{"title":"The Influence of Interlocking Effects in Conjugated Polymers Synthesized by Aldol Polycondensation on Field-Effect Transistor Properties and Morphology.","authors":"Yen-Han Shih, Guan-Lin Wu, Pin-Hsiang Chueh, Jing-Chun Chen, Chu-Yen Tsai, Ting-Yu Wang, Ming-Hsuan Yu, Yi-Pei Li, Wen-Chang Chen, Chu-Chen Chueh","doi":"10.1021/jacsau.5c00003","DOIUrl":"10.1021/jacsau.5c00003","url":null,"abstract":"<p><p>The environmental and economic drawbacks of traditional palladium-catalyzed coupling reactions in the synthesis of conjugated polymers have prompted the exploration of green alternatives. This study presents the synthesis and characterization of a series of ladder-type conjugated polymers via aldol and Knoevenagel condensation reactions, which use simple acid or base catalysts and produce only water as a byproduct. We explore the interlocking effect of the backbone and study its role in enhancing the backbone planarity, charge transport, and morphology. Intramolecular hydrogen bonding in polymers <b>P1</b> and <b>P5</b> promotes strong interlocking interactions, resulting in high electron mobilities (2.09 × 10<sup>-2</sup> cm<sup>2</sup> V<sup>-1</sup> s<sup>-1</sup> and 8.26 × 10<sup>-2</sup> cm<sup>2</sup> V<sup>-1</sup> s<sup>-1</sup>, respectively) and crystalline order. In contrast, their random copolymers (<b>P2-P4</b>) exhibited disrupted interlocking effects, leading to irregular backbone distortions and reduced charge transport. <b>P6</b>, designed with a rigid ladder-type backbone and bulky side chains, exhibits an exceptional hole mobility (3.27 × 10<sup>-1</sup> s cm<sup>2</sup> V<sup>-1</sup> s<sup>-1</sup>) despite an amorphous morphology, which is attributed to efficient intrachain transport. These findings demonstrate the potential of the green condensation approach in developing conjugated polymers with high charge transport properties and different morphologies through intramolecular interlocking effects.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1382-1391"},"PeriodicalIF":8.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733728","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}
JACS AuPub Date : 2025-02-27DOI: 10.1021/jacsau.4c0107110.1021/jacsau.4c01071
Jemin Jeon, Ching-Hsiu Chung, Shisang Roh, Evan Bergman, Miao Wang and Xiao Su*,
{"title":"Olefin-Assisted Electrochemical Recycling of Homogeneous Hydrosilylation Catalysts in Nonpolar Media","authors":"Jemin Jeon, Ching-Hsiu Chung, Shisang Roh, Evan Bergman, Miao Wang and Xiao Su*, ","doi":"10.1021/jacsau.4c0107110.1021/jacsau.4c01071","DOIUrl":"https://doi.org/10.1021/jacsau.4c01071https://doi.org/10.1021/jacsau.4c01071","url":null,"abstract":"<p >Homogeneous platinum catalysts for hydrosilylation are essential for the chemical industry and society, through the production of commodities such as functional silicones. However, the high boiling points of the products and the low concentration of the homogeneous catalysts make the implementation of traditional separation methods difficult. Catalyst loss becomes a core sustainability and techno-economic challenge. In addition, the highly active platinum-based catalysts for hydrosilylation have remarkable susceptibility to deactivation upon reaction completion. Recently, redox-mediated electrosorption has been successfully demonstrated in a number of electrically conductive media as a separation platform. However, industrial hydrosilylation systems are carried out in highly nonconductive media. Therefore, developing an electrochemical recycling system in realistic, nonconductive hydrosilylation media can be transformative for sustainable homogeneous catalysis and chemical manufacturing. Here, we overcome these challenges for hydrosilylation catalyst recycling by introducing a strongly coordinating vinyl ligand and enabling the recycling of these Pt catalysts in solvent-free, nonpolar reactant media through two distinct loops for catalyst recycling and electrosorbent regeneration. The coordinating olefin ligand maintains catalytic activity after the reaction and prevents particle aggregation, a primary mechanism for deactivation. The Pt catalyst stabilized by the coordinated ligand can be reversibly adsorbed and released by the electrosorbent, demonstrating 100% catalytic activity retention and over 90% Pt release efficiency. A techno-economic analysis supports the economic potential of the electrochemical recycling system, with cost savings of >5k USD/kg<sub>Pt</sub>. By combining chemical design and electrochemical engineering, we demonstrate the sustainable electrochemical recycling of industrially relevant hydrosilylation catalysts in practical nonconductive media.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1221–1231 1221–1231"},"PeriodicalIF":8.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c01071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675763","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}
