Pub Date : 2024-12-28DOI: 10.1038/s42004-024-01396-9
Mohd Nazish, Tim Patten, Yuqing Huang, Saroj Kumar Kushvaha, Lili Zhao, Anna Krawczuk, Gernot Frenking, Herbert W. Roesky
The search for stable compounds containing an antiaromatic cyclic 4π system is a challenge for inventive chemists that can look back on a long history. Here we report the isolation and characterization of the novel 4π-electron tetrasilacyclobutadiene, an analogue of a 4π neutral cyclobutadiene that exhibits surprising features of a Möbius-type aromatic ring. Reduction of RSiCl3 (R = (iPr)2PC6H4) with KC8 in the presence of cycloalkyl amino-carbene (cAAC) led to the formation of corresponding silylene 1. Compound 1 shows further reactivity when treated with RSiCl3 under reducing conditions resulting in the formation of unsymmetrical bis-silylene 2, which was isolated as a dark red crystalline solid. Compound 3 was obtained when chlorosilylene was reduced with potassium graphite in the presence of 2. Although 3 is, according to Hückel’s rule an antiaromatic system it possesses significant aromatic character due to the unusual delocalization of the HOMO-1 and the loss of degeneracy of the higher-lying π MOs. The aromatic character of 3 is indicated by the structural stability of the compound by the very similar Si-Si bond lengths and by the NICS values. There is an unusual π conjugation between the 4 π electrons in the nearly square-planar Si4 ring where the delocalization of the HOMO-1 occurs at two opposite sides of the ring. The reversal of the π conjugation resembles the twisting of the π conjugation in Möbius aromatic systems and it contributes to the stability of the compound. Introducing main group elements into neutral and charged cyclobutadienes enables the fine-tuning of their stability and electronic structures by disrupting their aromatic and antiaromatic character. Here, the authors report the isolation and characterization of a 4π-electron tetrasilacyclobutadiene, an analogue of a 4π neutral cyclobutadiene that exhibits features of a Möbius-type aromatic ring.
{"title":"Neutral 4π-electron tetrasilacyclobutadiene contains unusual features of a Möbius-type aromatic ring","authors":"Mohd Nazish, Tim Patten, Yuqing Huang, Saroj Kumar Kushvaha, Lili Zhao, Anna Krawczuk, Gernot Frenking, Herbert W. Roesky","doi":"10.1038/s42004-024-01396-9","DOIUrl":"10.1038/s42004-024-01396-9","url":null,"abstract":"The search for stable compounds containing an antiaromatic cyclic 4π system is a challenge for inventive chemists that can look back on a long history. Here we report the isolation and characterization of the novel 4π-electron tetrasilacyclobutadiene, an analogue of a 4π neutral cyclobutadiene that exhibits surprising features of a Möbius-type aromatic ring. Reduction of RSiCl3 (R = (iPr)2PC6H4) with KC8 in the presence of cycloalkyl amino-carbene (cAAC) led to the formation of corresponding silylene 1. Compound 1 shows further reactivity when treated with RSiCl3 under reducing conditions resulting in the formation of unsymmetrical bis-silylene 2, which was isolated as a dark red crystalline solid. Compound 3 was obtained when chlorosilylene was reduced with potassium graphite in the presence of 2. Although 3 is, according to Hückel’s rule an antiaromatic system it possesses significant aromatic character due to the unusual delocalization of the HOMO-1 and the loss of degeneracy of the higher-lying π MOs. The aromatic character of 3 is indicated by the structural stability of the compound by the very similar Si-Si bond lengths and by the NICS values. There is an unusual π conjugation between the 4 π electrons in the nearly square-planar Si4 ring where the delocalization of the HOMO-1 occurs at two opposite sides of the ring. The reversal of the π conjugation resembles the twisting of the π conjugation in Möbius aromatic systems and it contributes to the stability of the compound. Introducing main group elements into neutral and charged cyclobutadienes enables the fine-tuning of their stability and electronic structures by disrupting their aromatic and antiaromatic character. Here, the authors report the isolation and characterization of a 4π-electron tetrasilacyclobutadiene, an analogue of a 4π neutral cyclobutadiene that exhibits features of a Möbius-type aromatic ring.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-7"},"PeriodicalIF":5.9,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01396-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892517","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}
