Synthesis and antiviral activity of 3'-deoxy-3'-C-hydroxymethyl nucleosides

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Abstract
A series of 3''-branched-chain sugar nucleosides, in particular 3''-deoxy-3''-C-hydroxymethyl nucleosides, have been synthesized and evaluated as antiviral agents. Reaction of 1-(2,3-epoxy-5-O-trityl-.beta.-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-.beta.-D-arabino-pentofuranosyl nucleosides 21 and 22. Desilylation afforded the 1-(3-deoxy-3C-formyl-.beta.-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)-.beta.-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 1-(3-deoxy-3-deoxy-3-C-(hydroxymethyl)-.beta.-D-lyxo-pentofuranosyl) and 1-(2,3-dideoxy-3-C-(hydroxymethyl)-.beta.-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 simples virus types-1 and -2, varicella zoster virus, human cytomegalovirus and influenza A. Of the compounds tested only (E)-5-(2-bromovinyl)-1-[3-deoxy-3-C-(hydroxymethyl)-.beta.-D-arabino-pentofuranosyl]uracil (10) inhibited VZV (alone), but did so at concentrations well below the cytotoxicity threshold.