IF 8.5

JACS Au Pub Date : 2025-03-03 DOI: 10.1021/jacsau.4c0084010.1021/jacsau.4c00840

Gourab Dey, Evalyn Yakobovich, Jure Loboda, Reut Sinai-Turyansky, Chen Abramovitch-Dahan, Emmanuelle Merquiol, Nikhila Sridharan, Gal Itzhak, Boris Turk, Ori Wald, Dusan Turk, Simon Yona, Noam Levaot and Galia Blum*,

{"title":"Development and Application of Small Molecule–Peptide Conjugates as Cathepsin K-Specific Covalent Irreversible Inhibitors in Human Osteoclast and Lung Cancer","authors":"Gourab Dey, Evalyn Yakobovich, Jure Loboda, Reut Sinai-Turyansky, Chen Abramovitch-Dahan, Emmanuelle Merquiol, Nikhila Sridharan, Gal Itzhak, Boris Turk, Ori Wald, Dusan Turk, Simon Yona, Noam Levaot and Galia Blum*, ","doi":"10.1021/jacsau.4c0084010.1021/jacsau.4c00840","DOIUrl":"https://doi.org/10.1021/jacsau.4c00840https://doi.org/10.1021/jacsau.4c00840","url":null,"abstract":"Cathepsin K (CTSK), a proteolytic enzyme that degrades the extracellular matrix, is recognized as a significant therapeutic target for osteoporosis, osteoarthritis, and rheumatoid arthritis. Due to adverse effects, no clinically approved drugs exist for CTSK. In order to develop safer therapeutics, highly selective CTSK inhibitors are required to elucidate the origins of side effects. Here, we developed various hybrid inhibitors by combining peptide sequences with small organic molecules. An acyloxymethyl ketone electrophile was incorporated as a bioisostere of the glycine–glycine cleavage site and inverse peptide sequences to enhance prime site interactions, as seen in the crystal structure. Additionally, a diphenyl group was incorporated to improve nonprime site interactions, culminating in highly selective and potent irreversible CTSK inhibitors with negligible off-target binding by closely related cathepsins. These novel inhibitors were also designed to attach to targeting moieties, further reducing off-target effects in vivo. Our findings demonstrate that these highly selective inhibitors are nontoxic, effectively inhibit bone resorption by human osteoclasts, block CTSK activity in cells and their nuclei, and inhibit activity in human lung cancer tissue. This study highlights significant advancements in designing CTSK inhibitors with potential clinical applications for lung cancer and osteoclast-related conditions.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1104–1120 1104–1120"},"PeriodicalIF":8.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c00840","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675880","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

Bioinspired Synthesis of Alstoscholarinoids A and B.

IF 8.5

JACS Au Pub Date : 2025-03-03 eCollection Date: 2025-03-24 DOI: 10.1021/jacsau.5c00102

Nicolas Kratena, Maximilian Kaiser, Kirill Naumov, Martin Waxmann, Peter Gaertner

引用次数: 0

Bioinspired Synthesis of Alstoscholarinoids A and B

IF 8.5

JACS Au Pub Date : 2025-03-03 DOI: 10.1021/jacsau.5c0010210.1021/jacsau.5c00102

Nicolas Kratena*, Maximilian Kaiser, Kirill Naumov, Martin Waxmann and Peter Gaertner,

引用次数: 0

Development and Application of Small Molecule-Peptide Conjugates as Cathepsin K-Specific Covalent Irreversible Inhibitors in Human Osteoclast and Lung Cancer. 开发小分子-多肽共轭物，并将其应用于人类破骨细胞和肺癌中的特异性共价不可逆抑制剂。

IF 8.5

JACS Au Pub Date : 2025-03-03 eCollection Date: 2025-03-24 DOI: 10.1021/jacsau.4c00840

Gourab Dey, Evalyn Yakobovich, Jure Loboda, Reut Sinai-Turyansky, Chen Abramovitch-Dahan, Emmanuelle Merquiol, Nikhila Sridharan, Gal Itzhak, Boris Turk, Ori Wald, Dusan Turk, Simon Yona, Noam Levaot, Galia Blum

