ASYMMETRIC-SYNTHESIS OF 1,3-DIOXOLANE PYRIMIDINE NUCLEOSIDES AND THEIR ANTI-HIV ACTIVITY

被引:120
作者
KIM, HO
AHN, SK
ALVES, AJ
BEACH, JW
JEONG, LS
CHOI, BG
VANROEY, P
SCHINAZI, RF
CHU, CK
机构
[1] UNIV GEORGIA,COLL PHARM,DEPT MED CHEM,ATHENS,GA 30602
[2] MED FDN BUFFALO INC,BUFFALO,NY 14203
[3] EMORY UNIV,SCH MED,VET AFFAIRS MED CTR,ATLANTA,GA 30322
[4] EMORY UNIV,SCH MED,DEPT PEDIAT,ATLANTA,GA 30322
关键词
D O I
10.1021/jm00089a007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-D-mannose (1), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, cytosine derivative 19 was found to exhibit the most potent anti-HIV agent although it is the most toxic. The order of anti-HIV potency was as follows: cytosine (beta-isomer) > thymine > cytosine (alpha-isomer) > 5-chlorouracil > 5-bromouracil > 5-fluorouracil derivatives. Uracil, 5-methylcytosine, and 5-iodouracil derivatives were found to be inactive. Interestingly, alpha-isomer 20 showed good anti-HIV activity without cytotoxicity. As expected, other alpha-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.
引用
收藏
页码:1987 / 1995
页数:9
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