{"title":"Olefin-Assisted Electrochemical Recycling of Homogeneous Hydrosilylation Catalysts in Nonpolar Media.","authors":"Jemin Jeon, Ching-Hsiu Chung, Shisang Roh, Evan Bergman, Miao Wang, Xiao Su","doi":"10.1021/jacsau.4c01071","DOIUrl":"10.1021/jacsau.4c01071","url":null,"abstract":"<p><p>Homogeneous platinum catalysts for hydrosilylation are essential for the chemical industry and society, through the production of commodities such as functional silicones. However, the high boiling points of the products and the low concentration of the homogeneous catalysts make the implementation of traditional separation methods difficult. Catalyst loss becomes a core sustainability and techno-economic challenge. In addition, the highly active platinum-based catalysts for hydrosilylation have remarkable susceptibility to deactivation upon reaction completion. Recently, redox-mediated electrosorption has been successfully demonstrated in a number of electrically conductive media as a separation platform. However, industrial hydrosilylation systems are carried out in highly nonconductive media. Therefore, developing an electrochemical recycling system in realistic, nonconductive hydrosilylation media can be transformative for sustainable homogeneous catalysis and chemical manufacturing. Here, we overcome these challenges for hydrosilylation catalyst recycling by introducing a strongly coordinating vinyl ligand and enabling the recycling of these Pt catalysts in solvent-free, nonpolar reactant media through two distinct loops for catalyst recycling and electrosorbent regeneration. The coordinating olefin ligand maintains catalytic activity after the reaction and prevents particle aggregation, a primary mechanism for deactivation. The Pt catalyst stabilized by the coordinated ligand can be reversibly adsorbed and released by the electrosorbent, demonstrating 100% catalytic activity retention and over 90% Pt release efficiency. A techno-economic analysis supports the economic potential of the electrochemical recycling system, with cost savings of >5k USD/kg<sub>Pt</sub>. By combining chemical design and electrochemical engineering, we demonstrate the sustainable electrochemical recycling of industrially relevant hydrosilylation catalysts in practical nonconductive media.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1221-1231"},"PeriodicalIF":8.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733815","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}
JACS AuPub Date : 2025-02-26DOI: 10.1021/jacsau.5c0004710.1021/jacsau.5c00047
Yujie Cao, Justin S. M. Perry, Eryun Zhang, Andy Trinh, Arnav Kacker, Shayne Cruz, Hannah Ceballos, Aaron Pan, Wendong Huang* and Kevin G. M. Kou*,
{"title":"Synthesis of Protoberberine Alkaloids by C–H Functionalization and Anionic Aza-6π-Electrocyclization: Dual Activity as AMPK Activators and Inhibitors","authors":"Yujie Cao, Justin S. M. Perry, Eryun Zhang, Andy Trinh, Arnav Kacker, Shayne Cruz, Hannah Ceballos, Aaron Pan, Wendong Huang* and Kevin G. M. Kou*, ","doi":"10.1021/jacsau.5c0004710.1021/jacsau.5c00047","DOIUrl":"https://doi.org/10.1021/jacsau.5c00047https://doi.org/10.1021/jacsau.5c00047","url":null,"abstract":"<p >5′-Adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in maintaining cellular energy homeostasis, and its activation has garnered attention for treating chronic metabolic diseases. Inhibitors of AMPK are underdeveloped but bear implications in treating cancers, controlling autophagy, and elderly wasting. Protoberberine alkaloids are typically regarded as AMPK activators. Herein, we report a modular synthesis strategy to access a collection of oxyberberine alkaloids, including the first synthesis of stepharotudine. In vitro assays reveal how subtle structural modifications can negate AMPK activation while conferring unprecedented inhibitory properties within the same class of compounds, which was previously unknown. Key steps in the synthesis include an oxidative Rh(III)-catalyzed C–H functionalization using electron-rich alkenes, NaH-mediated reductive <i>N</i>–O bond cleavage, and a rare example of an anionic aza-6π-electrocyclization. Additionally, we provide mechanistic support for nucleophilic hydride transfer reactivity with NaH in DMF.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1429–1438 1429–1438"},"PeriodicalIF":8.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675809","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}
