{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T21:40:34Z","timestamp":1776894034561,"version":"3.51.2"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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\u2013brain barrier (BBB) and improve neurological status of patients, as reported for a natural isoflavone, 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4\u2009<jats:italic>H<\/jats:italic>-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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2019s tyrosine kinase activity, effects on lysosomal storage, potential ability to cross BBB.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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<jats:italic>in silico<\/jats:italic>) than the natural isoflavone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Some compounds tested in this study might be promising candidates for further studies on therapeutic agents in MPS types with neurological symptoms.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1479-5876-10-153","type":"journal-article","created":{"date-parts":[[2012,7,31]],"date-time":"2012-07-31T10:08:05Z","timestamp":1343729285000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Synthetic genistein derivatives as modulators of glycosaminoglycan storage"],"prefix":"10.1186","volume":"10","author":[{"given":"Anna","family":"Kloska","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Narajczyk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Jak\u00f3bkiewicz-Banecka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grzegorz","family":"Grynkiewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wies\u0142aw","family":"Szeja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Gabig-Cimi\u0144ska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grzegorz","family":"W\u0119grzyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2012,7,30]]},"reference":[{"key":"1097_CR1","first-page":"13","volume-title":"Genetic Metabolic Disorders: Management, Costs and Sociomedical Aspects","author":"M Beck","year":"2007","unstructured":"Beck M: Mucopolysaccharidoses: clinical features and management. Genetic Metabolic Disorders: Management, Costs and Sociomedical Aspects. Edited by: Dahl S, Wendel U, Strohmeyer G. 2007, Deutscher Arzte-Verlag, Cologne, 13-18."},{"key":"1097_CR2","first-page":"3421","volume-title":"The metabolic and molecular bases of inherited disease","author":"EF Neufeld","year":"2001","unstructured":"Neufeld EF, Muenzer J: The mucopolysaccharidoses. The metabolic and molecular bases of inherited disease. Edited by: Scriver CR, Beaudet AL, Sly WS, Valle D. 2001, McGraw-Hill Co, New York, 3421-3452."},{"key":"1097_CR3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/iub.284","volume":"62","author":"M Beck","year":"2010","unstructured":"Beck M: Therapy for lysosomal storage disorders. IUBMB Life. 2010, 62: 33-40.","journal-title":"IUBMB Life"},{"key":"1097_CR4","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/1750-1172-6-55","volume":"6","author":"MH de Ru","year":"2011","unstructured":"de Ru MH, Boelens JJ, Das AM, Jones SA, van der Lee JH, Mahlaoui N, Mengel E, Offringa M, O'Meara A, Parini R: Enzyme replacement therapy and\/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis. 2011, 6: 55-10.1186\/1750-1172-6-55.","journal-title":"Orphanet J Rare Dis"},{"issue":"Suppl 1","key":"1097_CR5","first-page":"63","volume":"47","author":"JE Wraith","year":"2009","unstructured":"Wraith JE: Enzyme replacement therapy for the management of the mucopolysaccharidoses. Int J Clin Pharmacol Ther. 2009, 47 (Suppl 1): 63-65.","journal-title":"Int J Clin Pharmacol Ther"},{"key":"1097_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00439-006-0280-4","volume":"121","author":"M Beck","year":"2007","unstructured":"Beck M: New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet. 2007, 121: 1-22. 