title: Lysosomal storage of sulfated glycosaminoglycans induced by two bis-aminomethyl anthrachinones.
abstract: Several immunomomodulatory drugs, all of them symmetrically substituted dicationic amphiphilic compounds, are known to cause lysosomal storage of sulfated glycosaminoglycans (GAGs) in intact animals and cultured fibroblasts. The storage is due to impaired GAG degradation. The standard compound is tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one). In the present study two bis-aminomethyl anthrachinones were examined for their ability to induce lysosomal GAG storage in cultured bovine corneal fibroblasts. For reference, a bis-aminoethoxy-anthrachinone compound (RMI-10.024) was included, which is known to be a potent inducer of lysosomal GAG storage. The present morphological, radiochemical, and biochemical results show that the bis-aminomethyl anthrachinone compounds investigated cause lysosomal storage of GAGs, although with significantly lower potencies than the bis-aminoethoxy anthrachinone. Dermatan sulfate contributed approximately 90% to the drug-induced increment of intracellular GAGs. The present results suggest that the length of the side chains, i.e., the distance between the aromatic ring system and the protonizable nitrogen of the side chains, and the position of the side chains relative to the aromatic ring system are important molecular features influencing the potency of inducing lysosomal GAG storage.
authors.affiliation: Department of Pharmacology, University of Kiel, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Fischer
authors.forename: R
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.forename: E
authors.initials: E
authors.lastname: Stubbe
authors.forename: B
authors.initials: B
authors.lastname: von Witzendorff
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000633:toxicity*; D002417:Cattle; D002478:Cells, Cultured; D003871:Dermatan Sulfate / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005449:Fluorenes / Q000633:toxicity*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D007632:Keratan Sulfate / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism*; D009083:Mucopolysaccharidoses / Q000139:chemically induced / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D003871:Dermatan Sulfate; D005449:Fluorenes; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D007632:Keratan Sulfate; C102329:2,6-aminomethylanthrachinone; C102330:2,7-aminomethylanthrachinone; C102327:RMI 10024