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Synthetic genistein derivatives as modulators of glycosaminoglycan storage

BACKGROUND: Mucopolysaccharidoses (MPS) are severe metabolic disorders caused by accumulation of undegraded glycosaminoglycans (GAGs) in lysosomes due to defects in certain lysosomal hydrolases. Substrate reduction therapy (SRT) has been proposed as one of potential treatment procedures of MPS. Impo...

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Autores principales: Kloska, Anna, Narajczyk, Magdalena, Jakóbkiewicz-Banecka, Joanna, Grynkiewicz, Grzegorz, Szeja, Wiesław, Gabig-Cimińska, Magdalena, Węgrzyn, Grzegorz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441846/
https://www.ncbi.nlm.nih.gov/pubmed/22846663
http://dx.doi.org/10.1186/1479-5876-10-153
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author Kloska, Anna
Narajczyk, Magdalena
Jakóbkiewicz-Banecka, Joanna
Grynkiewicz, Grzegorz
Szeja, Wiesław
Gabig-Cimińska, Magdalena
Węgrzyn, Grzegorz
author_facet Kloska, Anna
Narajczyk, Magdalena
Jakóbkiewicz-Banecka, Joanna
Grynkiewicz, Grzegorz
Szeja, Wiesław
Gabig-Cimińska, Magdalena
Węgrzyn, Grzegorz
author_sort Kloska, Anna
collection PubMed
description BACKGROUND: Mucopolysaccharidoses (MPS) are severe metabolic disorders caused by accumulation of undegraded glycosaminoglycans (GAGs) in lysosomes due to defects in certain lysosomal hydrolases. Substrate reduction therapy (SRT) has been proposed as one of potential treatment procedures of MPS. Importantly, small molecules used in such a therapy might potentially cross the blood–brain barrier (BBB) and improve neurological status of patients, as reported for a natural isoflavone, 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4 H-1-benzopyran-4-one, also known as genistein. Although genistein is able to cross BBB to some extent, its delivery to the central nervous system is still relatively poor (below 10% efficiency). Thus, we aimed to develop a set of synthetically modified genistein molecules and characterize physicochemical as well as biological properties of these compounds. METHODS: Following parameters were determined for the tested synthetic derivatives of genistein: cytotoxicity, effects on cell proliferation, kinetics of GAG synthesis, effects on epidermal growth factor (EGF) receptor’s tyrosine kinase activity, effects on lysosomal storage, potential ability to cross BBB. RESULTS: We observed that some synthetic derivatives inhibited GAG synthesis similarly to, or more efficiently than, genistein and were able to reduce lysosomal storage in MPS III fibroblasts. The tested compounds were generally of low cytotoxicity and had minor effects on cell proliferation. Moreover, synthetic derivatives of genistein revealed higher lipophilicity (assessed in silico) than the natural isoflavone. CONCLUSION: Some compounds tested in this study might be promising candidates for further studies on therapeutic agents in MPS types with neurological symptoms.
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spelling pubmed-34418462012-09-15 Synthetic genistein derivatives as modulators of glycosaminoglycan storage Kloska, Anna Narajczyk, Magdalena Jakóbkiewicz-Banecka, Joanna Grynkiewicz, Grzegorz Szeja, Wiesław Gabig-Cimińska, Magdalena Węgrzyn, Grzegorz J Transl Med Research BACKGROUND: Mucopolysaccharidoses (MPS) are severe metabolic disorders caused by accumulation of undegraded glycosaminoglycans (GAGs) in lysosomes due to defects in certain lysosomal hydrolases. Substrate reduction therapy (SRT) has been proposed as one of potential treatment procedures of MPS. Importantly, small molecules used in such a therapy might potentially cross the blood–brain barrier (BBB) and improve neurological status of patients, as reported for a natural isoflavone, 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4 H-1-benzopyran-4-one, also known as genistein. Although genistein is able to cross BBB to some extent, its delivery to the central nervous system is still relatively poor (below 10% efficiency). Thus, we aimed to develop a set of synthetically modified genistein molecules and characterize physicochemical as well as biological properties of these compounds. METHODS: Following parameters were determined for the tested synthetic derivatives of genistein: cytotoxicity, effects on cell proliferation, kinetics of GAG synthesis, effects on epidermal growth factor (EGF) receptor’s tyrosine kinase activity, effects on lysosomal storage, potential ability to cross BBB. RESULTS: We observed that some synthetic derivatives inhibited GAG synthesis similarly to, or more efficiently than, genistein and were able to reduce lysosomal storage in MPS III fibroblasts. The tested compounds were generally of low cytotoxicity and had minor effects on cell proliferation. Moreover, synthetic derivatives of genistein revealed higher lipophilicity (assessed in silico) than the natural isoflavone. CONCLUSION: Some compounds tested in this study might be promising candidates for further studies on therapeutic agents in MPS types with neurological symptoms. BioMed Central 2012-07-30 /pmc/articles/PMC3441846/ /pubmed/22846663 http://dx.doi.org/10.1186/1479-5876-10-153 Text en Copyright ©2012 Kloska et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Kloska, Anna
Narajczyk, Magdalena
Jakóbkiewicz-Banecka, Joanna
Grynkiewicz, Grzegorz
Szeja, Wiesław
Gabig-Cimińska, Magdalena
Węgrzyn, Grzegorz
Synthetic genistein derivatives as modulators of glycosaminoglycan storage
title Synthetic genistein derivatives as modulators of glycosaminoglycan storage
title_full Synthetic genistein derivatives as modulators of glycosaminoglycan storage
title_fullStr Synthetic genistein derivatives as modulators of glycosaminoglycan storage
title_full_unstemmed Synthetic genistein derivatives as modulators of glycosaminoglycan storage
title_short Synthetic genistein derivatives as modulators of glycosaminoglycan storage
title_sort synthetic genistein derivatives as modulators of glycosaminoglycan storage
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441846/
https://www.ncbi.nlm.nih.gov/pubmed/22846663
http://dx.doi.org/10.1186/1479-5876-10-153
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