10.1007\/s00439-006-0280-4.","journal-title":"Hum Genet"},{"key":"1097_CR7","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1038\/sj.ejhg.5201623","volume":"14","author":"E Piotrowska","year":"2006","unstructured":"Piotrowska E, Jakobkiewicz-Banecka J, Baranska S, Tylki-Szymanska A, Czartoryska B, Wegrzyn A, Wegrzyn G: Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur J Hum Genet. 2006, 14: 846-852. 10.1038\/sj.ejhg.5201623.","journal-title":"Eur J Hum Genet"},{"key":"1097_CR8","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/0012-1606(87)90306-X","volume":"122","author":"MM Pisano","year":"1987","unstructured":"Pisano MM, Greene RM: Epidermal growth factor potentiates the induction of ornithine decarboxylase activity by prostaglandins in embryonic palate mesenchymal cells: effects on cell proliferation and glycosaminoglycan synthesis. Dev Biol. 1987, 122: 419-431. 10.1016\/0012-1606(87)90306-X.","journal-title":"Dev Biol"},{"key":"1097_CR9","doi-asserted-by":"publisher","first-page":"4787","DOI":"10.1074\/jbc.272.8.4787","volume":"272","author":"E Tirone","year":"1997","unstructured":"Tirone E, D'Alessandris C, Hascall VC, Siracusa G, Salustri A: Hyaluronan synthesis by mouse cumulus cells is regulated by interactions between follicle-stimulating hormone (or epidermal growth factor) and a soluble oocyte factor (or transforming growth factor beta1). J Biol Chem. 1997, 272: 4787-4794. 10.1074\/jbc.272.8.4787.","journal-title":"J Biol Chem"},{"key":"1097_CR10","doi-asserted-by":"crossref","first-page":"5592","DOI":"10.1016\/S0021-9258(18)45614-1","volume":"262","author":"T Akiyama","year":"1987","unstructured":"Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y: Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987, 262: 5592-5595.","journal-title":"J Biol Chem"},{"key":"1097_CR11","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1423-0127-16-26","volume":"16","author":"J Jakobkiewicz-Banecka","year":"2009","unstructured":"Jakobkiewicz-Banecka J, Piotrowska E, Narajczyk M, Baranska S, Wegrzyn G: Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway. J Biomed Sci. 2009, 16: 26-10.1186\/1423-0127-16-26.","journal-title":"J Biomed Sci"},{"key":"1097_CR12","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1042\/BST0380695","volume":"38","author":"G Wegrzyn","year":"2010","unstructured":"Wegrzyn G, Jakobkiewicz-Banecka J, Gabig-Ciminska M, Piotrowska E, Narajczyk M, Kloska A, Malinowska M, Dziedzic D, Golebiewska I, Moskot M, Wegrzyn A: Genistein: a natural isoflavone with a potential for treatment of genetic diseases. Biochem Soc Trans. 2010, 38: 695-701. 10.1042\/BST0380695.","journal-title":"Biochem Soc Trans"},{"key":"1097_CR13","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.2174\/138920111798376932","volume":"12","author":"J Jakobkiewicz-Banecka","year":"2011","unstructured":"Jakobkiewicz-Banecka J, Piotrowska E, Gabig-Ciminska M, Borysiewicz E, Slominska-Wojewodzka M, Narajczyk M, Wegrzyn A, Wegrzyn G: Substrate reduction therapies for mucopolysaccharidoses. Curr Pharm Biotechnol. 2011, 12: 1860-1865. 10.2174\/138920111798376932.","journal-title":"Curr Pharm Biotechnol"},{"key":"1097_CR14","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/iub.1007","volume":"64","author":"A Wegrzyn","year":"2012","unstructured":"Wegrzyn A: Gene expression-targeted isoflavone therapy. IUBMB Life. 2012, 64: 307-315. 10.1002\/iub.1007.","journal-title":"IUBMB Life"},{"key":"1097_CR15","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.chroma.2004.10.048","volume":"1073","author":"TH Tsai","year":"2005","unstructured":"Tsai TH: Concurrent measurement of unbound genistein in the blood, brain and bile of anesthetized rats using microdialysis and its pharmacokinetic application. J Chromatogr A. 2005, 1073: 317-322. 