Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01385-y
Juba Salhi, Michele Mattera, Imad Arfaoui, Jan Patrick Calupitan, Sandra Alves, Claire Troufflard, Céline Paris, Guillaume Izzet, Anna Proust, David Kreher, Guilhem Simon, Alexandre Dazzi, Florence Volatron
Bottom-up engineering is a very attractive field. However, the periodic organization of molecules on a solid substrate is challenging, particularly in the selection of the appropriate characterization technique which is suitable for both large area and accurate analysis at the nanoscale. Here, this study demonstrates the unambiguous identification of complex molecular layers by infrared absorption microscopy at the nanometric scale. This technique allowed for the direct observation of the presence of isolated polyoxometalate-based nanoclusters dispersed all over a substrate. The periodic organization of molecules on a solid substrate is attractive for a range of applications, but selecting the appropriate characterization technique that is suitable for both large area and accurate analysis at the nanoscale remains challenging. Here, the authors showcase the utility of infrared absorption microscopy in the unambiguous identification of complex molecular layers, directly observing isolated polyoxometalate-based nanoclusters dispersed on a substrate.
{"title":"Single polyoxometalate-based nanoclusters characterized by infrared absorption nanospectroscopy","authors":"Juba Salhi, Michele Mattera, Imad Arfaoui, Jan Patrick Calupitan, Sandra Alves, Claire Troufflard, Céline Paris, Guillaume Izzet, Anna Proust, David Kreher, Guilhem Simon, Alexandre Dazzi, Florence Volatron","doi":"10.1038/s42004-024-01385-y","DOIUrl":"10.1038/s42004-024-01385-y","url":null,"abstract":"Bottom-up engineering is a very attractive field. However, the periodic organization of molecules on a solid substrate is challenging, particularly in the selection of the appropriate characterization technique which is suitable for both large area and accurate analysis at the nanoscale. Here, this study demonstrates the unambiguous identification of complex molecular layers by infrared absorption microscopy at the nanometric scale. This technique allowed for the direct observation of the presence of isolated polyoxometalate-based nanoclusters dispersed all over a substrate. The periodic organization of molecules on a solid substrate is attractive for a range of applications, but selecting the appropriate characterization technique that is suitable for both large area and accurate analysis at the nanoscale remains challenging. Here, the authors showcase the utility of infrared absorption microscopy in the unambiguous identification of complex molecular layers, directly observing isolated polyoxometalate-based nanoclusters dispersed on a substrate.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01385-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01392-z
Ron M. Versteegen, Raffaella Rossin, Ivo A. W. Filot, Freek J. M. Hoeben, Arthur H. A. M. van Onzen, Henk M. Janssen, Marc S. Robillard
The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and in particular in click-cleavable antibody-drug conjugates (ADCs). However, clinical translation is hampered by an inverse correlation between click reactivity and payload release yield, requiring high doses of less reactive tetrazines to drive in vivo TCO reactions and payload release to completion. Herein we report that the cause for the low release when using the highly reactive bis-(2-pyridinyl)-tetrazine is the stability of the initially formed 4,5-dihydropyridazine product, precluding tautomerization to the releasing 1,4-dihydropyridazine tautomer. We demonstrate that efficient tautomerization and payload elimination can be achieved by ortho-substituting bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups, achieving a.o. release yields of 96% with 18-fold more reactive tetrazines. Applied to on-tumor activation of a click-cleavable ADC in mice, these tetrazines afforded near-quantitative ADC conversion at a ca. 10- to 20-fold lower dose than what was previously needed, resulting in a strong therapeutic response. The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene-linked payloads has strong potential in click-to-release drug delivery, however, an inverse correlation between click reactivity and payload release yield is hampering their clinical translation. Here, the authors develop ortho-substituted bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups for efficient tautomerization and payload elimination, achieving release yields of 96% with 18-fold more reactive tetrazines.