{"title":"Development and Application of Small Molecule-Peptide Conjugates as Cathepsin K-Specific Covalent Irreversible Inhibitors in Human Osteoclast and Lung Cancer.","authors":"Gourab Dey, Evalyn Yakobovich, Jure Loboda, Reut Sinai-Turyansky, Chen Abramovitch-Dahan, Emmanuelle Merquiol, Nikhila Sridharan, Gal Itzhak, Boris Turk, Ori Wald, Dusan Turk, Simon Yona, Noam Levaot, Galia Blum","doi":"10.1021/jacsau.4c00840","DOIUrl":"10.1021/jacsau.4c00840","url":null,"abstract":"Cathepsin K (CTSK), a proteolytic enzyme that degrades the extracellular matrix, is recognized as a significant therapeutic target for osteoporosis, osteoarthritis, and rheumatoid arthritis. Due to adverse effects, no clinically approved drugs exist for CTSK. In order to develop safer therapeutics, highly selective CTSK inhibitors are required to elucidate the origins of side effects. Here, we developed various hybrid inhibitors by combining peptide sequences with small organic molecules. An acyloxymethyl ketone electrophile was incorporated as a bioisostere of the glycine-glycine cleavage site and inverse peptide sequences to enhance prime site interactions, as seen in the crystal structure. Additionally, a diphenyl group was incorporated to improve nonprime site interactions, culminating in highly selective and potent irreversible CTSK inhibitors with negligible off-target binding by closely related cathepsins. These novel inhibitors were also designed to attach to targeting moieties, further reducing off-target effects in vivo. Our findings demonstrate that these highly selective inhibitors are nontoxic, effectively inhibit bone resorption by human osteoclasts, block CTSK activity in cells and their nuclei, and inhibit activity in human lung cancer tissue. This study highlights significant advancements in designing CTSK inhibitors with potential clinical applications for lung cancer and osteoclast-related conditions.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1104-1120"},"PeriodicalIF":8.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733680","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

Control Synthesis of Multicolor Emitting Carbonized Polymer Dots Using Different Dihydroxynaphthalene Isomers.

IF 8.5

JACS Au Pub Date : 2025-02-28 eCollection Date: 2025-03-24 DOI: 10.1021/jacsau.4c01220

Xingzhong Chen, Fang Yan, Jiurong Li, Xiao Gong

{"title":"Control Synthesis of Multicolor Emitting Carbonized Polymer Dots Using Different Dihydroxynaphthalene Isomers.","authors":"Xingzhong Chen, Fang Yan, Jiurong Li, Xiao Gong","doi":"10.1021/jacsau.4c01220","DOIUrl":"10.1021/jacsau.4c01220","url":null,"abstract":"Carbonized polymer dots (CDs) with sizes smaller than 10 nm have gained significant interest, particularly in the pursuit of multicolor fluorescence, which is a fascinating field of research. Here, we report the control synthesis of multicolor CDs with tunable emissions via the rational selection of isomer-based reaction precursors. Using cost-friendly dihydroxynaphthalene (DHN) isomers (1,7-DHN, 1,6-DHN, or 2,7-DHN) and l-methionine as the precursors, multicolor CDs with blue, green, and red fluorescence were obtained under ethanol-thermal conditions. It can be observed that structural changes in the coordination of the hydroxyl group within the aromatic compound DHN lead to a significant redshift in the emission of the synthesized CDs. Notably, the red-emitting CDs (r-CDs, 10 μM) at very low concentrations exhibit high sensitivity to tetracycline (TC), and the ratiometric fluorescent probe based on r-CDs enables quantitative and visual detection of TC. Compared with ratiometric fluorescent probes containing metal and rare earth elements, CDs-based ratiometric fluorescent probes are more cost-effective and environmentally friendly.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1350-1358"},"PeriodicalIF":8.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733652","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

Selective Aerobic Peroxidation of Styrene Catalyzed by a Cobalt tert-Butylperoxo Complex.