C-glycosides are significant in medicinal chemistry due to their resistance to enzymatic hydrolysis, making them more stable and bioavailable compared to O-glycosides. Their unique structure also offers potential for developing drugs with improved therapeutic properties, particularly in treating diseases like diabetes and cancer. The main challenge in synthesizing C-glycosides lies in forming the carbon-carbon bond between the sugar and aglycone efficiently, while controlling the stereochemistry and minimizing side reactions. Starting from glycal derivatives, the Zweifel olefination presents an elegant opportunity to access C-glycosides in a selective manner. α-Lithiation of D-glucal, L-rhamnal, D-xylal and L-arabinal scaffolds was employed as a starting point in the synthesis of corresponding unsaturated aryl-, heteroaryl- and alkenyl-C-glycosides. This provides a straightforward strategy towards pharmacorelevant gliflozins and other unreported rhamnal- and xylal-analogs. Carbohydrates play a pivotal role in drug discovery and the pharmaceutical industry, however, synthetic methods for C-glycosylation remain challenging. Here, the authors report Zweifel olefination to access C-glycosides selectively by starting from unsaturated glycal derivatives.
{"title":"Zweifel olefination for C-glycosylation","authors":"Florian Trauner, Bilel Boutet, Fabian Pilz, Verena Weber, Dorian Didier","doi":"10.1038/s42004-024-01339-4","DOIUrl":"10.1038/s42004-024-01339-4","url":null,"abstract":"C-glycosides are significant in medicinal chemistry due to their resistance to enzymatic hydrolysis, making them more stable and bioavailable compared to O-glycosides. Their unique structure also offers potential for developing drugs with improved therapeutic properties, particularly in treating diseases like diabetes and cancer. The main challenge in synthesizing C-glycosides lies in forming the carbon-carbon bond between the sugar and aglycone efficiently, while controlling the stereochemistry and minimizing side reactions. Starting from glycal derivatives, the Zweifel olefination presents an elegant opportunity to access C-glycosides in a selective manner. α-Lithiation of D-glucal, L-rhamnal, D-xylal and L-arabinal scaffolds was employed as a starting point in the synthesis of corresponding unsaturated aryl-, heteroaryl- and alkenyl-C-glycosides. This provides a straightforward strategy towards pharmacorelevant gliflozins and other unreported rhamnal- and xylal-analogs. Carbohydrates play a pivotal role in drug discovery and the pharmaceutical industry, however, synthetic methods for C-glycosylation remain challenging. Here, the authors report Zweifel olefination to access C-glycosides selectively by starting from unsaturated glycal derivatives.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-10"},"PeriodicalIF":5.9,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01339-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862419","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 : 2024-12-20DOI: 10.1038/s42004-024-01382-1
Klemensas Šimelis, Roman Belle, Akane Kawamura
Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases use 2OG and O2 cofactors to catalyse substrate oxidation and yield oxidised product, succinate, and CO2. Simultaneous detection of substrate and cofactors is difficult, contributing to a poor understanding of the dynamics between substrate oxidation and 2OG decarboxylation activities. Here, we profile 5-methylcytosine (5mC)-oxidising Ten-Eleven Translocation (TET) enzymes using MS and 1H NMR spectroscopy methods and reveal a high degree of substrate oxidation-independent 2OG turnover under a range of conditions. 2OG decarboxylase activity is substantial (>20% 2OG turned over after 1 h) in the absence of substrate, while, under substrate-saturating conditions, half of total 2OG consumption is uncoupled from substrate oxidation. 2OG kinetics are affected by substrate and non-substrate DNA oligomers, and the sequence-agnostic effects are observed in amoeboflagellate Naegleria gruberi NgTet1 and human TET2. TET inhibitors also alter uncoupled 2OG kinetics, highlighting the potential effect of 2OG dioxygenase inhibitors on the intracellular balance of 2OG/succinate. The ten-eleven translocation (TET) dioxygenase subfamily catalyse the sequential oxidation of 5-methylcytosine (5mC) in DNA and belong to the Fe(II)-/2-oxoglutarate (2OG)-dependent dioxygenases that use 2OG and O2 cofactors to yield succinate and CO2. Here, the authors profile the TET-catalysed 5mC DNA oxidation and 2OG decarboxylation using MS and 1H NMR spectroscopy methods, revealing a high degree of substrate oxidation-independent 2OG turnover in TETs.
