The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1039/d0md00366b http://hdl.handle.net/11449/210261 |
Resumo: | The conceptual technology of small molecule glycomimetics, exemplified by compounds C1-4, has shown promising protective effects against lipid-induced endothelial dysfunction, restorative effects on diabetic endothelial colony forming cells, and preventative effects on downstream vascular calcification amongst other important in vitro and ex vivo studies. We report the optimised synthesis of an array of 17 small molecule glycomimetics, including the regio-, enantio- and diastereo-meric sulfated scaffolds of a hit structure along with novel desulfated examples. For the first time, the absolute stereochemical configurations of C1-4 have been clarified based on an identified and consistent anomaly with the Sharpless asymmetric dihydroxylation reaction. We have investigated the role and importance of sulfation pattern, location, regioisomers, and spatial orientation of distal sulfate groups on the modulation of endothelial dysfunction through their interaction with hepatocyte growth factor (HGF). In silico studies demonstrated the key interactions the persulfated glycomimetics make with HGF and revealed the importance of both sulfate density and positioning (both point chirality and vector) to biological activity. In vitro biological data of the most efficient binding motifs, along with desulfated comparators, support the modulatory effects of sulfated small molecule glycomimetics in the downstream signaling cascade of endothelial dysfunction. In vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) data demonstrate the glycomimetic approach to be a promising approach for hit-to-lead studies. |
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The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studiesThe conceptual technology of small molecule glycomimetics, exemplified by compounds C1-4, has shown promising protective effects against lipid-induced endothelial dysfunction, restorative effects on diabetic endothelial colony forming cells, and preventative effects on downstream vascular calcification amongst other important in vitro and ex vivo studies. We report the optimised synthesis of an array of 17 small molecule glycomimetics, including the regio-, enantio- and diastereo-meric sulfated scaffolds of a hit structure along with novel desulfated examples. For the first time, the absolute stereochemical configurations of C1-4 have been clarified based on an identified and consistent anomaly with the Sharpless asymmetric dihydroxylation reaction. We have investigated the role and importance of sulfation pattern, location, regioisomers, and spatial orientation of distal sulfate groups on the modulation of endothelial dysfunction through their interaction with hepatocyte growth factor (HGF). In silico studies demonstrated the key interactions the persulfated glycomimetics make with HGF and revealed the importance of both sulfate density and positioning (both point chirality and vector) to biological activity. In vitro biological data of the most efficient binding motifs, along with desulfated comparators, support the modulatory effects of sulfated small molecule glycomimetics in the downstream signaling cascade of endothelial dysfunction. In vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) data demonstrate the glycomimetic approach to be a promising approach for hit-to-lead studies.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)University of BirminghamWellcome TrustAlexander Von Humboldt FoundationInternational Atherosclerosis Society (IAS; USA)Healthcare Science Research CentreUniv Birmingham, Sch Pharm, Edgbaston B15 2TT, EnglandIBILCE, Dept Fis, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP, BrazilManchester Metropolitan Univ, Dept Nat Sci, Manchester M1 5GD, Lancs, EnglandBeni Suef Univ, Physiol Div, Dept Zool, Fac Sci, Bani Suwayf, EgyptCharite Univ Med Berlin, Dept Endocrinol Diabet & Nutr, Ctr Cardiovasc Res CCR, Berlin, GermanyManchester Metropolitan Univ, Ctr Biomed, Manchester M1 5GD, Lancs, EnglandIBILCE, Dept Fis, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP, BrazilCAPES: 001Wellcome Trust: 202151/Z/16/ZAlexander Von Humboldt Foundation: 1158232Royal Soc ChemistryUniv BirminghamUniversidade Estadual Paulista (Unesp)Manchester Metropolitan UnivBeni Suef UnivCharite Univ Med BerlinGill, Daniel M.Povinelli, Ana Paula R. [UNESP]Zazeri, Gabriel [UNESP]Shamir, Sabrina A.Mahmoud, Ayman M.Wilkinson, Fiona L.Alexander, M. YvonneCornelio, Marinonio L. [UNESP]Jones, Alan M.2021-06-25T15:02:57Z2021-06-25T15:02:57Z2021-04-23info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article12http://dx.doi.org/10.1039/d0md00366bRsc Medicinal Chemistry. Cambridge: Royal Soc Chemistry, 12 p., 2021.http://hdl.handle.net/11449/21026110.1039/d0md00366bWOS:000642593700001Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengRsc Medicinal Chemistryinfo:eu-repo/semantics/openAccess2021-10-23T20:17:25Zoai:repositorio.unesp.br:11449/210261Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T15:06:34.245689Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
