title: Disubstituted naphthyl β-D-xylopyranosides: Synthesis, GAG priming, and histone acetyltransferase (HAT) inhibition.
abstract: Xylosides are a group of compounds that can induce glycosaminoglycan (GAG) chain synthesis independently of a proteoglycan core protein. We have previously shown that the xyloside 2-(6-hydroxynaphthyl)β-D-xylopyranoside has a tumor-selective growth inhibitory effect both in vitro and in vivo, and that the effect in vitro was correlated to a reduction in histone H3 acetylation. In addition, GAG chains have previously been reported to inhibit histone acetyltransferases (HAT). To investigate if xylosides, or the corresponding xyloside-primed GAG chains, can be used as HAT inhibitors, we have synthesized a series of naphthoxylosides carrying structural motifs similar to the aromatic moieties of the known HAT inhibitors garcinol and curcumin, and studied their biological activities. Here, we show that the disubstituted naphthoxylosides induced GAG chain synthesis, and that the ones with at least one free phenolic group exhibited moderate HAT inhibition in vitro, without affecting histone H3 acetylation in cell culture. The xyloside-primed GAG chains, on the other hand, had no effect on HAT activity, possibly explaining why the effect of the xylosides on histone H3 acetylation was absent in cell culture as the xylosides were recruited for GAG chain synthesis. Further investigations are required to find xylosides that are effective HAT inhibitors or xylosides producing GAG chains with HAT inhibitory effects.
authors.affiliation: Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, 221 00, Lund, SE, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Thorsheim
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, SE, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Persson
authors.affiliation: Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, 221 00, Lund, SE, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, SE, Sweden.
authors.forename: Emil
authors.initials: E
authors.lastname: Tykesson
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, SE, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westergren-Thorsson
authors.affiliation: Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, SE, Sweden.
authors.forename: Katrin
authors.initials: K
authors.lastname: Mani
authors.affiliation: Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, 221 00, Lund, SE, Sweden. ulf.ellervik@chem.lu.se.
authors.forename: Ulf
authors.initials: U
authors.lastname: Ellervik
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D006027:Glycosides; D051548:Histone Acetyltransferases
keywords: Biosynthesis; Glycosaminoglycan; HAT; Inhibitor; Phenol; Proteoglycan; Tumor; Xyloside; β4GalT7