cutaneous and peripheral T-cell lymphomas and in multiple myeloma. However, first-generation HDAC inhibitors are often associated with weak-to-modest patient benefits, dose-limited efficacies, pharmacokinetic liabilities, and recurring clinical toxicities. Alternative inhibitor design to target single enzymes and avoid toxic Zn<sup>2+</sup>-binding moieties have not overcome these limitations. Instead, recent literature has seen a shift toward noncanonical mechanistic approaches focused on slow-binding and covalent inhibition. Such compounds hold the potential of improving the pharmacokinetic and pharmacodynamic profiles of HDAC inhibitors through the extension of the drug–target residence time. This perspective aims to capture this emerging paradigm and discuss its potential to improve the preclinical/clinical outlook of HDAC inhibitors in the coming years.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4148–4161 4148–4161"},"PeriodicalIF":8.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00828","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Kinetic and Mechanistic Studies of Native Chemical Ligation with Phenyl α-Selenoester Peptides 与苯基 α-硒酯肽原生化学连接的动力学和机理研究
IF 8.5
JACS Au Pub Date : 2024-10-30 DOI: 10.1021/jacsau.4c0070510.1021/jacsau.4c00705
Iván Sánchez-Campillo,  and , Juan B. Blanco-Canosa*, 
{"title":"Kinetic and Mechanistic Studies of Native Chemical Ligation with Phenyl α-Selenoester Peptides","authors":"Iván Sánchez-Campillo,&nbsp; and ,&nbsp;Juan B. Blanco-Canosa*,&nbsp;","doi":"10.1021/jacsau.4c0070510.1021/jacsau.4c00705","DOIUrl":"https://doi.org/10.1021/jacsau.4c00705https://doi.org/10.1021/jacsau.4c00705","url":null,"abstract":"<p >Native chemical ligation (NCL) ligates two unprotected peptides in an aqueous buffer. One of the fragments features a C-terminal α-thioester functional group, and the second bears an N-terminal cysteine. The reaction mechanism depicts two steps: an intermolecular thiol–thioester exchange resulting in a transient thioester, followed by an intramolecular <i>S-to-N</i> acyl shift to yield the final native peptide bond. Although this mechanism is well established, the direct observation of the transient thioester has been elusive because the fast intramolecular rearrangement prevents its accumulation. Here, the use of α-selenoester peptides allows a faster first reaction and an early buildup of the intermediate, enabling its quantification and the kinetic monitoring of the first and second steps. The results show a correlation between the steric hindrance in the α-thioester residue and the rearrangement rate. In bulky residues, the <i>S-to-N</i> acyl shift has a significant contribution to the overall reaction rate. This is particularly notable for valine and likely for other similar β-branched amino acids.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4374–4382 4374–4382"},"PeriodicalIF":8.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00705","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
eCyanation Using 5-Aminotetrazole As a Safer Electrophilic and Nucleophilic Cyanide Source 使用 5-氨基四氮唑作为更安全的亲电和亲核氰化源的电子氰化法
IF 8.5
JACS Au Pub Date : 2024-10-30 DOI: 10.1021/jacsau.4c0076810.1021/jacsau.4c00768
Valerio Morlacci, Marco Milia, Jérémy Saiter, Irene Preet Bhela, Matthew C. Leech and Kevin Lam*, 
{"title":"eCyanation Using 5-Aminotetrazole As a Safer Electrophilic and Nucleophilic Cyanide Source","authors":"Valerio Morlacci,&nbsp;Marco Milia,&nbsp;Jérémy Saiter,&nbsp;Irene Preet Bhela,&nbsp;Matthew C. Leech and Kevin Lam*,&nbsp;","doi":"10.1021/jacsau.4c0076810.1021/jacsau.4c00768","DOIUrl":"https://doi.org/10.1021/jacsau.4c00768https://doi.org/10.1021/jacsau.4c00768","url":null,"abstract":"<p >An electrochemical method for carrying out safer cyanation reactions is reported. The use of 5-aminotetrazole as a cyanide source enabled the successful electrogeneration of both electrophilic and nucleophilic cyanide sources. To demonstrate the versatility of the method, a variety of cyanation reactions were carried out, including the synthesis of cyanamides, <i>N</i>-heterocycles, and aromatic nitriles, as well as the nucleophilic addition of cyanides to a variety of electrophiles without the need to handle highly toxic cyanide salts. Finally, as a proof of concept for scalability, the cyanation methodology was rapidly transferred to a flow electrosynthesis setup, which demonstrated its potential for large-scale applications.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4199–4205 4199–4205"},"PeriodicalIF":8.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integration of Single Atoms for Tandem Catalysis 整合单原子实现串联催化
IF 8.5
JACS Au Pub Date : 2024-10-30 DOI: 10.1021/jacsau.4c0078410.1021/jacsau.4c00784
Cun Liu, Botao Qiao* and Tao Zhang*, 