JACS AuPub Date : 2025-02-26DOI: 10.1021/jacsau.5c0005610.1021/jacsau.5c00056
Jaime Martín, Johannes Schörgenhumer and Cristina Nevado*,
{"title":"Interrogating the anti-Insertion of Alkynes into Gold(III)","authors":"Jaime Martín, Johannes Schörgenhumer and Cristina Nevado*, ","doi":"10.1021/jacsau.5c0005610.1021/jacsau.5c00056","DOIUrl":"https://doi.org/10.1021/jacsau.5c00056https://doi.org/10.1021/jacsau.5c00056","url":null,"abstract":"<p >Alkyne hydrofunctionalizations are a powerful strategy to efficiently build up structural complexity. The selectivity of these reactions is typically governed by the interaction between the alkyne and a metal-hydride, which commonly proceeds via a well-understood <i>syn</i>-insertion mechanism. In contrast, <i>anti</i>-insertions are far less common, with proposed mechanisms often extrapolated from literature precedents rather than grounded in direct experimental evidence. While gold complexes rank among the most efficient catalysts for such transformations, the mechanistic understanding of the key alkyne insertion step remains incomplete. In this study, we demonstrate that stable gold(III)-hydrides, featuring a (P<sup>∧</sup>N<sup>∧</sup>C) ligand, undergo selective insertion of alkynes to yield the corresponding <i>anti</i>-Markovnikov <i>Z</i>-vinyl complexes. A combination of control experiments, kinetic studies, and computational analyses reveals a nonradical, bimolecular insertion process, in which water plays a pivotal role by accelerating the reaction and potentially stabilizing a highly reactive, T-shaped gold(I) intermediate. Notably, this is the first demonstration of the insertion of both activated and unactivated terminal and internal alkynes into a gold(III)-hydride complex.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1439–1447 1439–1447"},"PeriodicalIF":8.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675810","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}
JACS AuPub Date : 2025-02-26eCollection Date: 2025-03-24DOI: 10.1021/jacsau.4c01126
Kenneth R Koedinger, Mark Blaser, Elizabeth A McLaughlin, Hui Cheng, David J Yaron
{"title":"Mathematics Matters or Maybe Not: An Astonishing Independence between Mathematics and the Rate of Learning in General Chemistry.","authors":"Kenneth R Koedinger, Mark Blaser, Elizabeth A McLaughlin, Hui Cheng, David J Yaron","doi":"10.1021/jacsau.4c01126","DOIUrl":"10.1021/jacsau.4c01126","url":null,"abstract":"<p><p>Research spanning nearly a century has found that mathematics plays an important role in the learning of chemistry. Here, we use a large dataset of student interactions with online courseware to investigate the details of this link between mathematics and chemistry. The activities in the courseware are labeled against a list of knowledge components (KCs) covered by the content, and student interactions are tracked over a full semester of general chemistry at a range of institutions. Logistic regression is used to model student performance as a function of the number of opportunities a student has taken to engage with a particular KC. This regression analysis generates estimates of both the initial knowledge and the learning rate for each student and each KC. Consistent with results from other domains, the initial knowledge varies substantially across students, but the learning rate is nearly the same for all students. The role of mathematics is investigated by labeling each KC with the level of math involved. The overwhelming result from regressions based on these labels is that only the initial knowledge varies strongly across students and across the level of math involved in a particular topic. The student learning rate is nearly independent of both the level of math involved in a KC and the prior mathematical preparation of an individual student. The observation that the primary challenge for students lies in initial knowledge, rather than learning rate, may have implications for course and curriculum design.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1268-1278"},"PeriodicalIF":8.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733779","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}
JACS AuPub Date : 2025-02-26DOI: 10.1021/jacsau.4c0112610.1021/jacsau.4c01126
Kenneth R. Koedinger, Mark Blaser, Elizabeth A. McLaughlin, Hui Cheng and David J. Yaron*,