IF 8.5

JACS Au Pub Date : 2025-02-28 eCollection Date: 2025-03-24 DOI: 10.1021/jacsau.5c00139

Yunzhou Chen, Huiying Song, Yiming Hao, Matthew Y Lui, Wing-Leung Wong, William W Y Lam, Bun Chan, Huatian Shi, Wai-Lun Man

{"title":"Selective Aerobic Peroxidation of Styrene Catalyzed by a Cobalt tert-Butylperoxo Complex.","authors":"Yunzhou Chen, Huiying Song, Yiming Hao, Matthew Y Lui, Wing-Leung Wong, William W Y Lam, Bun Chan, Huatian Shi, Wai-Lun Man","doi":"10.1021/jacsau.5c00139","DOIUrl":"10.1021/jacsau.5c00139","url":null,"abstract":"Selective oxidation of styrene to desired products is essential and challenging. In this study, we elucidate a unique pathway for the selective oxidation of styrene to polystyrene peroxo species, catalyzed by the cobalt(III) tert-butylperoxo complex, [CoIII(OO t Bu)(qpy)(NCCH3)]2+ (1), under ambient conditions. Mechanistic investigations, including the structural determination of the diperoxo complex, [CoIII(qpy)(OOCH(Ph)CH2OO t Bu)(NCCH3)]2+ (2), by X-ray analysis and theoretical calculations reveal that the reaction begins with the nucleophilic addition of styrene to the CoIII-OO t Bu moiety in 1. This step is followed by an addition with an O2 molecule, forming a diperoxyl radical (PhCOO•(H)CH2OOtBu), which subsequently rebounds with CoII(qpy) to yield 2. In the presence of excess O2, complex 2 can further react with additional styrene molecules, leading to the formation of cobalt(III) polystyrene peroxo species.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1090-1095"},"PeriodicalIF":8.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732904","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

Selective Aerobic Peroxidation of Styrene Catalyzed by a Cobalt tert-Butylperoxo Complex

IF 8.5

JACS Au Pub Date : 2025-02-28 DOI: 10.1021/jacsau.5c0013910.1021/jacsau.5c00139

Yunzhou Chen, Huiying Song, Yiming Hao, Matthew Y. Lui, Wing-Leung Wong, William W. Y. Lam, Bun Chan*, Huatian Shi* and Wai-Lun Man*,

{"title":"Selective Aerobic Peroxidation of Styrene Catalyzed by a Cobalt tert-Butylperoxo Complex","authors":"Yunzhou Chen, Huiying Song, Yiming Hao, Matthew Y. Lui, Wing-Leung Wong, William W. Y. Lam, Bun Chan*, Huatian Shi* and Wai-Lun Man*, ","doi":"10.1021/jacsau.5c0013910.1021/jacsau.5c00139","DOIUrl":"https://doi.org/10.1021/jacsau.5c00139https://doi.org/10.1021/jacsau.5c00139","url":null,"abstract":"Selective oxidation of styrene to desired products is essential and challenging. In this study, we elucidate a unique pathway for the selective oxidation of styrene to polystyrene peroxo species, catalyzed by the cobalt(III) tert-butylperoxo complex, [CoIII(OOtBu)(qpy)(NCCH3)]2+ (1), under ambient conditions. Mechanistic investigations, including the structural determination of the diperoxo complex, [CoIII(qpy)(OOCH(Ph)CH2OOtBu)(NCCH3)]2+ (2), by X-ray analysis and theoretical calculations reveal that the reaction begins with the nucleophilic addition of styrene to the CoIII–OOtBu moiety in 1. This step is followed by an addition with an O2 molecule, forming a diperoxyl radical (PhCOO•(H)CH2OOtBu), which subsequently rebounds with CoII(qpy) to yield 2. In the presence of excess O2, complex 2 can further react with additional styrene molecules, leading to the formation of cobalt(III) polystyrene peroxo species.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1090–1095 1090–1095"},"PeriodicalIF":8.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675770","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

