SYNTHESIS AND ANTIVIRAL ACTIVITY OF 3'-DEOXY-3'-C-HYDROXYMETHYL NUCLEOSIDES

被引:55
作者
BAMFORD, MJ [1 ]
COE, PL [1 ]
WALKER, RT [1 ]
机构
[1] UNIV BIRMINGHAM,SCH CHEM,POB 363,BIRMINGHAM B15 2TT,W MIDLANDS,ENGLAND
关键词
D O I
10.1021/jm00171a025
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 3’-branched-chain sugar nucleosides, in particular 3'-deoxy-3' x2018;-C-hydroxymethyl nucleosides, have been synthesized and evaluated as antiviral agents. Reaction of 1-(2,3-epoxy-5-O-trityl-β-D-lyxo-pentofuranosyl) derivatives 12 and 13, of uracil and thymine, respectively, with 5,6-dihydro-2-lithio-5-methyl-1,3,5-dithiazine 14 afforded the corresponding 3’-functionalized nucleosides 15 and 16, respectively. Replacement of the trityl group with tert-butyldiphenylsilyl allowed high yielding hydrolysis of the 3’-function to give the 3'-deoxy-3’-C-formyl-β-D-arabino-pentofuranosyl nucleosides 21 and 22. Desilylation afforded the l-(3-deoxy-3-C-formyl-β-D-lyxo-pentofuranosyl) 3’,5’-O-hemiacetal nucleosides 33 and 34, respectively. Reduction of the formyl group of 21 and 22, followed by desilylation, yielded the 3'-deoxy-3’-C'-(hydroxymethyl)-β-D-arabino-pentofuranosyl) analogues 7 and 8, respectively. The uracil base moiety of 7 was converted to 5-iodouracil and then to (E)-5-(2-bromovinyl)uracil to furnish an analogue 10 of BVaraU. The l-(3-deoxy-3-C-(hydroxymethyl)-β-D-lyxo-pentofuranosyl) and l-(2,3-dideoxy-3-C-(hydroxymethyl)-β-D-erythro-pentofuranosyl) derivatives of uracil (31 and 6, respectively) and 5-iodouracil (32 and 9, respectively) were also obtained. All novel, fully deprotected nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type-1, herpes simplex virus types-1 and -2, varicella zoster virus, human cytomegalovirus and influenza A. Of the compounds tested only (E)-5-(2-bromovinyl)-l-[3-deoxy-3-C-(hydroxymethyl)-β-D-arabino-pentofuranosyl]uracil (10) inhibited VZV (alone), but did so at concentrations well below the cytotoxicity threshold. © 1990, American Chemical Society. All rights reserved.
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页码:2494 / 2501
页数:8
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