{"title":"Unravelling 2-oxoglutarate turnover and substrate oxidation dynamics in 5-methylcytosine-oxidising TET enzymes","authors":"Klemensas Šimelis, Roman Belle, Akane Kawamura","doi":"10.1038/s42004-024-01382-1","DOIUrl":"10.1038/s42004-024-01382-1","url":null,"abstract":"Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases use 2OG and O2 cofactors to catalyse substrate oxidation and yield oxidised product, succinate, and CO2. Simultaneous detection of substrate and cofactors is difficult, contributing to a poor understanding of the dynamics between substrate oxidation and 2OG decarboxylation activities. Here, we profile 5-methylcytosine (5mC)-oxidising Ten-Eleven Translocation (TET) enzymes using MS and 1H NMR spectroscopy methods and reveal a high degree of substrate oxidation-independent 2OG turnover under a range of conditions. 2OG decarboxylase activity is substantial (>20% 2OG turned over after 1 h) in the absence of substrate, while, under substrate-saturating conditions, half of total 2OG consumption is uncoupled from substrate oxidation. 2OG kinetics are affected by substrate and non-substrate DNA oligomers, and the sequence-agnostic effects are observed in amoeboflagellate Naegleria gruberi NgTet1 and human TET2. TET inhibitors also alter uncoupled 2OG kinetics, highlighting the potential effect of 2OG dioxygenase inhibitors on the intracellular balance of 2OG/succinate. The ten-eleven translocation (TET) dioxygenase subfamily catalyse the sequential oxidation of 5-methylcytosine (5mC) in DNA and belong to the Fe(II)-/2-oxoglutarate (2OG)-dependent dioxygenases that use 2OG and O2 cofactors to yield succinate and CO2. Here, the authors profile the TET-catalysed 5mC DNA oxidation and 2OG decarboxylation using MS and 1H NMR spectroscopy methods, revealing a high degree of substrate oxidation-independent 2OG turnover in TETs.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01382-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862450","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/s42004-024-01388-9
Isabel R. Mathiesen, Ewen D. D. Calder, Simone Kunzelmann, Louise J. Walport
Covalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target. Here we demonstrate the direct discovery of covalent cyclic peptides using encoded libraries containing a weakly electrophilic cysteine-reactive fluoroamidine warhead. We combine direct incorporation of the warhead into peptide libraries using the flexible in vitro translation system with a peptide selection approach that identifies only covalent target binders. Using this approach, we identify potent and selective covalent inhibitors of the peptidyl arginine deiminase, PADI4 or PAD4, that react exclusively at the active site cysteine. We envisage this approach will enable covalent peptide inhibitor discovery for a range of related enzymes and expansion to alternative warheads in the future. Covalent peptide drugs can achieve high potency and selectivity with long dosing intervals, however, methods to discover them are limited. Here, the authors incorporate a genetically encoded, weakly electrophilic cysteine-reactive fluoroamidine warhead into mRNA display libraries and screen these to discover potent and selective covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4.
