AN ENANTIOSPECIFIC SYNTHESIS OF THE HUMAN CYTOMEGALOVIRUS ANTIVIRAL AGENT [(R)-3-((2-AMINO-1,6-DIHYDRO-6-OXO-9H-PURIN-9-YL)METHOXY)-4-HYDROXYBUTYL]PHOSPHONIC ACID

被引:26
作者
CHAMBERLAIN, SD
BIRON, KK
DORNSIFE, RE
AVERETT, DR
BEAUCHAMP, L
KOSZALKA, GW
机构
[1] Burroughs Wellcome Company, Research Triangle Park
关键词
D O I
10.1021/jm00035a018
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The racemic isosteric phosphonate of ganciclovir monophosphate (BW2482U89, SR3745, [3-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-4-hydroxybutyl]phosphonic acid, 1) has potent and selective in vitro;activity against human cytomegalovirus. An enantiospecific synthesis of the R-enantiomer of compound 1 starting from L-arabinose was developed. The synthesis involved (1) the preparation of a chiral acyclic moiety, (2) the coupling of the chiral acyclic moiety to diacetylguanine, (3) the introduction; of phosphorus, and (4) the final deprotection. The R-enantiomer, which has stereochemistry analogous to the natural compound GMP, was tested against human cytomegalovirus and had an IC50 Of 1.7 mu M, which was approximately 2-fold more active than the racemic material. Both racemic and chiral compounds were less toxic than ganciclovir to bone marrow progenitor cells in an in vitro assay.
引用
收藏
页码:1371 / 1377
页数:7
相关论文
共 39 条
[1]  
ANISUZZAMAN AKM, 1978, CARBOHYD RES, V61, P511
[2]   ANTI-HIV COMPOUND ASSESSMENT BY 2 NOVEL HIGH-CAPACITY ASSAYS [J].
AVERETT, DR .
JOURNAL OF VIROLOGICAL METHODS, 1989, 23 (03) :263-276
[3]   SYNTHESIS OF POTENTIAL ANTICANCER AGENTS .7. NUCLEOSIDES DERIVED FROM L-RHAMNOPYRANOSE [J].
BAKER, BR ;
HEWSON, K .
JOURNAL OF ORGANIC CHEMISTRY, 1957, 22 (08) :959-966
[4]   ON THE MECHANISM OF DEOXYGENATION OF SECONDARY ALCOHOLS BY TIN HYDRIDE REDUCTION OF METHYL XANTHATES AND OTHER THIOCARBONYL DERIVATIVES [J].
BARTON, DHR ;
JANG, DO ;
JASZBERENYI, JC .
TETRAHEDRON LETTERS, 1990, 31 (28) :3991-3994
[5]   NEW METHOD FOR DEOXYGENATION OF SECONDARY ALCOHOLS [J].
BARTON, DHR ;
MCCOMBIE, SW .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1975, (16) :1574-1585
[6]   UNIQUE SPECTRUM OF ACTIVITY OF 9-[(1,3-DIHYDROXY-2-PROPOXY)METHYL]-GUANINE AGAINST HERPESVIRUSES INVITRO AND ITS MODE OF ACTION AGAINST HERPES-SIMPLEX VIRUS TYPE-1 [J].
CHENG, YC ;
HUANG, ES ;
LIN, JC ;
MAR, EC ;
PAGANO, JS ;
DUTSCHMAN, GE ;
GRILL, SP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1983, 80 (09) :2767-2770
[7]  
CHOUNG UK, 1990, J MED CHEM, V33, P1207
[8]   SYNTHESIS OF 3 3-C-HYDROXYMETHYLPENTOSES WITH THE D-RIBO-CONFIGURATIONS, D-XYLO-CONFIGURATIONS AND L-LYXO-CONFIGURATIONS - IDENTIFICATION OF THE LATTER WITH A MONOSACCHARIDE ISOLATED FROM PHASE-I COXIELLA-BURNETII LIPOPOLYSACCHARIDE [J].
DAHLMAN, O ;
GAREGG, PJ ;
MAYER, H ;
SCHRAMEK, S .
ACTA CHEMICA SCANDINAVICA SERIES B-ORGANIC CHEMISTRY AND BIOCHEMISTRY, 1986, 40 (01) :15-20
[9]   RAPID ANTIVIRAL DNA-DNA HYBRIDIZATION ASSAY FOR HUMAN CYTOMEGALOVIRUS [J].
DANKNER, WM ;
SCHOLL, D ;
STANAT, SC ;
MARTIN, M ;
SONKE, RL ;
SPECTOR, SA .
JOURNAL OF VIROLOGICAL METHODS, 1990, 28 (03) :293-298
[10]   ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS SYNERGISM BY ZIDOVUDINE (3'-AZIDOTHYMIDINE) AND DIDANOSINE (DIDEOXYINOSINE) CONTRASTS WITH THEIR ADDITIVE INHIBITION OF NORMAL HUMAN MARROW PROGENITOR CELLS [J].
DORNSIFE, RE ;
STCLAIR, MH ;
HUANG, AT ;
PANELLA, TJ ;
KOSZALKA, GW ;
BURNS, CL ;
AVERETT, DR .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1991, 35 (02) :322-328