{"title":"Ortho-functionalized pyridinyl-tetrazines break the inverse correlation between click reactivity and cleavage yields in click-to-release chemistry","authors":"Ron M. Versteegen, Raffaella Rossin, Ivo A. W. Filot, Freek J. M. Hoeben, Arthur H. A. M. van Onzen, Henk M. Janssen, Marc S. Robillard","doi":"10.1038/s42004-024-01392-z","DOIUrl":"10.1038/s42004-024-01392-z","url":null,"abstract":"The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and in particular in click-cleavable antibody-drug conjugates (ADCs). However, clinical translation is hampered by an inverse correlation between click reactivity and payload release yield, requiring high doses of less reactive tetrazines to drive in vivo TCO reactions and payload release to completion. Herein we report that the cause for the low release when using the highly reactive bis-(2-pyridinyl)-tetrazine is the stability of the initially formed 4,5-dihydropyridazine product, precluding tautomerization to the releasing 1,4-dihydropyridazine tautomer. We demonstrate that efficient tautomerization and payload elimination can be achieved by ortho-substituting bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups, achieving a.o. release yields of 96% with 18-fold more reactive tetrazines. Applied to on-tumor activation of a click-cleavable ADC in mice, these tetrazines afforded near-quantitative ADC conversion at a ca. 10- to 20-fold lower dose than what was previously needed, resulting in a strong therapeutic response. The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene-linked payloads has strong potential in click-to-release drug delivery, however, an inverse correlation between click reactivity and payload release yield is hampering their clinical translation. Here, the authors develop ortho-substituted bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups for efficient tautomerization and payload elimination, achieving release yields of 96% with 18-fold more reactive tetrazines.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01392-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01374-1
Fruzsina Pilhál, Imre Jákli, Ernő Keszei, András Láng, András Perczel
Under physiological conditions in peptides or proteins, the -AsnGly- motif autonomously rearranges within hours/days to β-Asp and α-Asp containing sequence, via succinimide intermedier. The formation of the succinimide is the rate-limiting step, with a strong pH and temperature dependence. We found that Arg(+) at the (n + 2) position (relative to Asn in the nth position) favors isomerisation by forming a transition-state like structure, whereas Glu(-) disfavors isomerisation by adopting a β-turn like conformer. Four to six key intermediate structures (proton transfer, transition-state formation, ring-closure and ammonia-release steps) have been identified along the intrinsic reaction coordinate pathways. We explain how, under the right conditions, the N-atom of a backbone amide, hardly a potent nucleophile, can nevertheless initiate isomerisation. The new data are useful for the design of self-structuring motifs, more resistant protein backbones, antibodies, etc. AsnGly motif within peptides or proteins can rearrange to β-Asp and α-Asp by asparagine deamidation and isomerisation via a succinimide intermediate, however, the mechanism underlying this transition remains underexplored. Here, the authors present a quantitative kinetic model for the overall isomerisation reaction, show that for peptides containing both charged and neutral (n + 2) amino acid residues, geometry plays a more important role in their isomerisation reaction rates, and they also identify key reaction sub-steps within succinimide formation.