{"title":"Mathematics Matters or Maybe Not: An Astonishing Independence between Mathematics and the Rate of Learning in General Chemistry","authors":"Kenneth R. Koedinger, Mark Blaser, Elizabeth A. McLaughlin, Hui Cheng and David J. Yaron*, ","doi":"10.1021/jacsau.4c0112610.1021/jacsau.4c01126","DOIUrl":"https://doi.org/10.1021/jacsau.4c01126https://doi.org/10.1021/jacsau.4c01126","url":null,"abstract":"<p >Research spanning nearly a century has found that mathematics plays an important role in the learning of chemistry. Here, we use a large dataset of student interactions with online courseware to investigate the details of this link between mathematics and chemistry. The activities in the courseware are labeled against a list of knowledge components (KCs) covered by the content, and student interactions are tracked over a full semester of general chemistry at a range of institutions. Logistic regression is used to model student performance as a function of the number of opportunities a student has taken to engage with a particular KC. This regression analysis generates estimates of both the initial knowledge and the learning rate for each student and each KC. Consistent with results from other domains, the initial knowledge varies substantially across students, but the learning rate is nearly the same for all students. The role of mathematics is investigated by labeling each KC with the level of math involved. The overwhelming result from regressions based on these labels is that only the initial knowledge varies strongly across students and across the level of math involved in a particular topic. The student learning rate is nearly independent of both the level of math involved in a KC and the prior mathematical preparation of an individual student. The observation that the primary challenge for students lies in initial knowledge, rather than learning rate, may have implications for course and curriculum design.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1268–1278 1268–1278"},"PeriodicalIF":8.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c01126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675808","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}
JACS AuPub Date : 2025-02-26eCollection Date: 2025-03-24DOI: 10.1021/jacsau.5c00056
Jaime Martín, Johannes Schörgenhumer, Cristina Nevado
{"title":"Interrogating the <i>anti-</i>Insertion of Alkynes into Gold(III).","authors":"Jaime Martín, Johannes Schörgenhumer, Cristina Nevado","doi":"10.1021/jacsau.5c00056","DOIUrl":"10.1021/jacsau.5c00056","url":null,"abstract":"<p><p>Alkyne hydrofunctionalizations are a powerful strategy to efficiently build up structural complexity. The selectivity of these reactions is typically governed by the interaction between the alkyne and a metal-hydride, which commonly proceeds via a well-understood <i>syn</i>-insertion mechanism. In contrast, <i>anti</i>-insertions are far less common, with proposed mechanisms often extrapolated from literature precedents rather than grounded in direct experimental evidence. While gold complexes rank among the most efficient catalysts for such transformations, the mechanistic understanding of the key alkyne insertion step remains incomplete. In this study, we demonstrate that stable gold(III)-hydrides, featuring a (P<sup>∧</sup>N<sup>∧</sup>C) ligand, undergo selective insertion of alkynes to yield the corresponding <i>anti</i>-Markovnikov <i>Z</i>-vinyl complexes. A combination of control experiments, kinetic studies, and computational analyses reveals a nonradical, bimolecular insertion process, in which water plays a pivotal role by accelerating the reaction and potentially stabilizing a highly reactive, T-shaped gold(I) intermediate. Notably, this is the first demonstration of the insertion of both activated and unactivated terminal and internal alkynes into a gold(III)-hydride complex.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1439-1447"},"PeriodicalIF":8.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733770","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}
JACS AuPub Date : 2025-02-24DOI: 10.1021/jacsau.5c0001210.1021/jacsau.5c00012
Hui-Jun Nie, Hao Hu, Xinming Qi, Yin-Jue Zhou, Lu Liu and Xiao-Hua Chen*,
