Pub Date : 2024-07-17DOI: 10.1038/s42004-024-01240-0
Sharath Mohan, Kari Rissanen, Jas S. Ward
Halogen(I) complexes are widely used as halogenation reagents and traditionally feature homoleptic stabilising Lewis bases, though the recent revitalisation of iodine(I) carboxylate chemistry has provided isolable examples of heteroleptic iodine(I) complexes. This work reports iodine(I) pnictogenate complexes stabilised by a Lewis base (L), Ph2P(O)O─I─L, synthesised via cation exchange from the silver(I) precursor, (Ph2P(O)OAg)n. The complexes were characterised in both solution (1H, 1H-15N HMBC, 31P) and the solid state, and supplemented computationally by DFT studies. Interestingly, these iodine(I) pnictogenates demonstrate a range of stabilities, and have been found to excel as iodination reagents in comparison to carbonyl hypoiodites, with comparable reactivity to the eponymous Barluenga’s reagent in the iodination of antipyrine. Iodine(I) carboxylates have been explored as iodination reagents, but the role of the carbonyl group in promoting such reactivity remains poorly understood. Here, the authors prepare iodine(I) pnictogenates and find that they excel as iodination reagents in comparison to iodine(I) carboxylates.
{"title":"Iodine(I) pnictogenate complexes as Iodination reagents","authors":"Sharath Mohan, Kari Rissanen, Jas S. Ward","doi":"10.1038/s42004-024-01240-0","DOIUrl":"10.1038/s42004-024-01240-0","url":null,"abstract":"Halogen(I) complexes are widely used as halogenation reagents and traditionally feature homoleptic stabilising Lewis bases, though the recent revitalisation of iodine(I) carboxylate chemistry has provided isolable examples of heteroleptic iodine(I) complexes. This work reports iodine(I) pnictogenate complexes stabilised by a Lewis base (L), Ph2P(O)O─I─L, synthesised via cation exchange from the silver(I) precursor, (Ph2P(O)OAg)n. The complexes were characterised in both solution (1H, 1H-15N HMBC, 31P) and the solid state, and supplemented computationally by DFT studies. Interestingly, these iodine(I) pnictogenates demonstrate a range of stabilities, and have been found to excel as iodination reagents in comparison to carbonyl hypoiodites, with comparable reactivity to the eponymous Barluenga’s reagent in the iodination of antipyrine. Iodine(I) carboxylates have been explored as iodination reagents, but the role of the carbonyl group in promoting such reactivity remains poorly understood. Here, the authors prepare iodine(I) pnictogenates and find that they excel as iodination reagents in comparison to iodine(I) carboxylates.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11255316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632889","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 : 2024-07-13DOI: 10.1038/s42004-024-01225-z
Javier Yu Peng Koh, Yoko Itahana, Alexander Krah, Habib Mostafa, Mingmin Ong, Sahana Iwamura, Dona Mariya Vincent, Sabhashina Radha Krishnan, Weiying Ye, Pierre Wing Chi Yim, Tushar M. Khopade, Kunihiko Chen, Pui San Kong, Lin-Fa Wang, Roderick W. Bates, Yasuhisa Kimura, Rajesh Viswanathan, Peter J. Bond, Koji Itahana
Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers. ATP-binding cassette transporter ABCB1 is known to be involved in drug resistance in cancer treatment, however, current ABCB1 inhibitors have not been successful in clinical trials due to their potential cytotoxicity. Here, the authors hypothesize that potential ABCB1 substrates in bats could act as competitive inhibitors against ABCB1 in humans, and identify the tryptophan structure as a promising lead structure for the development of non-toxic ABCB1 inhibitors.
