SYNTHESIS OF 9-(1-DEOXY-1-PHOSPHONO-BETA-D-PSICOFURANOSYL)-1,9-DIHYDRO-6H-PURIN-6-ONE AS A POTENTIAL TRANSITION-STATE ANALOG INHIBITOR OF PURINE NUCLEOSIDE PHOSPHORYLASE

被引：32

作者：

ELLIOTT, RD

NIWAS, S

RIORDAN, JM

MONTGOMERY, JA

SECRIST, JA

机构：

[1] Kettering-Meyer Laboratories, Southern research Institute, Birmingham AL 35255-5305

来源：

NUCLEOSIDES & NUCLEOTIDES | 1992年 / 11卷 / 01期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

D O I：

10.1080/07328319208021155

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A fifteen-step synthesis of the proposed purine nucleoside phosphorylase (PNP) transition state analog inhibitor 9-(1-deoxy-1-phosphono-beta-D-psicofuranosyl)-1,9-dihydro-6H-purine-6-one (2) is described starting with 1,2:4,5-disopropylidene-beta-D-psicopyranose (12). Catalytic hydrogenation of 9-[3-O-benzyl-1-(dibenzyloxy-phosphinyl)-1-deoxy-beta-D-psicofuranosyl]-6-benzyloxypurine (27b) under basic conditions gave the unstable 2 which was found to have a half-life of 39 min at pH 7 and 81 min at pH 8. The low PNP inhibitory activity found for 2 (IC50 = 25-mu-M at 50 mM phosphate concentration) may be due entirely to the presence of the decomposition product hypoxanthine which is itself an inhibitor (IC50 = 8.6-mu-M).

引用

收藏

页码：97 / 119

页数：23

相关论文

共 30 条

[21] CONFORMATIONS OF CYCLOHEPTADECANE - A COMPARISON OF METHODS FOR CONFORMATIONAL SEARCHING [J].

SAUNDERS, M ;

HOUK, KN ;

WU, YD ;

STILL, WC ;

LIPTON, M ;

CHANG, G ;

GUIDA, WC .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1990, 112 (04) :1419-1427

[22] 2'-DEOXYGUANOSINE TOXICITY FOR B-LYMPHOID AND MATURE T-LYMPHOID CELL-LINES IS MEDIATED BY GUANINE RIBONUCLEOTIDE ACCUMULATION [J].

SIDI, Y ;

MITCHELL, BS .

JOURNAL OF CLINICAL INVESTIGATION, 1984, 74 (05) :1640-1648

[23] INHIBITORS OF HUMAN PURINE NUCLEOSIDE PHOSPHORYLASE - SYNTHESIS, PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITION, AND T-CELL CYTOTOXICITY OF 2,5-DIAMINOTHIAZOLO[5,4-D]PYRIMIDIN-7(6H)-ONE AND 2,5-DIAMINOTHIAZOLO[4,5-D]PYRIMIDIN-7(6H)-ONE - 2 THIO ISOSTERES OF 8-AMINOGUANINE [J].

SIRCAR, JC ;

SUTO, MJ ;

SCOTT, ME ;

DONG, MK ;

GILBERTSEN, RB .

JOURNAL OF MEDICINAL CHEMISTRY, 1986, 29 (09) :1804-1806

[24] INHIBITION OF HUMAN PURINE NUCLEOSIDE PHOSPHORYLASE BY ACYCLIC NUCLEOSIDES AND NUCLEOTIDES [J].

STEIN, JM ;

STOECKLER, JD ;

LI, SY ;

TOLMAN, RL ;

MACCOSS, M ;

CHEN, A ;

KARKAS, JD ;

ASHTON, WT ;

PARKS, RE .

BIOCHEMICAL PHARMACOLOGY, 1987, 36 (08) :1237-1244

[25] RAPID CHROMATOGRAPHIC TECHNIQUE FOR PREPARATIVE SEPARATIONS WITH MODERATE RESOLUTION [J].

STILL, WC ;

KAHN, M ;

MITRA, A .

JOURNAL OF ORGANIC CHEMISTRY, 1978, 43 (14) :2923-2925

[26]

STILL WC, 1988, MACROMODEL V2 0

[27] INHIBITORS OF PURINE NUCLEOSIDE PHOSPHORYLASE - C(8) AND C(5') SUBSTITUTIONS [J].

STOECKLER, JD ;

CAMBOR, C ;

KUHNS, V ;

CHU, SH ;

PARKS, RE .

BIOCHEMICAL PHARMACOLOGY, 1982, 31 (02) :163-171

[28] PHOSPHONO NUCLEOSIDE .1. SYNTHESIS OF 2,3'-ANHYDRO-1'-DEOXY-1'-PHOSPHONO-1-BETA-D-FRUCTOFURANOSYL URACIL [J].

TATSUOKA, T ;

IMAO, K ;

SUZUKI, K .

HETEROCYCLES, 1986, 24 (03) :617-620

[29] CYCLIC ACETALS OF KETOSES .4. RE-INVESTIGATION OF OXIDATION OF 1,2-4,5-DI-O-ISOPROPYLIDENE-BETA-D-FRUCTOPYRANOSE WITH METHYL SULFOXIDE-ACETIC ANHYDRIDE [J].

TIPSON, RS ;

BRADY, RF ;

WEST, BF .

CARBOHYDRATE RESEARCH, 1971, 16 (02) :383-&

[30] A NEW FORCE-FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC-ACIDS AND PROTEINS [J].

WEINER, SJ ;

KOLLMAN, PA ;

CASE, DA ;

SINGH, UC ;

GHIO, C ;

ALAGONA, G ;

PROFETA, S ;

WEINER, P .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1984, 106 (03) :765-784