Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure pres...
Ausführliche Beschreibung
Autor*in: |
Simone Gastaldi [verfasserIn] Valentina Boscaro [verfasserIn] Eleonora Gianquinto [verfasserIn] Christina F. Sandall [verfasserIn] Marta Giorgis [verfasserIn] Elisabetta Marini [verfasserIn] Federica Blua [verfasserIn] Margherita Gallicchio [verfasserIn] Francesca Spyrakis [verfasserIn] Justin A. MacDonald [verfasserIn] Massimo Bertinaria [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2021 |
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Schlagwörter: |
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Übergeordnetes Werk: |
In: Molecules - MDPI AG, 2003, 26(2021), 13, p 3975 |
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Übergeordnetes Werk: |
volume:26 ; year:2021 ; number:13, p 3975 |
Links: |
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DOI / URN: |
10.3390/molecules26133975 |
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Katalog-ID: |
DOAJ052372944 |
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10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975 |
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10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975 |
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10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975 |
allfieldsGer |
10.3390/molecules26133975 doi (DE-627)DOAJ052372944 (DE-599)DOAJ3c3494cec8624421abf07d12c3ebe214 DE-627 ger DE-627 rakwb eng QD241-441 Simone Gastaldi verfasserin aut Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. NLRP3 inhibitors pyroptosis interleukin-1β ATP hydrolysis MD simulations Organic chemistry Valentina Boscaro verfasserin aut Eleonora Gianquinto verfasserin aut Christina F. Sandall verfasserin aut Marta Giorgis verfasserin aut Elisabetta Marini verfasserin aut Federica Blua verfasserin aut Margherita Gallicchio verfasserin aut Francesca Spyrakis verfasserin aut Justin A. MacDonald verfasserin aut Massimo Bertinaria verfasserin aut In Molecules MDPI AG, 2003 26(2021), 13, p 3975 (DE-627)311313132 (DE-600)2008644-1 14203049 nnns volume:26 year:2021 number:13, p 3975 https://doi.org/10.3390/molecules26133975 kostenfrei https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 kostenfrei https://www.mdpi.com/1420-3049/26/13/3975 kostenfrei https://doaj.org/toc/1420-3049 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 26 2021 13, p 3975 |
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Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor |
abstract |
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. |
abstractGer |
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. |
abstract_unstemmed |
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds <b<9</b<, <b<13</b< and <b<18</b<, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. |
collection_details |
GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 |
container_issue |
13, p 3975 |
title_short |
Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2<i<H</i<-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor |
url |
https://doi.org/10.3390/molecules26133975 https://doaj.org/article/3c3494cec8624421abf07d12c3ebe214 https://www.mdpi.com/1420-3049/26/13/3975 https://doaj.org/toc/1420-3049 |
remote_bool |
true |
author2 |
Valentina Boscaro Eleonora Gianquinto Christina F. Sandall Marta Giorgis Elisabetta Marini Federica Blua Margherita Gallicchio Francesca Spyrakis Justin A. MacDonald Massimo Bertinaria |
author2Str |
Valentina Boscaro Eleonora Gianquinto Christina F. Sandall Marta Giorgis Elisabetta Marini Federica Blua Margherita Gallicchio Francesca Spyrakis Justin A. MacDonald Massimo Bertinaria |
ppnlink |
311313132 |
callnumber-subject |
QD - Chemistry |
mediatype_str_mv |
c |
isOA_txt |
true |
hochschulschrift_bool |
false |
doi_str |
10.3390/molecules26133975 |
callnumber-a |
QD241-441 |
up_date |
2024-07-04T00:48:48.412Z |
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1803607477754789888 |
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