{"title":"Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity","authors":"Fruzsina Pilhál, Imre Jákli, Ernő Keszei, András Láng, András Perczel","doi":"10.1038/s42004-024-01374-1","DOIUrl":"10.1038/s42004-024-01374-1","url":null,"abstract":"Under physiological conditions in peptides or proteins, the -AsnGly- motif autonomously rearranges within hours/days to β-Asp and α-Asp containing sequence, via succinimide intermedier. The formation of the succinimide is the rate-limiting step, with a strong pH and temperature dependence. We found that Arg(+) at the (n + 2) position (relative to Asn in the nth position) favors isomerisation by forming a transition-state like structure, whereas Glu(-) disfavors isomerisation by adopting a β-turn like conformer. Four to six key intermediate structures (proton transfer, transition-state formation, ring-closure and ammonia-release steps) have been identified along the intrinsic reaction coordinate pathways. We explain how, under the right conditions, the N-atom of a backbone amide, hardly a potent nucleophile, can nevertheless initiate isomerisation. The new data are useful for the design of self-structuring motifs, more resistant protein backbones, antibodies, etc. AsnGly motif within peptides or proteins can rearrange to β-Asp and α-Asp by asparagine deamidation and isomerisation via a succinimide intermediate, however, the mechanism underlying this transition remains underexplored. Here, the authors present a quantitative kinetic model for the overall isomerisation reaction, show that for peptides containing both charged and neutral (n + 2) amino acid residues, geometry plays a more important role in their isomerisation reaction rates, and they also identify key reaction sub-steps within succinimide formation.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-13"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01374-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01373-2
Satnam Singh, Doris Schicker, Helen Haug, Tilman Sauerwald, Andreas T. Grasskamp
Aroma compositions are usually complex mixtures of odor-active compounds exhibiting diverse molecular structures. Due to chemical interactions of these compounds in the olfactory system, assessing or even predicting the olfactory quality of such mixtures is a difficult task, not only for statistical models, but even for trained assessors. Here, we combine fast automated analytical assessment tools with human sensory data of 11 experienced panelists and machine learning algorithms. Using 16 previously analyzed whisky samples (American or Scotch origin), we apply the linear classifier OWSum to distinguish the samples based on their detected molecules and to gain insights into the key molecular structure characteristics and odor descriptors for sample type. Moreover, we use OWSum and a Convolutional Neural Network (CNN) architecture to classify the five most relevant odor attributes of each sample and predict their sensory scores with promising accuracies (up to F1: 0.71, MCC: 0.68, ROCAUC: 0.78). The predictions outperform the inter-panelist agreement and thus demonstrate previously impossible data-driven sensory assessment in mixtures. Aroma compositions are usually complex mixtures of odor-active compounds exhibiting diverse molecular structures, and assessing or predicting the olfactory qualities of such mixtures is challenging. Here, fast automated analytical assessment tools are combined with the human sensory data of 11 experienced panelists and machine learning algorithms, enabling samples to be distinguished and classified based on their detected molecules, and gaining insights into key molecular structure characteristics and odor descriptors.
{"title":"Odor prediction of whiskies based on their molecular composition","authors":"Satnam Singh, Doris Schicker, Helen Haug, Tilman Sauerwald, Andreas T. Grasskamp","doi":"10.1038/s42004-024-01373-2","DOIUrl":"10.1038/s42004-024-01373-2","url":null,"abstract":"Aroma compositions are usually complex mixtures of odor-active compounds exhibiting diverse molecular structures. Due to chemical interactions of these compounds in the olfactory system, assessing or even predicting the olfactory quality of such mixtures is a difficult task, not only for statistical models, but even for trained assessors. Here, we combine fast automated analytical assessment tools with human sensory data of 11 experienced panelists and machine learning algorithms. Using 16 previously analyzed whisky samples (American or Scotch origin), we apply the linear classifier OWSum to distinguish the samples based on their detected molecules and to gain insights into the key molecular structure characteristics and odor descriptors for sample type. Moreover, we use OWSum and a Convolutional Neural Network (CNN) architecture to classify the five most relevant odor attributes of each sample and predict their sensory scores with promising accuracies (up to F1: 0.71, MCC: 0.68, ROCAUC: 0.78). The predictions outperform the inter-panelist agreement and thus demonstrate previously impossible data-driven sensory assessment in mixtures. Aroma compositions are usually complex mixtures of odor-active compounds exhibiting diverse molecular structures, and assessing or predicting the olfactory qualities of such mixtures is challenging. Here, fast automated analytical assessment tools are combined with the human sensory data of 11 experienced panelists and machine learning algorithms, enabling samples to be distinguished and classified based on their detected molecules, and gaining insights into key molecular structure characteristics and odor descriptors.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01373-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01377-y