{"title":"Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors","authors":"Javier Yu Peng Koh, Yoko Itahana, Alexander Krah, Habib Mostafa, Mingmin Ong, Sahana Iwamura, Dona Mariya Vincent, Sabhashina Radha Krishnan, Weiying Ye, Pierre Wing Chi Yim, Tushar M. Khopade, Kunihiko Chen, Pui San Kong, Lin-Fa Wang, Roderick W. Bates, Yasuhisa Kimura, Rajesh Viswanathan, Peter J. Bond, Koji Itahana","doi":"10.1038/s42004-024-01225-z","DOIUrl":"10.1038/s42004-024-01225-z","url":null,"abstract":"Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers. ATP-binding cassette transporter ABCB1 is known to be involved in drug resistance in cancer treatment, however, current ABCB1 inhibitors have not been successful in clinical trials due to their potential cytotoxicity. Here, the authors hypothesize that potential ABCB1 substrates in bats could act as competitive inhibitors against ABCB1 in humans, and identify the tryptophan structure as a promising lead structure for the development of non-toxic ABCB1 inhibitors.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11246513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603342","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 : 2024-07-13DOI: 10.1038/s42004-024-01237-9
Cangtao Yin, Gábor Czakó
Criegee intermediates play an important role in the tropospheric oxidation models through their reactions with atmospheric trace chemicals. We develop a global full-dimensional potential energy surface for the CH2OO + SO2 system and reveal how the reaction happens step by step by quasi-classical trajectory simulations. A new pathway forming the main products (CH2O + SO3) and a new product channel (CO2 + H2 + SO2) are predicted in our simulations. The new pathway appears at collision energies greater than 10 kcal/mol whose behavior demonstrates a typical barrier-controlled reaction. This threshold is also consistent with the ab initio transition state barrier height. For the minor products, a loose complex OCH2O ∙ ∙ ∙ SO2 is formed first, and then in most cases it soon turns into HCOOH + SO2, in a few cases it decomposes into CO2 + H2 + SO2 which is a new product channel, and rarely it remains as ∙OCH2O ∙ + SO2. Criegee intermediates such as CH2OO play an important role in tropospheric oxidation models through their reactions with atmospheric trace chemicals. Here, the authors develop a global full-dimensional potential energy surface for the CH2OO + SO2 system, reveal how the reaction happens step by step using quasi-classical trajectory simulations, to show a new direct stripping pathway forming the main products CH2O and SO3 and a new product channel.
{"title":"Revealing new pathways for the reaction of Criegee intermediate CH2OO with SO2","authors":"Cangtao Yin, Gábor Czakó","doi":"10.1038/s42004-024-01237-9","DOIUrl":"10.1038/s42004-024-01237-9","url":null,"abstract":"Criegee intermediates play an important role in the tropospheric oxidation models through their reactions with atmospheric trace chemicals. We develop a global full-dimensional potential energy surface for the CH2OO + SO2 system and reveal how the reaction happens step by step by quasi-classical trajectory simulations. A new pathway forming the main products (CH2O + SO3) and a new product channel (CO2 + H2 + SO2) are predicted in our simulations. The new pathway appears at collision energies greater than 10 kcal/mol whose behavior demonstrates a typical barrier-controlled reaction. This threshold is also consistent with the ab initio transition state barrier height. For the minor products, a loose complex OCH2O ∙ ∙ ∙ SO2 is formed first, and then in most cases it soon turns into HCOOH + SO2, in a few cases it decomposes into CO2 + H2 + SO2 which is a new product channel, and rarely it remains as ∙OCH2O ∙ + SO2. Criegee intermediates such as CH2OO play an important role in tropospheric oxidation models through their reactions with atmospheric trace chemicals. Here, the authors develop a global full-dimensional potential energy surface for the CH2OO + SO2 system, reveal how the reaction happens step by step using quasi-classical trajectory simulations, to show a new direct stripping pathway forming the main products CH2O and SO3 and a new product channel.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11246420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603343","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}
The resonance-stabilization of the propargyl radical (C3H3) makes it among the most important reactive intermediates in extreme environments and grants it a long enough lifetime to recombine in both terrestrial combustion media and cold molecular clouds in space. This makes the propargyl self-reaction a pivotal step in the formation of benzene, the first aromatic ring, to eventually lead to polycyclic aromatic hydrocarbons in a variety of environments. In this work, by producing propargyl radicals in a flow tube where propyne reacted with F atoms and probing the reaction products by mass-selected threshold-photoelectron spectroscopy (TPES), we identified eight C6H6 products in total, including benzene. On top of providing the first comprehensive measurements of the branching ratios of the eight identified C6H6 isomers in the propargyl self reaction products (4 mbar, 298 K conditions), this study also highlights the advantages and disadvantages of using isomer-selective TPES to identify and quantify reaction products. The propargyl radical (C3H3) self-reaction is a pivotal step in the formation of benzene in nature, but experimental validation for the complex reaction channels and products is challenging to obtain. Here, the authors produce propargyl radicals in a flow tube and report the branching ratios of eight identified C6H6 isomers in the propargyl self-reaction using isomer-selective threshold-photoelectron spectroscopy.
