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

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MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniv Birmingham-
Autor(es): dc.contributorUniversidade Estadual Paulista (Unesp)-
Autor(es): dc.contributorManchester Metropolitan Univ-
Autor(es): dc.contributorBeni Suef Univ-
Autor(es): dc.contributorCharite Univ Med Berlin-
Autor(es): dc.creatorGill, Daniel M.-
Autor(es): dc.creatorPovinelli, Ana Paula R. [UNESP]-
Autor(es): dc.creatorZazeri, Gabriel [UNESP]-
Autor(es): dc.creatorShamir, Sabrina A.-
Autor(es): dc.creatorMahmoud, Ayman M.-
Autor(es): dc.creatorWilkinson, Fiona L.-
Autor(es): dc.creatorAlexander, M. Yvonne-
Autor(es): dc.creatorCornelio, Marinonio L. [UNESP]-
Autor(es): dc.creatorJones, Alan M.-
Data de aceite: dc.date.accessioned2022-02-22T00:59:18Z-
Data de disponibilização: dc.date.available2022-02-22T00:59:18Z-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2021-06-25-
Data de envio: dc.date.issued2021-04-23-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1039/d0md00366b-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/210261-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/210261-
Descrição: dc.descriptionThe 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.-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionUniversity of Birmingham-
Descrição: dc.descriptionWellcome Trust-
Descrição: dc.descriptionAlexander Von Humboldt Foundation-
Descrição: dc.descriptionInternational Atherosclerosis Society (IAS; USA)-
Descrição: dc.descriptionHealthcare Science Research Centre-
Descrição: dc.descriptionUniv Birmingham, Sch Pharm, Edgbaston B15 2TT, England-
Descrição: dc.descriptionIBILCE, Dept Fis, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil-
Descrição: dc.descriptionManchester Metropolitan Univ, Dept Nat Sci, Manchester M1 5GD, Lancs, England-
Descrição: dc.descriptionBeni Suef Univ, Physiol Div, Dept Zool, Fac Sci, Bani Suwayf, Egypt-
Descrição: dc.descriptionCharite Univ Med Berlin, Dept Endocrinol Diabet & Nutr, Ctr Cardiovasc Res CCR, Berlin, Germany-
Descrição: dc.descriptionManchester Metropolitan Univ, Ctr Biomed, Manchester M1 5GD, Lancs, England-
Descrição: dc.descriptionIBILCE, Dept Fis, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil-
Descrição: dc.descriptionCAPES: 001-
Descrição: dc.descriptionWellcome Trust: 202151/Z/16/Z-
Descrição: dc.descriptionAlexander Von Humboldt Foundation: 1158232-
Formato: dc.format12-
Idioma: dc.languageen-
Publicador: dc.publisherRoyal Soc Chemistry-
Relação: dc.relationRsc Medicinal Chemistry-
???dc.source???: dc.sourceWeb of Science-
Título: dc.titleThe 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-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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