title: Synthetic genistein derivatives as modulators of glycosaminoglycan storage.
abstract: 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.
  
  
  CONCLUSIONS
  Some compounds tested in this study might be promising candidates for further studies on therapeutic agents in MPS types with neurological symptoms.
authors: Department of Molecular Biology, University of Gdańsk, Kładki 24, Gdańsk, 80-822, Poland.
authors: Anna
authors: A
authors: Kloska
authors: Magdalena
authors: M
authors: Narajczyk
authors: Joanna
authors: J
authors: Jakóbkiewicz-Banecka
authors: Grzegorz
authors: G
authors: Grynkiewicz
authors: Wiesław
authors: W
authors: Szeja
authors: Magdalena
authors: M
authors: Gabig-Cimińska
authors: Grzegorz
authors: G
authors: Węgrzyn
mesh_terms: D001812:Blood-Brain Barrier; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D019833:Genistein / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron
chemical_list: D006025:Glycosaminoglycans; D019833:Genistein