10.1016\/j.chroma.2004.10.048.","journal-title":"J Chromatogr A"},{"key":"1097_CR16","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.ymgme.2009.06.013","volume":"98","author":"M Malinowska","year":"2009","unstructured":"Malinowska M, Wilkinson FL, Bennett W, Langford-Smith KJ, O'Leary HA, Jakobkiewicz-Banecka J, Wynn R, Wraith JE, Wegrzyn G, Bigger BW: Genistein reduces lysosomal storage in peripheral tissues of mucopolysaccharide IIIB mice. Mol Genet Metab. 2009, 98: 235-242. 10.1016\/j.ymgme.2009.06.013.","journal-title":"Mol Genet Metab"},{"key":"1097_CR17","doi-asserted-by":"publisher","first-page":"e14192","DOI":"10.1371\/journal.pone.0014192","volume":"5","author":"M Malinowska","year":"2010","unstructured":"Malinowska M, Wilkinson FL, Langford-Smith KJ, Langford-Smith A, Brown JR, Crawford BE, Vanier MT, Grynkiewicz G, Wynn RF, Wraith JE: Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. PLoS One. 2010, 5: e14192-10.1371\/journal.pone.0014192.","journal-title":"PLoS One"},{"key":"1097_CR18","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.curtheres.2008.04.002","volume":"63","author":"E Piotrowska","year":"2008","unstructured":"Piotrowska E, Jakobkiewicz-Banecka J, Tylki-Szymanska A, Liberek A, Maryniak A, Malinowska M, Czartoryska B, Puk E, Kloska A, Liberek T: Genistin-rich soy isoflavone extract in substrate reduction therapy for Sanfilippo syndrome: An open-label, pilot study in 10 pediatric patients. Curr Ther Res Clin Exp. 2008, 63: 166-179.","journal-title":"Curr Ther Res Clin Exp"},{"key":"1097_CR19","doi-asserted-by":"publisher","first-page":"CR196","DOI":"10.12659\/MSM.881715","volume":"17","author":"E Piotrowska","year":"2011","unstructured":"Piotrowska E, Jakobkiewicz-Banecka J, Maryniak A, Tylki-Szymanska A, Puk E, Liberek A, Wegrzyn A, Czartoryska B, Slominska-Wojewodzka M, Wegrzyn G: Two-year follow-up of Sanfilippo Disease patients treated with a genistein-rich isoflavone extract: assessment of effects on cognitive functions and general status of patients. Med Sci Monit. 2011, 17: CR196-CR202.","journal-title":"Med Sci Monit"},{"key":"1097_CR20","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1007\/s10545-011-9342-4","volume":"34","author":"V Delgadillo","year":"2011","unstructured":"Delgadillo V, O'Callaghan Mdel M, Artuch R, Montero R, Pineda M: Genistein supplementation in patients affected by Sanfilippo disease. J Inherit Metab Dis. 2011, 34: 1039-1044. 10.1007\/s10545-011-9342-4.","journal-title":"J Inherit Metab Dis"},{"key":"1097_CR21","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/8904_2011_87","volume":"5","author":"V Malinova","year":"2012","unstructured":"Malinova V, Wegrzyn G, Narajczyk M: The use of elevated doses of genistein-rich soy extract in the gene expression-targeted isoflavone therapy (GET IT) for Sanfilippo disease patients. JIMD Rep. 2012, 5: 21-25.","journal-title":"JIMD Rep"},{"key":"1097_CR22","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1002\/ana.22643","volume":"71","author":"J de Ruijter","year":"2012","unstructured":"de Ruijter J, Valstar MJ, Narajczyk M, Wegrzyn G, Kulik W, Ijlst L, Wagemans T, van der Wal WM, Wijburg FA: Genistein in Sanfilippo disease: a randomized controlled crossover trial. Ann Neurol. 2012, 71: 110-120. 10.1002\/ana.22643.","journal-title":"Ann Neurol"},{"key":"1097_CR23","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/s10545-009-9029-2","volume":"33","author":"A Arfi","year":"2010","unstructured":"Arfi A, Richard M, Gandolphe C, Scherman D: Storage correction in cells of patients suffering from mucopolysaccharidoses types IIIA and VII after treatment with genistein and other isoflavones. J Inherit Metab Dis. 2010, 33: 61-67. 