{"title":"General Platform for Efficient and Modular Assembly of GalNAc–siRNA Conjugates via Primary Amines and o-Nitrobenzyl Alcohol Cyclization Photoclick Chemistry Enabling Rapid Access to Therapeutic Oligonucleotides","authors":"Hui-Jun Nie, Hao Hu, Xinming Qi, Yin-Jue Zhou, Lu Liu and Xiao-Hua Chen*, ","doi":"10.1021/jacsau.5c0001210.1021/jacsau.5c00012","DOIUrl":"https://doi.org/10.1021/jacsau.5c00012https://doi.org/10.1021/jacsau.5c00012","url":null,"abstract":"<p >Oligonucleotide-based therapies, especially ligand-conjugated siRNAs, offer significant therapeutic potential for a wide array of diseases. However, conventional solid-phase synthesis and current postsynthetic in-solution conjugation methods face notable challenges related to efficiency, accessibility, and the scalability of diverse ligand–oligonucleotide conjugates. Herein, we introduce a novel strategy for highly efficient, rapid, and modular assembly of GalNAc–siRNA conjugates based on light-induced primary amine and <i>o</i>-nitrobenzyl alcohol cyclization (PANAC) chemistry. Leveraging the advantages of PANAC photoclick chemistry and modular conjugation linkers, our method enables the direct assembly of trivalent GalNAc (tGalNAc) with commercially available primary-amine-modified siRNAs. This approach demonstrates the efficient and rapid assembly of therapeutically relevant oligonucleotides with ligands of interest, offering operational simplicity and practicality; thus, it effectively overcomes the limitations of existing methods. More importantly, the developed siRNA–tGalNAc conjugates showed a robust gene silencing effect superior to the parent siRNA conjugate, highlighting the effectiveness of our method in generating and screening siRNA conjugates to enhance in vivo potency. Overall, our method enables modular and rapid assembly of therapeutically relevant oligonucleotide–tGalNAc conjugates using readily accessible oligonucleotides and commercially available tGalNAc-amine ligands. This approach expands the toolkit for generating ligand–oligonucleotide conjugates, providing a general and efficient platform with broad applicability, thereby advancing the optimization and development of oligonucleotide-based therapeutics.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1402–1412 1402–1412"},"PeriodicalIF":8.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675807","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}
JACS AuPub Date : 2025-02-24eCollection Date: 2025-03-24DOI: 10.1021/jacsau.5c00012
Hui-Jun Nie, Hao Hu, Xinming Qi, Yin-Jue Zhou, Lu Liu, Xiao-Hua Chen
{"title":"General Platform for Efficient and Modular Assembly of GalNAc-siRNA Conjugates via Primary Amines and <i>o</i>-Nitrobenzyl Alcohol Cyclization Photoclick Chemistry Enabling Rapid Access to Therapeutic Oligonucleotides.","authors":"Hui-Jun Nie, Hao Hu, Xinming Qi, Yin-Jue Zhou, Lu Liu, Xiao-Hua Chen","doi":"10.1021/jacsau.5c00012","DOIUrl":"10.1021/jacsau.5c00012","url":null,"abstract":"<p><p>Oligonucleotide-based therapies, especially ligand-conjugated siRNAs, offer significant therapeutic potential for a wide array of diseases. However, conventional solid-phase synthesis and current postsynthetic in-solution conjugation methods face notable challenges related to efficiency, accessibility, and the scalability of diverse ligand-oligonucleotide conjugates. Herein, we introduce a novel strategy for highly efficient, rapid, and modular assembly of GalNAc-siRNA conjugates based on light-induced primary amine and <i>o</i>-nitrobenzyl alcohol cyclization (PANAC) chemistry. Leveraging the advantages of PANAC photoclick chemistry and modular conjugation linkers, our method enables the direct assembly of trivalent GalNAc (tGalNAc) with commercially available primary-amine-modified siRNAs. This approach demonstrates the efficient and rapid assembly of therapeutically relevant oligonucleotides with ligands of interest, offering operational simplicity and practicality; thus, it effectively overcomes the limitations of existing methods. More importantly, the developed siRNA-tGalNAc conjugates showed a robust gene silencing effect superior to the parent siRNA conjugate, highlighting the effectiveness of our method in generating and screening siRNA conjugates to enhance in vivo potency. Overall, our method enables modular and rapid assembly of therapeutically relevant oligonucleotide-tGalNAc conjugates using readily accessible oligonucleotides and commercially available tGalNAc-amine ligands. This approach expands the toolkit for generating ligand-oligonucleotide conjugates, providing a general and efficient platform with broad applicability, thereby advancing the optimization and development of oligonucleotide-based therapeutics.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1402-1412"},"PeriodicalIF":8.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733713","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}