Synthesis and biological evaluation of a radiolabeled analog of methyl 2-acetamido-2,4-dideoxy-beta-D-xylo-hexopyranoside directed towards influencing cellular glycosaminoglycan biosynthesis.
Two methods are presented for the synthesis of methyl 2-acetamido-2,4-dideoxy-beta-D-xylo-hexopyranoside. The first method employs the Barton-McCombie deoxygenation methodology, and the second method utilizes an oxidation-beta-elimination methodology that allows for the incorporation of hydrogen isotopes into the title compound. Hence, methyl 2-acetamido-2,4-dideoxy-beta-D-xylo-hexopyranoside (4) and methyl 2-acetamido-2,4-dideoxy-beta-D-xylo-hexopyranoside-6-t (14) were synthesized and evaluated for their ability to inhibit hepatocyte, cell-surface glycosaminoglycan biosynthesis and to incorporate a [(3)H] radiolabel into isolated glycosaminoglycans, respectively. Compound 4, at a concentration of 1.0 mM, demonstrated a reduction of D-[(3)H]glucosamine and [(35)S]sulfate incorporation into isolated glycosaminoglycans by 69 and 59%, of the control cultures, respectively. At 10 and 20 mM, 4 demonstrated a maximum inhibition of incorporation of both radiolabels to approximately 10% of the control cultures. Compound 14 demonstrated a maximum incorporation of a [(3)H] radiolabel into isolated cell-surface glycosaminoglycans at 10 and 20 mM. The mechanism of inhibition of glycosaminoglycan biosynthesis is due, in part, to the incorporation of a 4-deoxy moiety into glycosaminoglycan chains resulting in premature chain termination.
Berkin
Ali
A
Department of Chemistry, Queen's University, Kinston, Ont., Canada K7L 3N6.
Szarek
Walter A
WA
Kisilevsky
Robert
R
D000605:Amino Alcohols / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D005260:Female; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D013462:Sulfur Radioisotopes / Q000737:chemistry*; D014316:Tritium / Q000737:chemistry*; D014994:Xylose / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000605:Amino Alcohols; D006025:Glycosaminoglycans; D013462:Sulfur Radioisotopes; C452000:diiodoalditol; D014316:Tritium; D014994:Xylose