丙炔基（C3H3）的共振稳定性使其成为极端环境中最重要的反应中间体之一，并赋予其足够长的寿命，使其能够在地球燃烧介质和太空冷分子云中重新结合。这使得丙炔自反应成为形成苯（第一个芳香环）的关键步骤，最终在各种环境中形成多环芳烃。在这项研究中，我们通过在丙炔与 F 原子反应的流动管中产生丙炔自由基，并通过质量选择阈值光电子能谱（TPES）探测反应产物，总共确定了包括苯在内的八种 C6H6 产物。本研究首次全面测量了丙炔自反应产物（4 毫巴、298 K 条件下）中已识别的八种 C6H6 异构体的支化率，此外还强调了使用异构体选择性 TPES 识别和量化反应产物的优缺点。
{"title":"The isomer distribution of C6H6 products from the propargyl radical gas-phase recombination investigated by threshold-photoelectron spectroscopy","authors":"Helgi Rafn Hrodmarsson, Gustavo A. Garcia, Lyna Bourehil, Laurent Nahon, Bérenger Gans, Séverine Boyé-Péronne, Jean-Claude Guillemin, Jean-Christophe Loison","doi":"10.1038/s42004-024-01239-7","DOIUrl":"10.1038/s42004-024-01239-7","url":null,"abstract":"The resonance-stabilization of the propargyl radical (C3H3) makes it among the most important reactive intermediates in extreme environments and grants it a long enough lifetime to recombine in both terrestrial combustion media and cold molecular clouds in space. This makes the propargyl self-reaction a pivotal step in the formation of benzene, the first aromatic ring, to eventually lead to polycyclic aromatic hydrocarbons in a variety of environments. In this work, by producing propargyl radicals in a flow tube where propyne reacted with F atoms and probing the reaction products by mass-selected threshold-photoelectron spectroscopy (TPES), we identified eight C6H6 products in total, including benzene. On top of providing the first comprehensive measurements of the branching ratios of the eight identified C6H6 isomers in the propargyl self reaction products (4 mbar, 298 K conditions), this study also highlights the advantages and disadvantages of using isomer-selective TPES to identify and quantify reaction products. The propargyl radical (C3H3) self-reaction is a pivotal step in the formation of benzene in nature, but experimental validation for the complex reaction channels and products is challenging to obtain. Here, the authors produce propargyl radicals in a flow tube and report the branching ratios of eight identified C6H6 isomers in the propargyl self-reaction using isomer-selective threshold-photoelectron spectroscopy.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11245511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598837","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 : 2024-07-09DOI: 10.1038/s42004-024-01238-8
Zhifang Yang, Jun Xu, Yuli Sun, Xuemin Li, Bohan Jia, Yunfei Du
The existing hypervalent I(III) reagents bearing ONO2 group are limited in types and their applications primarily focused on the nitrooxylation reactions featuring a fully-exo fashion. Herein, a benziodazole-type O2NO-I(III) compound was prepared and its reaction with β-monosubstituted enamines in the presence of CuI could trigger a radical nitration/cyclization/dehydration cascade to provide a series of less explored but biologically interesting furazan heterocycles. Mechanistically, the benziodazole-type O2NO-I(III) compound acts as a nitrating reagent and incorporates its NO moiety into the final furazan product in a fully-endo model, a process of which was proposed to involve nitration, cyclization and dehydration. Hypervalent iodine(III) reagents show promising properties in organic synthesis, however, the application of nitrooxyl (O2NO)-containing I(III) reagents remains underexplored. Here, the authors report the synthesis of a benziodazole-type O2NO-I(III) reagent, which can be applied to the synthesis of furazan heterocycles as a nitrating agent, by reaction with β-monosubstituted enamines via a copper-catalyzed radical nitration/cyclization/dehydration cascade.
