Synthesis and biological evaluation of a radiolabeled analog of methyl 2-acetamido-2,4-dideoxy-β- d- xylo-hexopyranoside directed towards influencing cellular glycosaminoglycan biosynthesis

Abstract

Two methods are presented for the synthesis of methyl 2-acetamido-2,4-dideoxy-β- d- xylo-hexopyranoside. The first method employs the Barton–McCombie deoxygenation methodology, and the second method utilizes an oxidation–β-elimination methodology that allows for the incorporation of hydrogen isotopes into the title compound. Hence, methyl 2-acetamido-2,4-dideoxy-β- d- xylo-hexopyranoside ( 4) and methyl 2-acetamido-2,4-dideoxy-β- d- xylo-hexopyranoside-6- t ( 14) were synthesized and evaluated for their ability to inhibit hepatocyte, cell-surface glycosaminoglycan biosynthesis and to incorporate a [ 3H] radiolabel into isolated glycosaminoglycans, respectively. Compound 4, at a concentration of 1.0 mM, demonstrated a reduction of d-[ 3H]glucosamine and [ 35S]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 [ 3H] 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.