{"title":"Integration of Single Atoms for Tandem Catalysis","authors":"Cun Liu,&nbsp;Botao Qiao* and Tao Zhang*,&nbsp;","doi":"10.1021/jacsau.4c0078410.1021/jacsau.4c00784","DOIUrl":"https://doi.org/10.1021/jacsau.4c00784https://doi.org/10.1021/jacsau.4c00784","url":null,"abstract":"<p >Tandem catalysis represents an efficient pathway which greatly saves the overall facilities and energy inputs. The intermediates are transported from one active site to the other site more efficiently due to the ease of mass transfer in one reactor system. However, sometimes the indiscriminative usage of this concept can be misleading, and thereby, this Perspective first aims for differentiating “tandem catalysis” from liable-to-muddling concepts, such as “synergy” and “domino/cascade catalysis.” The prerequisites for figuring out tandem catalysis mainly lie in (1) the two or more independent catalytic cycles involved in one system, where the products of one reaction cycle can be immediately relayed to a subsequent reaction cycle as the reactants, and (2) these cycles occurring in different catalytic mechanisms. As a frontier in heterogeneous catalysis, single-atom catalysts possess the unique property of high selectivity toward transformation of specific chemical bonds and can also bridge the homo- and heterogeneous catalysis. However, despite their wide range of applications, single-atom catalysts (SACs) are not solutions to all catalytic processes, particularly those reactions requiring active sites containing multiatoms in their proximity. To this end, the strategy of combining SACs within tandem processes is a feasible way to broaden the scope of chemical reactions achievable over SACs. Therein, according to the category of the participating active species, four subsections are thoroughly introduced, including tandem catalysis over the integration of (1) different/identical single atom(s), (2) single atoms and nanoparticles, and (3) single atoms and the adjacent support. Nonetheless, with regard to the investigation of the involved single-atom catalysts, some issues still remain regarding the exact characterization and explicit comparison of catalytic performance with that over their nanoparticle counterparts. Moreover, some intriguing subjects are still waiting to be systematically explored to broaden and deepen single-atom-integrated tandem processes in the branch of catalytic science.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4129–4140 4129–4140"},"PeriodicalIF":8.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00784","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling 烟酰胺核苷和 CD38:共价抑制和活细胞标记
IF 8.5
JACS Au Pub Date : 2024-10-30 DOI: 10.1021/jacsau.4c0069510.1021/jacsau.4c00695
Guoyun Kao, Xiao-Nan Zhang, Fariborz Nasertorabi, Benjamin B. Katz, Zeyang Li, Zhefu Dai, Zeyu Zhang, Lei Zhang, Stan G. Louie, Vadim Cherezov and Yong Zhang*, 
{"title":"Nicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling","authors":"Guoyun Kao,&nbsp;Xiao-Nan Zhang,&nbsp;Fariborz Nasertorabi,&nbsp;Benjamin B. Katz,&nbsp;Zeyang Li,&nbsp;Zhefu Dai,&nbsp;Zeyu Zhang,&nbsp;Lei Zhang,&nbsp;Stan G. Louie,&nbsp;Vadim Cherezov and Yong Zhang*,&nbsp;","doi":"10.1021/jacsau.4c0069510.1021/jacsau.4c00695","DOIUrl":"https://doi.org/10.1021/jacsau.4c00695https://doi.org/10.1021/jacsau.4c00695","url":null,"abstract":"<p >Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is required for a myriad of metabolic, signaling, and post-translational events in cells. Its levels in tissues and organs are closely associated with health conditions. The homeostasis of NAD<sup>+</sup> is regulated by biosynthetic pathways and consuming enzymes. As a membrane-bound protein with robust NAD<sup>+</sup> hydrolase activity, cluster of differentiation 38 (CD38) is a major degrader of NAD<sup>+</sup>. Deficiency or inhibition of CD38 enhances NAD<sup>+</sup> levels in vivo, resulting in various therapeutic benefits. As a metabolic precursor of NAD<sup>+</sup>, nicotinamide mononucleotide can be rapidly hydrolyzed by CD38, whereas nicotinamide riboside (NR) lacks CD38 substrate activity. Given their structural similarities, we explored the inhibition potential of NR. To our surprise, NR exhibits marked inhibitory activity against CD38 by forming a stable ribosyl–ester bond with the glutamate residue 226 at the active site. Inspired by this discovery, we designed and synthesized a clickable NR featuring an azido substitution at the 5′-OH position. This cell-permeable NR analogue enables covalent labeling and imaging of both extracellular and intracellular CD38 in live cells. Our work discovers an unrecognized molecular function of NR and generates a covalent probe for health-related CD38. These findings offer new insights into the role of NR in modulating NAD<sup>+</sup> metabolism and CD38-mediated signaling as well as an innovative tool for in-depth studies of CD38 in physiology and pathophysiology.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"4 11","pages":"4345–4360 4345–4360"},"PeriodicalIF":8.5,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00695","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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