现有的带有 ONO2 基团的高价 I(III)试剂种类有限，其应用主要集中在以全外向型为特征的硝基氧化反应。本文制备了一种苯并碘唑型 O2NO-I(III) 化合物，在 CuI 存在下，它与β-单取代烯胺的反应可引发自由基硝化/环化/脱水级联反应，从而提供一系列探索较少但具有生物学意义的呋喃杂环。从机理上讲，苯并咪唑型 O2NO-I(III)化合物起着硝化试剂的作用，并以全内向模式将其 NO 分子结合到最终的呋喃产物中，其过程涉及硝化、环化和脱水。
{"title":"Preparation of a benziodazole-type iodine(III) compound and its application as a nitrating reagent for synthesis of furazans via a copper-catalyzed cascade process","authors":"Zhifang Yang, Jun Xu, Yuli Sun, Xuemin Li, Bohan Jia, Yunfei Du","doi":"10.1038/s42004-024-01238-8","DOIUrl":"10.1038/s42004-024-01238-8","url":null,"abstract":"The existing hypervalent I(III) reagents bearing ONO2 group are limited in types and their applications primarily focused on the nitrooxylation reactions featuring a fully-exo fashion. Herein, a benziodazole-type O2NO-I(III) compound was prepared and its reaction with β-monosubstituted enamines in the presence of CuI could trigger a radical nitration/cyclization/dehydration cascade to provide a series of less explored but biologically interesting furazan heterocycles. Mechanistically, the benziodazole-type O2NO-I(III) compound acts as a nitrating reagent and incorporates its NO moiety into the final furazan product in a fully-endo model, a process of which was proposed to involve nitration, cyclization and dehydration. Hypervalent iodine(III) reagents show promising properties in organic synthesis, however, the application of nitrooxyl (O2NO)-containing I(III) reagents remains underexplored. Here, the authors report the synthesis of a benziodazole-type O2NO-I(III) reagent, which can be applied to the synthesis of furazan heterocycles as a nitrating agent, by reaction with β-monosubstituted enamines via a copper-catalyzed radical nitration/cyclization/dehydration cascade.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01238-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562841","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 : 2024-07-08DOI: 10.1038/s42004-024-01222-2
Tianchen Qin, Tao Wang, Junfa Zhu
Nanoporous graphene (NPG) materials are generated by removing internal degree-3 vertices from graphene and introducing nanopores with specific topological structures, which have been widely explored and exploited for applications in electronic devices, membranes, and energy storage. The inherent properties of NPGs, such as the band structures, field effect mobilities and topological properties, are crucially determined by the geometric structure of nanopores. On-surface synthesis is an emerging strategy to fabricate low-dimensional carbon nanostructures with atomic precision. In this review, we introduce the progress of on-surface synthesis of atomically precise NPGs, and classify NPGs from the aspects of element types, topological structures, pore shapes, and synthesis strategies. We aim to provide a comprehensive overview of the recent advancements, promoting interdisciplinary collaboration to further advance the synthesis and applications of NPGs. On-surface synthesis is a useful approach for the construction of nanoporous graphene materials, which are in turn of interest for various electronic applications. Here, the authors review the latest developments in the on-surface synthesis of atomically precise pristine and hetero-atom doped nanoporous graphene materials.
{"title":"Recent progress in on-surface synthesis of nanoporous graphene materials","authors":"Tianchen Qin, Tao Wang, Junfa Zhu","doi":"10.1038/s42004-024-01222-2","DOIUrl":"10.1038/s42004-024-01222-2","url":null,"abstract":"Nanoporous graphene (NPG) materials are generated by removing internal degree-3 vertices from graphene and introducing nanopores with specific topological structures, which have been widely explored and exploited for applications in electronic devices, membranes, and energy storage. The inherent properties of NPGs, such as the band structures, field effect mobilities and topological properties, are crucially determined by the geometric structure of nanopores. On-surface synthesis is an emerging strategy to fabricate low-dimensional carbon nanostructures with atomic precision. In this review, we introduce the progress of on-surface synthesis of atomically precise NPGs, and classify NPGs from the aspects of element types, topological structures, pore shapes, and synthesis strategies. We aim to provide a comprehensive overview of the recent advancements, promoting interdisciplinary collaboration to further advance the synthesis and applications of NPGs. On-surface synthesis is a useful approach for the construction of nanoporous graphene materials, which are in turn of interest for various electronic applications. Here, the authors review the latest developments in the on-surface synthesis of atomically precise pristine and hetero-atom doped nanoporous graphene materials.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01222-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558220","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 : 2024-07-06DOI: 10.1038/s42004-024-01235-x
François Keiff, Freddy A. Bernal, Melanie Joch, Thibault J. W. Jacques dit Lapierre, Yan Li, Phil Liebing, Hans-Martin Dahse, Ivan Vilotijevic, Florian Kloss
Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered. Herein, we present a study of the influence of electron-withdrawing groups on the propensity of HMC formation in whole cells for a series of C-6-substituted BTZs obtained through reductive fluorocarbonylation as a late-stage functionalization key step. Gibbs free energy of reaction and Mulliken charges and Fukui indices on C-5 at quantum mechanics level were found as good indicators of in vitro HMC formation propensity. These results provide a first blueprint for the evaluation of HMC formation in drug development and set the stage for rational pharmacokinetic optimization of BTZs and similar drug candidates. Benzothiazinones (BTZs) are being developed as new antibiotics against the infection caused by Mycobacterium tuberculosis, however, BTZs can undergo an in vivo biotransformation to hydride-Meisenheimer complexes (HMC). Here, the authors show that HMC formation can be modulated by C-6 substitution of BTZ.