title |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
spellingShingle |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies Gill, Daniel M. |
title_short |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
title_full |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
title_fullStr |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
title_full_unstemmed |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
title_sort |
The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies |
author |
Gill, Daniel M. |
author_facet |
Gill, Daniel M. Povinelli, Ana Paula R. [UNESP] Zazeri, Gabriel [UNESP] Shamir, Sabrina A. Mahmoud, Ayman M. Wilkinson, Fiona L. Alexander, M. Yvonne Cornelio, Marinonio L. [UNESP] Jones, Alan M. |
author_role |
author |
author2 |
Povinelli, Ana Paula R. [UNESP] Zazeri, Gabriel [UNESP] Shamir, Sabrina A. Mahmoud, Ayman M. Wilkinson, Fiona L. Alexander, M. Yvonne Cornelio, Marinonio L. [UNESP] Jones, Alan M. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Univ Birmingham Universidade Estadual Paulista (Unesp) Manchester Metropolitan Univ Beni Suef Univ Charite Univ Med Berlin |
dc.contributor.author.fl_str_mv |
Gill, Daniel M. Povinelli, Ana Paula R. [UNESP] Zazeri, Gabriel [UNESP] Shamir, Sabrina A. Mahmoud, Ayman M. Wilkinson, Fiona L. Alexander, M. Yvonne Cornelio, Marinonio L. [UNESP] Jones, Alan M. |
description |
The conceptual technology of small molecule glycomimetics, exemplified by compounds C1-4, has shown promising protective effects against lipid-induced endothelial dysfunction, restorative effects on diabetic endothelial colony forming cells, and preventative effects on downstream vascular calcification amongst other important in vitro and ex vivo studies. We report the optimised synthesis of an array of 17 small molecule glycomimetics, including the regio-, enantio- and diastereo-meric sulfated scaffolds of a hit structure along with novel desulfated examples. For the first time, the absolute stereochemical configurations of C1-4 have been clarified based on an identified and consistent anomaly with the Sharpless asymmetric dihydroxylation reaction. We have investigated the role and importance of sulfation pattern, location, regioisomers, and spatial orientation of distal sulfate groups on the modulation of endothelial dysfunction through their interaction with hepatocyte growth factor (HGF). In silico studies demonstrated the key interactions the persulfated glycomimetics make with HGF and revealed the importance of both sulfate density and positioning (both point chirality and vector) to biological activity. In vitro biological data of the most efficient binding motifs, along with desulfated comparators, support the modulatory effects of sulfated small molecule glycomimetics in the downstream signaling cascade of endothelial dysfunction. In vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) data demonstrate the glycomimetic approach to be a promising approach for hit-to-lead studies. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-06-25T15:02:57Z 2021-06-25T15:02:57Z 2021-04-23 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1039/d0md00366b Rsc Medicinal Chemistry. Cambridge: Royal Soc Chemistry, 12 p., 2021. http://hdl.handle.net/11449/210261 10.1039/d0md00366b WOS:000642593700001 |
url |
http://dx.doi.org/10.1039/d0md00366b http://hdl.handle.net/11449/210261 |
identifier_str_mv |
Rsc Medicinal Chemistry. Cambridge: Royal Soc Chemistry, 12 p., 2021. 10.1039/d0md00366b WOS:000642593700001 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Rsc Medicinal Chemistry |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
12 |
dc.publisher.none.fl_str_mv |
Royal Soc Chemistry |
publisher.none.fl_str_mv |
Royal Soc Chemistry |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
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1808128463775727616 |