Lysosomal storage of sulphated glycosaminoglycans induced by dicationic amphiphilic drug molecules: significance of the central planar ring system.
The immunomodulatory drug tilorone (2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one) and several congeners are known to disturb the lysosomal degradation of sulphated glycosaminoglycans and thereby induce lysosomal storage of glycosaminoglycans in cultured cells and intact organisms. The molecules of tilorone and congeners consist of a planar aromatic ring system symmetrically substituted with two aliphatic side chains each carrying a protonizable nitrogen. In a previous study it was proposed that non-degradable glycosaminoglycan-drug complexes are formed by electrostatic interactions and that additionally intermolecular interactions between the drug molecules due to electronic coupling of their central planar ring system are important for formation and stabilization of the glycosaminoglycan-drug complexes and thus for the drug side effect in question. The significance of the central planar ring system was tested in the present study by comparing tilorone and the compound bis(beta-diethylamino-ethylether)hexestrol (DH) with respect to their potencies to cause lysosomal glycosaminoglycan storage in cultured bovine corneal fibroblasts. DH has the same side chains as tilorone, but its central apolar moiety lacks planarity. At a concentration (1.75 muM) which did not cause enhanced secretion of the lysosomal enzyme beta-hexosaminidase (E.C. 3.2.1.52), DH was significantly less potent than tilorone in causing storage of [35S]glycosaminoglycans. This is taken as support of the hypothesis that the planar tricyclic ring system is essential for the high potency of tilorone and its congeners to exert this adverse action.
Lüllmann-Rauch
R
R
Department of Anatomy, University of Kiel, Germany.
von Witzendorff
B
B
D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003315:Cornea / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D006025:Glycosaminoglycans / Q000378:metabolism*; D006589:Hexestrol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism*; D008854:Microscopy, Electron; D013329:Structure-Activity Relationship; D013994:Tilorone / Q000008:administration & dosage / Q000633:toxicity*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D000276:Adjuvants, Immunologic; D006025:Glycosaminoglycans; D006589:Hexestrol; D001619:beta-N-Acetylhexosaminidases; D013994:Tilorone; C100116:hexestrol bis(diethylaminoethyl ether)