Charlotte Riley, Hwan-Hee Cho, Alexander C. Brannan, Nguyen Le Phuoc, Mikko Linnolahti, Neil C. Greenham, Alexander S. Romanov
Energy-efficient and deep-blue organic light-emitting diode (OLED) with long operating stability remains a key challenge to enable a disruptive change in OLED display and lighting technology. Part of the challenge is associated with a very narrow choice of the robust host materials having over 3 eV triplet energy level to facilitate efficient deep-blue emission and deliver excellent performance in the OLED device. Here we show the molecular design of new 1,3,5-oxadiazines (NON)-host materials with high triplet energy over 3.2 eV, enabling deep-blue OLED devices with a peak external quantum efficiency of 21%. A series of NON-host materials are prepared by the condensation of substituted arylhydrazines and cyclohexylcarbaldehyde in a 2:3 ratio. This straightforward “one-pot” procedure enables the formation of indoline-containing derivatives with three fused heterocyclic rings and two stereogenic centres. All materials emit UV-fluorescence in the range of 315–338 nm while possessing highly desirable characteristics for application in deep-blue OLED devices: good thermal stability, a wide energy gap (3.9 eV), a high triplet energy level of (3.3 eV), and excellent volatility during sublimation. Diluting phosphorescent and thermally activated delayed fluorescence emitter molecules in solid-state host matrices has proven to be a useful strategy to hinder self-quenching mechanisms, but host materials must meet several criteria to enable energy efficient and stable OLEDs. Here, the authors report the synthesis of a series of 1,3,5-oxadiazines from a one-pot interrupted Fischer indolization, and demonstrate that they possess highly desirable characteristics as host materials in deep-blue OLED devices.
{"title":"High triplet energy host material with a 1,3,5-oxadiazine core from a one-step interrupted Fischer indolization","authors":"Charlotte Riley, Hwan-Hee Cho, Alexander C. Brannan, Nguyen Le Phuoc, Mikko Linnolahti, Neil C. Greenham, Alexander S. Romanov","doi":"10.1038/s42004-024-01377-y","DOIUrl":"10.1038/s42004-024-01377-y","url":null,"abstract":"Energy-efficient and deep-blue organic light-emitting diode (OLED) with long operating stability remains a key challenge to enable a disruptive change in OLED display and lighting technology. Part of the challenge is associated with a very narrow choice of the robust host materials having over 3 eV triplet energy level to facilitate efficient deep-blue emission and deliver excellent performance in the OLED device. Here we show the molecular design of new 1,3,5-oxadiazines (NON)-host materials with high triplet energy over 3.2 eV, enabling deep-blue OLED devices with a peak external quantum efficiency of 21%. A series of NON-host materials are prepared by the condensation of substituted arylhydrazines and cyclohexylcarbaldehyde in a 2:3 ratio. This straightforward “one-pot” procedure enables the formation of indoline-containing derivatives with three fused heterocyclic rings and two stereogenic centres. All materials emit UV-fluorescence in the range of 315–338 nm while possessing highly desirable characteristics for application in deep-blue OLED devices: good thermal stability, a wide energy gap (3.9 eV), a high triplet energy level of (3.3 eV), and excellent volatility during sublimation. Diluting phosphorescent and thermally activated delayed fluorescence emitter molecules in solid-state host matrices has proven to be a useful strategy to hinder self-quenching mechanisms, but host materials must meet several criteria to enable energy efficient and stable OLEDs. Here, the authors report the synthesis of a series of 1,3,5-oxadiazines from a one-pot interrupted Fischer indolization, and demonstrate that they possess highly desirable characteristics as host materials in deep-blue OLED devices.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-8"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01377-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01386-x
Micha J. Birklbauer, Fränze Müller, Sowmya Sivakumar Geetha, Manuel Matzinger, Karl Mechtler, Viktoria Dorfer
