• JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
  • JoomlaWorks Simple Image Rotator
 
  Bookmark and Share
 
 
Doctoral Thesis
DOI
10.11606/T.60.2018.tde-25052018-072452
Document
Author
Full name
Andreza da Silva Figuerêdo
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2018
Supervisor
Committee
Carvalho, Ivone (President)
Baruffi, Marcelo Dias
Alves, Ricardo José
Clososki, Giuliano Cesar
Crotti, Antonio Eduardo Miller
Title in Portuguese
Síntese e avaliação biológica de glycoclusters com potencial aplicação para o tratamento de diabetes e doença de Chagas
Keywords in Portuguese
Efeito multivalente; Glycoclusters; Síntese de carboidratos; Glucosidases; Trans-sialidase
Abstract in Portuguese
As funções abrangentes e complexas de carboidratos nos sistemas biológicos oferecem muitas possibilidades para explorar essas estruturas no desenvolvimento de estratégias terapêuticas. Como consequência de sua estrutura e função, algumas glicosidases e glicosiltransferases envolvidas em patologias significativas como diabetes e doença de Chagas são alvos interessantes na busca por inibidores enzimáticos baseados em carboidratos. Assim, o conhecimento de características estruturais e mecanismo de ação de ?- e ?-glucosidases e trans-sialidases e as sólidas evidências de que glicosidases são sensíveis a efeito de multivalência sustentaram o planejamento de glycoclusters potencialmente inibidores dessas enzimas contendo três, quatro ou seis unidades correlatas aos seus substratos naturais (glicose e galactose/ácido siálico). Adicionalmente foram propostos glycoclusters baseados na estrutura do glicoaminoácido ?-GalNAc-O-Thr. Empregando reações de cicloadição CuAAC, treze dos dezesseis glycoclusters tetra- e hexavalentes inicialmente propostos foram obtidos em bons rendimentos, sendo 8 derivados de glicose, 4 de galactose e o derivado tetravalente de ácido siálico 7. Dez desses compostos são inéditos na literatura. Com a finalidade de gerar diversidade estrutural o derivado trivalente 29 foi preparado e permitiu o acoplamento de um imino-açúcar D-gluco ou L-gulo DNJ a estruturas trivalentes de glicose. A mesma estratégia levou à obtenção do glycocluster 85, contendo unidades de galactose e um resíduo de ácido siálico. Ensaios de cinética em ?-glucosidases de arroz e Saccharomyces cerevisiae e ?-glucosidase de amêndoas com os glycoclusters derivados de glicose 1-4, 9-12 e 63-66 mostraram atividade interessante apenas para os compostos mistos, evidenciando a importância do imino-açúcar para a interação com essas enzimas. No que diz respeito aos derivados multivalentes de galactose e/ou ácido siálico 5-7, 13, 14 e 85, inibição expressiva da enzima TcTS foi alcançada pelo derivado 7 (IC50 450 ?M). Ensaios de atividade tripanocida, bloqueio de invasão e citotoxicidade sobre fibroblastos de mamífero não-infectados cultivados in vitro evidenciaram atividade de todos esses compostos contra a forma amastigota e bloqueio de invasão celular por T. cruzi (diminuindo a infecção em concentrações de até 25?M).
Title in English
Synthesis and biological evaluation of glycoclusters with potential applications in diabetes and Chagas disease
Keywords in English
Carbohydrate synthesis; Glucosidases 5; Trans-sialidase; Glycoclusters; Multivalent effect
Abstract in English
The comprehensive and elaborate functions of carbohydrates in biological systems offer countless possibilities to apply these structures in the development of therapeutic strategies. Because of their structure and function, some glycosidases and glycosyltransferases involved in pathological conditions such as diabetes and Chagas disease are interesting targets in the search for carbohydrate-based enzyme inhibitors. Thus, the knowledge of structural features and the mechanism of action of ?- and ?-glucosidases and trans-sialidases, combined with strong evidences that glycosidases are sensitive to multivalent effect, have supported the design of substrate-based glycoclusters with potential glycosidases inhibitory properties. In addition, glycoclusters based on the structure of the ?-GalNAc-O-Thr glycoamino acid have been planned. Using CuAAC cycloaddition reactions, thirteen of the sixteen tetra- and hexavalent glycoclusters were obtained in good yields, being 8 glucose derivatives, 4 galactose, and the tetravalent sialic acid derivative 7. Ten of these compounds are unpublished. In order to generate structural diversity, the trivalent block 29 was prepared and allowed the coupling of trivalent glucose clusters to iminosugars D-gluco or L-gulo DNJ isomers. The same strategy afforded glycocluster 85, containing galactose units and a sialic acid residue. Kinetic assays in ? and ?-glucosidases with the glucose-derived glycoclusters 1-4, 9-12 and 63-66 showed interesting activity only for the heteroclusters compounds, evidencing the relevance of iminosugars for the interaction with these enzymes. Regarding galactose and/or sialic acid cluster 5-7, 13, 14 and 85, significant inhibition of the TcTS enzyme was achieved by derivative 7 (IC50 450 ?M). In vitro assays for trypanocidal activity and cytotoxicity showed good results for of all these compounds. They appear to block host cell invasion by T. cruzi (reducing infection index in concentrations up to 25?M).
 
WARNING - Viewing this document is conditioned on your acceptance of the following terms of use:
This document is only for private use for research and teaching activities. Reproduction for commercial use is forbidden. This rights cover the whole data about this document as well as its contents. Any uses or copies of this document in whole or in part must include the author's name.
There are withheld file due to requirements (data publishing, patents or rights).
Release Date
2020-05-24
Publishing Date
2018-08-15
 
WARNING: Learn what derived works are clicking here.
All rights of the thesis/dissertation are from the authors
CeTI-SC/STI
Digital Library of Theses and Dissertations of USP. Copyright © 2001-2019. All rights reserved.