{"title":"Modulation of the Meisenheimer complex metabolism of nitro-benzothiazinones by targeted C-6 substitution","authors":"François Keiff, Freddy A. Bernal, Melanie Joch, Thibault J. W. Jacques dit Lapierre, Yan Li, Phil Liebing, Hans-Martin Dahse, Ivan Vilotijevic, Florian Kloss","doi":"10.1038/s42004-024-01235-x","DOIUrl":"10.1038/s42004-024-01235-x","url":null,"abstract":"Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered. Herein, we present a study of the influence of electron-withdrawing groups on the propensity of HMC formation in whole cells for a series of C-6-substituted BTZs obtained through reductive fluorocarbonylation as a late-stage functionalization key step. Gibbs free energy of reaction and Mulliken charges and Fukui indices on C-5 at quantum mechanics level were found as good indicators of in vitro HMC formation propensity. These results provide a first blueprint for the evaluation of HMC formation in drug development and set the stage for rational pharmacokinetic optimization of BTZs and similar drug candidates. Benzothiazinones (BTZs) are being developed as new antibiotics against the infection caused by Mycobacterium tuberculosis, however, BTZs can undergo an in vivo biotransformation to hydride-Meisenheimer complexes (HMC). Here, the authors show that HMC formation can be modulated by C-6 substitution of BTZ.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544626","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 : 2024-07-05DOI: 10.1038/s42004-024-01236-w
Andreas Prester, Markus Perbandt, Marina Galchenkova, Dominik Oberthuer, Nadine Werner, Alessandra Henkel, Julia Maracke, Oleksandr Yefanov, Johanna Hakanpää, Guillaume Pompidor, Jan Meyer, Henry Chapman, Martin Aepfelbacher, Winfried Hinrichs, Holger Rohde, Christian Betzel
The emergence and spread of antibiotic resistance represent a growing threat to public health. Of particular concern is the appearance of β-lactamases, which are capable to hydrolyze and inactivate the most important class of antibiotics, the β-lactams. Effective β-lactamase inhibitors and mechanistic insights into their action are central in overcoming this type of resistance, and in this context boronate-based β-lactamase inhibitors were just recently approved to treat multidrug-resistant bacteria. Using boric acid as a simplified inhibitor model, time-resolved serial crystallography was employed to obtain mechanistic insights into binding to the active site serine of β-lactamase CTX-M-14, identifying a reaction time frame of 80–100 ms. In a next step, the subsequent 1,2-diol boric ester formation with glycerol in the active site was monitored proceeding in a time frame of 100–150 ms. Furthermore, the displacement of the crucial anion in the active site of the β-lactamase was verified as an essential part of the binding mechanism of substrates and inhibitors. In total, 22 datasets of β-lactamase intermediate complexes with high spatial resolution of 1.40–2.04 Å and high temporal resolution range of 50–10,000 ms were obtained, allowing a detailed analysis of the studied processes. Mechanistic details captured here contribute to the understanding of molecular processes and their time frames in enzymatic reactions. Moreover, we could demonstrate that time-resolved crystallography can serve as an additional tool for identifying and investigating enzymatic reactions. Boronate-based ß-lactamase inhibitors play an important role in treating multidrug-resistant bacteria infection, however, the molecular mechanism of inhibition remains unclear. Here, the authors use time-resolved serial crystallography to investigate the binding process by using boric acid as a model against β-lactamase CTX-M-14, revealing the binding to the active site serine within 80–100 ms, a subsequent 1,2-diol boric ester formation with glycerol within 100–150 ms, as well as the displacement of the sulfate anion in the active site.