The field of crosslinking mass spectrometry has seen substantial advancements over the past decades, enabling the structural analysis of proteins and protein complexes and serving as a powerful tool in protein–protein interaction studies. However, data analysis of large non-cleavable crosslink studies is still a mostly unsolved problem due to its n-squared complexity. We here introduce an algorithm for the identification of non-cleavable crosslinks implemented in our crosslinking search engine MS Annika that is based on sparse matrix multiplication and allows for proteome-wide searches on commodity hardware. We compare our algorithm to other state-of-the-art crosslinking search engines commonly used in the field and conclude that MS Annika unifies high sensitivity, accurate FDR estimation and computational performance, outperforming competing tools. Application of this algorithm enabled us to employ a proteome-wide search of C. elegans nuclei samples, where we were able to uncover previously unknown protein interactions and conclude a comprehensive structural analysis that provides a detailed view of the Box C/D complex. Moreover, our algorithm will enable researchers to conduct similar studies that were previously unfeasible. Crosslinking mass spectrometry enables the structural analysis of proteins and protein complexes and serves as a powerful tool in protein-protein interaction studies, however, the data analysis of large non-cleavable crosslink studies remains challenging. Here, the authors report an algorithm MS Annika 3.0 for proteome-wide identification of non-cleavable crosslinks showing high sensitivity, accurate FDR estimation and computational performance, uncovering the structure of the C. elegans Box C/D complex.
{"title":"Proteome-wide non-cleavable crosslink identification with MS Annika 3.0 reveals the structure of the C. elegans Box C/D complex","authors":"Micha J. Birklbauer, Fränze Müller, Sowmya Sivakumar Geetha, Manuel Matzinger, Karl Mechtler, Viktoria Dorfer","doi":"10.1038/s42004-024-01386-x","DOIUrl":"10.1038/s42004-024-01386-x","url":null,"abstract":"The field of crosslinking mass spectrometry has seen substantial advancements over the past decades, enabling the structural analysis of proteins and protein complexes and serving as a powerful tool in protein–protein interaction studies. However, data analysis of large non-cleavable crosslink studies is still a mostly unsolved problem due to its n-squared complexity. We here introduce an algorithm for the identification of non-cleavable crosslinks implemented in our crosslinking search engine MS Annika that is based on sparse matrix multiplication and allows for proteome-wide searches on commodity hardware. We compare our algorithm to other state-of-the-art crosslinking search engines commonly used in the field and conclude that MS Annika unifies high sensitivity, accurate FDR estimation and computational performance, outperforming competing tools. Application of this algorithm enabled us to employ a proteome-wide search of C. elegans nuclei samples, where we were able to uncover previously unknown protein interactions and conclude a comprehensive structural analysis that provides a detailed view of the Box C/D complex. Moreover, our algorithm will enable researchers to conduct similar studies that were previously unfeasible. Crosslinking mass spectrometry enables the structural analysis of proteins and protein complexes and serves as a powerful tool in protein-protein interaction studies, however, the data analysis of large non-cleavable crosslink studies remains challenging. Here, the authors report an algorithm MS Annika 3.0 for proteome-wide identification of non-cleavable crosslinks showing high sensitivity, accurate FDR estimation and computational performance, uncovering the structure of the C. elegans Box C/D complex.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-17"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01386-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-19DOI: 10.1038/s42004-024-01372-3
Jiajun Ren, Anugraha Mathew, María Rodríguez-García, Tobias Kohler, Olivier Blacque, Anthony Linden, Leo Eberl, Simon Sieber, Karl Gademann
Chirality plays a critical role in the biochemistry of life and often only one enantiomeric series is observed (homochirality). Only a few natural products have been obtained as racemates, e.g. the signalling molecule valdiazen produced by Burkholderia cenocepacia H111. In this study, we investigated the ham biosynthetic gene cluster and discovered that both the enantiomerically pure (R)-fragin and the racemic valdiazen result from the same pathway. This stereodivergence is based on the unusual heterocyclic intermediate dihydrosydnone N-oxide, as evident from gene knockout, stable isotope feeding experiments, and mass spectrometry experiments. Both non-enzymatic racemisation via keto-enol tautomerisation and enzyme-mediated dynamic kinetic resolution were found to be crucial to this stereodivergent pathway. This novel mechanism underpins the production of configurationally and biologically distinct metabolites from a single gene cluster. Our findings highlight the intricate design of an intertwined biosynthetic pathway and provide a deeper understanding of microbial secondary metabolism related to microbial communication. The ham gene cluster in Burkholderia cenocepacia H111 produces two compounds: the signalling molecule valdiazen as racemate and the antifungal fragin in enantiopure form. Here, the authors demonstrate that the stereodivergence is based on the heterocyclic intermediate dihydrosydnone N-oxide, with both non-enzymatic racemization and enzyme-mediated dynamic kinetic resolution occurring in parallel.
