title: Synthesis of glycopyranosylphosphonate analogues of certain natural nucleoside diphosphate sugars as potential inhibitors of glycosyltransferases.
abstract: The synthesis of alpha-D-glucopyranosyl-, alpha-D-galactopyranosyl-, and alpha-D-mannopyranosylphosphonate is described. Condensation of tris(trimethylsilyl) phosphite with 2,3,4,6-tetrakis-O-(phenylmethyl)-1-O-acetyl-alpha-D-glucopyranose generated 2,3,4,6-tetrakis-O-(phenylmethyl)-alpha-D-glucopyranosylphosphonic acetic anhydride (13). The benzyl blocking groups were removed by catalytic hydrogenation, and the anhydride bond was cleaved by alkaline hydrolysis to obtain alpha-D-glucopyranosylphosphonate (15). alpha-D-Galactopyranosylphosphonate (17) and alpha-D-mannopyranosylphosphonate (19) were also similarly synthesized. The anomeric configuration of 15 was assigned by single-crystal X-ray analysis, and the structural assignments of 17 and 19 were made on the basis of comparative NMR spectral studies. Compound 15 was then coupled with adenosine 5'-phosphoric di-n-butylphosphinothioic anhydride in dry pyridine to give adenosine 5'-phosphoric alpha-D-glucopyranosylphosphonic anhydride (23). Similarly, uridine 5'-phosphoric alpha-D-galactopyranosylphosphonic anhydride (24) and guanosine 5'-phosphoric alpha-D-mannopyranosylphosphonic anhydride (25) were synthesized from 17 and 19, respectively. With ovalbumin as an acceptor for [3H]galactose, provided by UDP-[3H]galactose, only uridine 5'-phosphoric alpha-D-galactopyranosylphosphonic anhydride (24) was shown to inhibit glycoprotein beta-D-galactosyltransferase (EC 2.4.1.38), with an apparent Ki equal to 165 microM. Even though these ionic compounds hardly penetrate the cell membrane, preliminary in vitro antitumor screening shows that compounds 23 and 25 are slightly active against human B-lymphoblastic leukemia and human T-lymphoblastic leukemia. None of these compounds show any antiviral activity.
mesh_terms: D000818:Animals; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006602:Hexosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000201:enzymology; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013403:Sugar Phosphates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D014780:Viruses / Q000187:drug effects
chemical_list: D063065:Organophosphonates; D013403:Sugar Phosphates; D006602:Hexosyltransferases