10.1007\/s10545-009-9029-2.","journal-title":"J Inherit Metab Dis"},{"key":"1097_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11011-011-9233-2","volume":"26","author":"A Kloska","year":"2011","unstructured":"Kloska A, Jakobkiewicz-Banecka J, Narajczyk M, Banecka-Majkutewicz Z, Wegrzyn G: Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses. Metab Brain Dis. 2011, 26: 1-8. 10.1007\/s11011-011-9233-2.","journal-title":"Metab Brain Dis"},{"issue":"Suppl 2","key":"1097_CR25","first-page":"99","volume":"52","author":"G Grynkiewicz","year":"2002","unstructured":"Grynkiewicz G: Synthetic genistein as a prospective active ingredient for nutrition and medicine. Pol J Food Nutr Sci. 2002, 52 (Suppl 2): 99-105.","journal-title":"Pol J Food Nutr Sci"},{"key":"1097_CR26","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.molstruc.2004.03.015","volume":"694","author":"G Grynkiewicz","year":"2004","unstructured":"Grynkiewicz G, Zegrocka-Stendel O, Pucko W, Ramza J, Ko\u015bcielecka A, Ko\u0142odziejski W, Wo\u017aniak K: X-ray and 13\u2009C CP MAS investigations of structure of two genistein derivatives. J Mol Struct. 2004, 694: 121-129. 10.1016\/j.molstruc.2004.03.015.","journal-title":"J Mol Struct"},{"key":"1097_CR27","doi-asserted-by":"crossref","first-page":"23","DOI":"10.18388\/abp.2010_2368","volume":"57","author":"A Rusin","year":"2010","unstructured":"Rusin A, Krawczyk Z, Grynkiewicz G, Gogler A, Zawisza-Puchalka J, Szeja W: Synthetic derivatives of genistein, their properties and possible applications. Acta Biochim Pol. 2010, 57: 23-34.","journal-title":"Acta Biochim Pol"},{"key":"1097_CR28","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1021\/js980402t","volume":"88","author":"DE Clark","year":"1999","unstructured":"Clark DE: Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood\u2013brain barrier penetration. J Pharm Sci. 1999, 88: 815-821. 10.1021\/js980402t.","journal-title":"J Pharm Sci"},{"key":"1097_CR29","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1007\/BF03195237","volume":"48","author":"J Jakobkiewicz-Banecka","year":"2007","unstructured":"Jakobkiewicz-Banecka J, Wegrzyn A, Wegrzyn G: Substrate deprivation therapy: a new hope for patients suffering from neuronopathic forms of inherited lysosomal storage diseases. J Appl Genet. 2007, 48: 383-388. 10.1007\/BF03195237.","journal-title":"J Appl Genet"},{"key":"1097_CR30","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1203\/01.pdr.0000233037.00707.da","volume":"60","author":"AL Roberts","year":"2006","unstructured":"Roberts AL, Thomas BJ, Wilkinson AS, Fletcher JM, Byers S: Inhibition of glycosaminoglycan synthesis using rhodamine B in a mouse model of mucopolysaccharidosis type IIIA. Pediatr Res. 2006, 60: 309-314. 10.1203\/01.pdr.0000233037.00707.da.","journal-title":"Pediatr Res"},{"key":"1097_CR31","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.ymgme.2007.06.016","volume":"92","author":"AL Roberts","year":"2007","unstructured":"Roberts AL, Rees MH, Klebe S, Fletcher JM, Byers S: Improvement in behaviour after substrate deprivation therapy with rhodamine B in a mouse model of MPS IIIA. Mol Genet Metab. 2007, 92: 115-121. 10.1016\/j.ymgme.2007.06.016.","journal-title":"Mol Genet Metab"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1479-5876-10-153.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T23:40:42Z","timestamp":1714261242000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/1479-5876-10-153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7,30]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["1097"],"URL":"https:\/\/doi.org\/10.1186\/1479-5876-10-153","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,7,30]]},"assertion":[{"value":"29 May 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"153"}}