{"title":"Functional biosynthetic stereodivergence in a gene cluster via a dihydrosydnone N-oxide","authors":"Jiajun Ren, Anugraha Mathew, María Rodríguez-García, Tobias Kohler, Olivier Blacque, Anthony Linden, Leo Eberl, Simon Sieber, Karl Gademann","doi":"10.1038/s42004-024-01372-3","DOIUrl":"10.1038/s42004-024-01372-3","url":null,"abstract":"Chirality plays a critical role in the biochemistry of life and often only one enantiomeric series is observed (homochirality). Only a few natural products have been obtained as racemates, e.g. the signalling molecule valdiazen produced by Burkholderia cenocepacia H111. In this study, we investigated the ham biosynthetic gene cluster and discovered that both the enantiomerically pure (R)-fragin and the racemic valdiazen result from the same pathway. This stereodivergence is based on the unusual heterocyclic intermediate dihydrosydnone N-oxide, as evident from gene knockout, stable isotope feeding experiments, and mass spectrometry experiments. Both non-enzymatic racemisation via keto-enol tautomerisation and enzyme-mediated dynamic kinetic resolution were found to be crucial to this stereodivergent pathway. This novel mechanism underpins the production of configurationally and biologically distinct metabolites from a single gene cluster. Our findings highlight the intricate design of an intertwined biosynthetic pathway and provide a deeper understanding of microbial secondary metabolism related to microbial communication. The ham gene cluster in Burkholderia cenocepacia H111 produces two compounds: the signalling molecule valdiazen as racemate and the antifungal fragin in enantiopure form. Here, the authors demonstrate that the stereodivergence is based on the heterocyclic intermediate dihydrosydnone N-oxide, with both non-enzymatic racemization and enzyme-mediated dynamic kinetic resolution occurring in parallel.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01372-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1038/s42004-024-01390-1
Arnab Dey, Rajesh Kancherla, Kuntal Pal, Nathan Kloszewski, Magnus Rueping
Synthetic chemistry approaches for direct C–H bond alkylation offers a promising alternative to traditional functional-group-centered strategies which often involve multi-step procedures and may suffer from a variety of challenges including scalability. Here, we introduce resonant mixing as an efficient method for meta-C–H alkylation of arenes using a Ru-catalyst, avoiding the need for bulk solvents, external temperature, or light. The described methodology is highly rapid, enabling multigram-scale synthesis of meta-alkylation products within a short reaction time and achieving a very high turnover frequency. The reaction operates via a radical mechanism and is characterized by its mild reaction conditions, substrate compatibility, and exceptional meta-selectivity, all while significantly reducing reaction times. Synthetic chemistry approaches for direct C–H bond alkylation offers a promising alternative to traditional functional-group-centered strategies which often involve multi-step procedures and may suffer from a variety of challenges including scalability. Here, the authors introduce resonant acoustic mixing as an efficient method for meta-C–H alkylation of arenes using a Ru-catalyst via a radical mechanism, avoiding the need for bulk solvents, external temperature, or light.