{"title":"Time-resolved crystallography of boric acid binding to the active site serine of the β-lactamase CTX-M-14 and subsequent 1,2-diol esterification","authors":"Andreas Prester, Markus Perbandt, Marina Galchenkova, Dominik Oberthuer, Nadine Werner, Alessandra Henkel, Julia Maracke, Oleksandr Yefanov, Johanna Hakanpää, Guillaume Pompidor, Jan Meyer, Henry Chapman, Martin Aepfelbacher, Winfried Hinrichs, Holger Rohde, Christian Betzel","doi":"10.1038/s42004-024-01236-w","DOIUrl":"10.1038/s42004-024-01236-w","url":null,"abstract":"The emergence and spread of antibiotic resistance represent a growing threat to public health. Of particular concern is the appearance of β-lactamases, which are capable to hydrolyze and inactivate the most important class of antibiotics, the β-lactams. Effective β-lactamase inhibitors and mechanistic insights into their action are central in overcoming this type of resistance, and in this context boronate-based β-lactamase inhibitors were just recently approved to treat multidrug-resistant bacteria. Using boric acid as a simplified inhibitor model, time-resolved serial crystallography was employed to obtain mechanistic insights into binding to the active site serine of β-lactamase CTX-M-14, identifying a reaction time frame of 80–100 ms. In a next step, the subsequent 1,2-diol boric ester formation with glycerol in the active site was monitored proceeding in a time frame of 100–150 ms. Furthermore, the displacement of the crucial anion in the active site of the β-lactamase was verified as an essential part of the binding mechanism of substrates and inhibitors. In total, 22 datasets of β-lactamase intermediate complexes with high spatial resolution of 1.40–2.04 Å and high temporal resolution range of 50–10,000 ms were obtained, allowing a detailed analysis of the studied processes. Mechanistic details captured here contribute to the understanding of molecular processes and their time frames in enzymatic reactions. Moreover, we could demonstrate that time-resolved crystallography can serve as an additional tool for identifying and investigating enzymatic reactions. Boronate-based ß-lactamase inhibitors play an important role in treating multidrug-resistant bacteria infection, however, the molecular mechanism of inhibition remains unclear. Here, the authors use time-resolved serial crystallography to investigate the binding process by using boric acid as a model against β-lactamase CTX-M-14, revealing the binding to the active site serine within 80–100 ms, a subsequent 1,2-diol boric ester formation with glycerol within 100–150 ms, as well as the displacement of the sulfate anion in the active site.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01236-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537717","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 : 2024-07-04DOI: 10.1038/s42004-024-01234-y
Christopher Brasnett, Armin Kiani, Selim Sami, Sijbren Otto, Siewert J. Marrink
Biomolecular condensates are phase separated systems that play an important role in the spatio-temporal organisation of cells. Their distinct physico-chemical nature offers a unique environment for chemical reactions to occur. The compartmentalisation of chemical reactions is also believed to be central to the development of early life. To demonstrate how molecular dynamics may be used to capture chemical reactions in condensates, here we perform reactive molecular dynamics simulations using the coarse-grained Martini forcefield. We focus on the formation of rings of benzene-1,3-dithiol inside a synthetic peptide-based condensate, and find that the ring size distribution shifts to larger macrocycles compared to when the reaction takes place in an aqueous environment. Moreover, reaction rates are noticeably increased when the peptides simultaneously undergo phase separation, hinting that condensates may act as chaperones in recruiting molecules to reaction hubs. Biomolecular condensates show distinct physicochemical properties that may affect the rate of enzymatic activity and control cellular redox reactions, however, their influence on the other types of chemical reaction remains underexplored. Here, the authors use reactive Martini simulations to probe the non-enzymatic macrocyclization reaction of benzene-1,3-dithiol in the presence of peptide condensates.