{"title":"Discovering covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4 (PADI4) using mRNA-display with a genetically encoded electrophilic warhead","authors":"Isabel R. Mathiesen, Ewen D. D. Calder, Simone Kunzelmann, Louise J. Walport","doi":"10.1038/s42004-024-01388-9","DOIUrl":"10.1038/s42004-024-01388-9","url":null,"abstract":"Covalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target. Here we demonstrate the direct discovery of covalent cyclic peptides using encoded libraries containing a weakly electrophilic cysteine-reactive fluoroamidine warhead. We combine direct incorporation of the warhead into peptide libraries using the flexible in vitro translation system with a peptide selection approach that identifies only covalent target binders. Using this approach, we identify potent and selective covalent inhibitors of the peptidyl arginine deiminase, PADI4 or PAD4, that react exclusively at the active site cysteine. We envisage this approach will enable covalent peptide inhibitor discovery for a range of related enzymes and expansion to alternative warheads in the future. Covalent peptide drugs can achieve high potency and selectivity with long dosing intervals, however, methods to discover them are limited. Here, the authors incorporate a genetically encoded, weakly electrophilic cysteine-reactive fluoroamidine warhead into mRNA display libraries and screen these to discover potent and selective covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-10"},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01388-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862442","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/s42004-024-01381-2
Jonas Grill, Jelena Popovic-Neuber
A stable solid electrolyte interphase (SEI) is of great importance for battery electrodes in terms of cycling as well as for its shelf life. While SEI formation on silicon anodes is generally only studied after the first charge and discharge of cells and initial reaction of electrolyte, we show the formation of a liquid/solid SEI in symmetric cells with silicon electrodes in contact with carbonate and glyme-based electrolytes under close to open circuit conditions and its behavior during long-term ageing. Activation energies of SEIs were measured via temperature-dependent electrochemical impedance spectroscopy (EIS) to study the contribution of liquid/solid phases to ion transport. The effect of different solvents, salts, their concentrations, and final water content of the glyme-electrolyte on the SEI was studied in detail. SEIs formed in cells with glyme-based electrolytes are generally more porous than the ones in cells with carbonate-based electrolytes. The addition of vinylene carbonate to glyme electrolyte is shown to be beneficial for its SEI, as it causes lower and more stable SEI resistances over time. A small amount of water in glyme electrolytes causes a denser SEI without much change in SEI resistance. A stable solid electrolyte interphase (SEI) is of great importance for battery electrodes for charging/discharging purposes, but the mechanism of SEI formation is not fully understood. Here, the authors study the formation and long-term evolution of the SEI near open circuit conditions in symmetric silicon cells containing different electrolyte chemistries.
{"title":"Long term porosity of solid electrolyte interphase on model silicon anodes with liquid battery electrolytes","authors":"Jonas Grill, Jelena Popovic-Neuber","doi":"10.1038/s42004-024-01381-2","DOIUrl":"10.1038/s42004-024-01381-2","url":null,"abstract":"A stable solid electrolyte interphase (SEI) is of great importance for battery electrodes in terms of cycling as well as for its shelf life. While SEI formation on silicon anodes is generally only studied after the first charge and discharge of cells and initial reaction of electrolyte, we show the formation of a liquid/solid SEI in symmetric cells with silicon electrodes in contact with carbonate and glyme-based electrolytes under close to open circuit conditions and its behavior during long-term ageing. Activation energies of SEIs were measured via temperature-dependent electrochemical impedance spectroscopy (EIS) to study the contribution of liquid/solid phases to ion transport. The effect of different solvents, salts, their concentrations, and final water content of the glyme-electrolyte on the SEI was studied in detail. SEIs formed in cells with glyme-based electrolytes are generally more porous than the ones in cells with carbonate-based electrolytes. The addition of vinylene carbonate to glyme electrolyte is shown to be beneficial for its SEI, as it causes lower and more stable SEI resistances over time. A small amount of water in glyme electrolytes causes a denser SEI without much change in SEI resistance. A stable solid electrolyte interphase (SEI) is of great importance for battery electrodes for charging/discharging purposes, but the mechanism of SEI formation is not fully understood. Here, the authors study the formation and long-term evolution of the SEI near open circuit conditions in symmetric silicon cells containing different electrolyte chemistries.","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/s42004-024-01381-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845177","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/s42004-024-01385-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}
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