{"title":"Rapid and scalable ruthenium catalyzed meta-C–H alkylation enabled by resonant acoustic mixing","authors":"Arnab Dey, Rajesh Kancherla, Kuntal Pal, Nathan Kloszewski, Magnus Rueping","doi":"10.1038/s42004-024-01390-1","DOIUrl":"10.1038/s42004-024-01390-1","url":null,"abstract":"Synthetic chemistry approaches for direct C–H bond alkylation offers a promising alternative to traditional functional-group-centered strategies which often involve multi-step procedures and may suffer from a variety of challenges including scalability. Here, we introduce resonant mixing as an efficient method for meta-C–H alkylation of arenes using a Ru-catalyst, avoiding the need for bulk solvents, external temperature, or light. The described methodology is highly rapid, enabling multigram-scale synthesis of meta-alkylation products within a short reaction time and achieving a very high turnover frequency. The reaction operates via a radical mechanism and is characterized by its mild reaction conditions, substrate compatibility, and exceptional meta-selectivity, all while significantly reducing reaction times. Synthetic chemistry approaches for direct C–H bond alkylation offers a promising alternative to traditional functional-group-centered strategies which often involve multi-step procedures and may suffer from a variety of challenges including scalability. Here, the authors introduce resonant acoustic mixing as an efficient method for meta-C–H alkylation of arenes using a Ru-catalyst via a radical mechanism, avoiding the need for bulk solvents, external temperature, or light.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-7"},"PeriodicalIF":5.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01390-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-18DOI: 10.1038/s42004-024-01391-0
Sergi Bujosa, Llorenç Rubert, Carmen Rotger, Bartolome Soberats
Supramolecular self-assembly is an advanced approach for constructing ordered nanoscale architectures with broad applications. While the principles of supramolecular polymerization have been thoroughly explored in artificial small molecules, polymer transformations remain barely explored, likely due to the lack of suitable reference models presenting well-defined and reversible transitions between aggregates. In this study, we introduce a series of bisdendronized squaramides (SQs) 1-3, showcasing complex self-assembly behaviours involving four distinct aggregates, three different interaction patterns, and various thermodynamically controlled polymorph transformations. Notably, SQ 3, with ethyl spacers between the SQ cores and the dendrons, exhibits a concentration and temperature-dependent equilibrium among three polymorphs: the particle-like Agg-A and fibrillar Agg-C, formed by slipped hydrogen bonds, and the fibrillar Agg-B, formed by head-to-tail hydrogen bonds. Additional solid-state experiments revealed that these SQs also form columnar liquid crystals, assembled by π–π interactions in SQ 1 and hydrogen bonding in SQ 2 and SQ 3. This work positions SQ units as valuable models for understanding polymorph equilibrium in solution and solid-state, which is crucial for developing stimuli-responsive supramolecular polymers. Squaramides are compelling self-assembly models, known for exhibiting diverse interaction patterns and supramolecular polymorphism. In this study, the authors investigate a series of bisdendronized squaramides to uncover polymorphic transformations in supramolecular polymers, linking insights from solution-phase assemblies to solid-state liquid-crystalline structures.
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Pub Date : 2024-12-17DOI: 10.1038/s42004-024-01340-x
Christa L. Brosseau, Emiliano Cortés
Communications Chemistry is pleased to introduce a Collection of articles on the topic of plasmon-mediated chemistry. Here, the Guest Editors discuss different themes within and look towards the future of the field.
{"title":"Charting a new course with plasmon-mediated chemistry","authors":"Christa L. Brosseau, Emiliano Cortés","doi":"10.1038/s42004-024-01340-x","DOIUrl":"10.1038/s42004-024-01340-x","url":null,"abstract":"Communications Chemistry is pleased to introduce a Collection of articles on the topic of plasmon-mediated chemistry. Here, the Guest Editors discuss different themes within and look towards the future of the field.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-2"},"PeriodicalIF":5.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01340-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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