{"title":"Capturing chemical reactions inside biomolecular condensates with reactive Martini simulations","authors":"Christopher Brasnett, Armin Kiani, Selim Sami, Sijbren Otto, Siewert J. Marrink","doi":"10.1038/s42004-024-01234-y","DOIUrl":"10.1038/s42004-024-01234-y","url":null,"abstract":"Biomolecular condensates are phase separated systems that play an important role in the spatio-temporal organisation of cells. Their distinct physico-chemical nature offers a unique environment for chemical reactions to occur. The compartmentalisation of chemical reactions is also believed to be central to the development of early life. To demonstrate how molecular dynamics may be used to capture chemical reactions in condensates, here we perform reactive molecular dynamics simulations using the coarse-grained Martini forcefield. We focus on the formation of rings of benzene-1,3-dithiol inside a synthetic peptide-based condensate, and find that the ring size distribution shifts to larger macrocycles compared to when the reaction takes place in an aqueous environment. Moreover, reaction rates are noticeably increased when the peptides simultaneously undergo phase separation, hinting that condensates may act as chaperones in recruiting molecules to reaction hubs. Biomolecular condensates show distinct physicochemical properties that may affect the rate of enzymatic activity and control cellular redox reactions, however, their influence on the other types of chemical reaction remains underexplored. Here, the authors use reactive Martini simulations to probe the non-enzymatic macrocyclization reaction of benzene-1,3-dithiol in the presence of peptide condensates.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11222477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497316","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 : 2024-07-03DOI: 10.1038/s42004-024-01233-z
Alex Morehead, Jianlin Cheng
Generative deep learning methods have recently been proposed for generating 3D molecules using equivariant graph neural networks (GNNs) within a denoising diffusion framework. However, such methods are unable to learn important geometric properties of 3D molecules, as they adopt molecule-agnostic and non-geometric GNNs as their 3D graph denoising networks, which notably hinders their ability to generate valid large 3D molecules. In this work, we address these gaps by introducing the Geometry-Complete Diffusion Model (GCDM) for 3D molecule generation, which outperforms existing 3D molecular diffusion models by significant margins across conditional and unconditional settings for the QM9 dataset and the larger GEOM-Drugs dataset, respectively. Importantly, we demonstrate that GCDM’s generative denoising process enables the model to generate a significant proportion of valid and energetically-stable large molecules at the scale of GEOM-Drugs, whereas previous methods fail to do so with the features they learn. Additionally, we show that extensions of GCDM can not only effectively design 3D molecules for specific protein pockets but can be repurposed to consistently optimize the geometry and chemical composition of existing 3D molecules for molecular stability and property specificity, demonstrating new versatility of molecular diffusion models. Code and data are freely available on GitHub . Geometric deep learning methods have the advantage of being expressive, while denoising diffusion probabilistic models have great generative power. Here, the authors introduce a geometry-complete diffusion model for effective 3D molecule generation for specific protein pockets that can also consistently optimize the geometry and chemical composition of existing 3D molecules for molecular stability and property specificity
{"title":"Geometry-complete diffusion for 3D molecule generation and optimization","authors":"Alex Morehead, Jianlin Cheng","doi":"10.1038/s42004-024-01233-z","DOIUrl":"10.1038/s42004-024-01233-z","url":null,"abstract":"Generative deep learning methods have recently been proposed for generating 3D molecules using equivariant graph neural networks (GNNs) within a denoising diffusion framework. However, such methods are unable to learn important geometric properties of 3D molecules, as they adopt molecule-agnostic and non-geometric GNNs as their 3D graph denoising networks, which notably hinders their ability to generate valid large 3D molecules. In this work, we address these gaps by introducing the Geometry-Complete Diffusion Model (GCDM) for 3D molecule generation, which outperforms existing 3D molecular diffusion models by significant margins across conditional and unconditional settings for the QM9 dataset and the larger GEOM-Drugs dataset, respectively. Importantly, we demonstrate that GCDM’s generative denoising process enables the model to generate a significant proportion of valid and energetically-stable large molecules at the scale of GEOM-Drugs, whereas previous methods fail to do so with the features they learn. Additionally, we show that extensions of GCDM can not only effectively design 3D molecules for specific protein pockets but can be repurposed to consistently optimize the geometry and chemical composition of existing 3D molecules for molecular stability and property specificity, demonstrating new versatility of molecular diffusion models. Code and data are freely available on GitHub . Geometric deep learning methods have the advantage of being expressive, while denoising diffusion probabilistic models have great generative power. Here, the authors introduce a geometry-complete diffusion model for effective 3D molecule generation for specific protein pockets that can also consistently optimize the geometry and chemical composition of existing 3D molecules for molecular stability and property specificity","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11222514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497350","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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