SYNTHESIS OF GLYCOPYRANOSYLPHOSPHONATE ANALOGS OF CERTAIN NATURAL NUCLEOSIDE DIPHOSPHATE SUGARS AS POTENTIAL INHIBITORS OF GLYCOSYLTRANSFERASES
SYNTHESIS OF GLYCOPYRANOSYLPHOSPHONATE ANALOGS OF CERTAIN NATURAL NUCLEOSIDE DIPHOSPHATE SUGARS AS POTENTIAL INHIBITORS OF GLYCOSYLTRANSFERASES
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DOI：
10.1021/jm00391a020
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发表时间：
1987-08-01
影响因子：
7.3
通讯作者：
ROBINS, RK
中科院分区：
文献类型：
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作者：
VAGHEFI, MM;BERNACKI, RJ;ROBINS, RK
合成α- D-吡喃葡萄糖基-，α- D-吡喃半乳糖基-和α-描述了D-吡喃甘露糖基膦酸酯。三（三甲基甲硅烷基）亚磷酸酯与2，3，4，6-四-O-（苯甲基）-1-O-乙酰基-α-亚磷酸酯的缩合D-吡喃葡萄糖生成2，3，4，6-四-O-（苯甲基）-α- D-吡喃葡萄糖基膦酸乙酸酐（13）。通过催化氢化除去苄基封端基团，并通过碱性水解裂解酸酐键，得到α- D-吡喃葡萄糖基膦酸盐（15）。 α- D-吡喃半乳糖基膦酸酯（17）和α- D-吡喃甘露糖基膦酸酯（19）也类似地合成。通过单晶X-射线分析确定了15的异头构型，并根据比较NMR光谱研究确定了17和19的结构归属。然后将化合物15与腺苷5“-磷酸二-正丁基硫代膦酸酐在无水吡啶中偶联，得到腺苷5”-磷酸-α- D-吡喃葡萄糖基膦酸酐（23）。类似地，尿苷5 ″-磷酸α- D-吡喃半乳糖基膦酸酐（24）和鸟苷5“-磷酸α-分别以17和19为原料合成了D-吡喃甘露糖膦酸酐（25）。用卵清蛋白作为由UDP-[3 H]半乳糖提供的[3 H]半乳糖的受体，仅尿苷5“-磷酸α-半乳糖被用作受体。D-吡喃半乳糖基膦酸酐（24）显示出抑制糖蛋白β- D-半乳糖基转移酶（EC 2.4.1.38），表观K1等于165 Ki等于165 μ M尽管这些离子化合物几乎不能穿透细胞膜，但初步的体外抗肿瘤筛选表明，化合物23和25对人B-淋巴母细胞白血病和人T-淋巴母细胞白血病有轻微的活性。这些化合物均未显示任何抗病毒活性。
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 K1 equal to 165 Ki equal to 165 .mu.M. 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.