Control Synthesis of Multicolor Emitting Carbonized Polymer Dots Using Different Dihydroxynaphthalene Isomers 利用不同的二羟基萘异构体控制多色发光碳化聚合物点的合成

IF 8.5

JACS Au Pub Date : 2025-02-28 DOI: 10.1021/jacsau.4c0122010.1021/jacsau.4c01220

Xingzhong Chen, Fang Yan, Jiurong Li and Xiao Gong*,

{"title":"Control Synthesis of Multicolor Emitting Carbonized Polymer Dots Using Different Dihydroxynaphthalene Isomers","authors":"Xingzhong Chen, Fang Yan, Jiurong Li and Xiao Gong*, ","doi":"10.1021/jacsau.4c0122010.1021/jacsau.4c01220","DOIUrl":"https://doi.org/10.1021/jacsau.4c01220https://doi.org/10.1021/jacsau.4c01220","url":null,"abstract":"Carbonized polymer dots (CDs) with sizes smaller than 10 nm have gained significant interest, particularly in the pursuit of multicolor fluorescence, which is a fascinating field of research. Here, we report the control synthesis of multicolor CDs with tunable emissions via the rational selection of isomer-based reaction precursors. Using cost-friendly dihydroxynaphthalene (DHN) isomers (1,7-DHN, 1,6-DHN, or 2,7-DHN) and l-methionine as the precursors, multicolor CDs with blue, green, and red fluorescence were obtained under ethanol-thermal conditions. It can be observed that structural changes in the coordination of the hydroxyl group within the aromatic compound DHN lead to a significant redshift in the emission of the synthesized CDs. Notably, the red-emitting CDs (r-CDs, 10 μM) at very low concentrations exhibit high sensitivity to tetracycline (TC), and the ratiometric fluorescent probe based on r-CDs enables quantitative and visual detection of TC. Compared with ratiometric fluorescent probes containing metal and rare earth elements, CDs-based ratiometric fluorescent probes are more cost-effective and environmentally friendly.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1350–1358 1350–1358"},"PeriodicalIF":8.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c01220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675769","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

Synthesis of Protoberberine Alkaloids by C-H Functionalization and Anionic Aza-6π-Electrocyclization: Dual Activity as AMPK Activators and Inhibitors.

IF 8.5

JACS Au Pub Date : 2025-02-27 eCollection Date: 2025-03-24 DOI: 10.1021/jacsau.5c00047

Yujie Cao, Justin S M Perry, Eryun Zhang, Andy Trinh, Arnav Kacker, Shayne Cruz, Hannah Ceballos, Aaron Pan, Wendong Huang, 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, Kevin G M Kou","doi":"10.1021/jacsau.5c00047","DOIUrl":"10.1021/jacsau.5c00047","url":null,"abstract":"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 N-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.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1429-1438"},"PeriodicalIF":8.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733631","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

The Influence of Interlocking Effects in Conjugated Polymers Synthesized by Aldol Polycondensation on Field-Effect Transistor Properties and Morphology

IF 8.5

JACS Au Pub Date : 2025-02-27 DOI: 10.1021/jacsau.5c0000310.1021/jacsau.5c00003

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 and Chu-Chen Chueh*,

{"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 and Chu-Chen Chueh*, ","doi":"10.1021/jacsau.5c0000310.1021/jacsau.5c00003","DOIUrl":"https://doi.org/10.1021/jacsau.5c00003https://doi.org/10.1021/jacsau.5c00003","url":null,"abstract":"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 P1 and P5 promotes strong interlocking interactions, resulting in high electron mobilities (2.09 × 10–2 cm2 V–1 s–1 and 8.26 × 10–2 cm2 V–1 s–1, respectively) and crystalline order. In contrast, their random copolymers (P2–P4) exhibited disrupted interlocking effects, leading to irregular backbone distortions and reduced charge transport. P6, designed with a rigid ladder-type backbone and bulky side chains, exhibits an exceptional hole mobility (3.27 × 10–1 s cm2 V–1 s–1) 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.","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 3","pages":"1382–1391 1382–1391"},"PeriodicalIF":8.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143675813","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

JACS Au最新文献