A short high yielding synthesis of the potent anti-varicella-zoster virus (VZV) carbocyclic nucleoside analogue carba-BVDU 1 starting from aminodiol 2 is described. Reaction of 2 with acyl carbamate 3 and subsequent ring closure under acidic conditions afforded 5-ethyl-2'-deoxy-4'a-carbauridine 5. In situ acetylation of 5 afforded 3',5'-di-O-acetyl-5-ethyl-2'-deoxy-4'a-carbauridine 6 in 78% overall yield from 2. Radical bromination of 6 with either bromine or NBS and subsequent treatment with triethylamine gave an efficient conversion to 3',5'-di-O-acetyl-5-(E)-(2-bromovinyl)-2'-deoxy-4'a-carbauridine 7. Deacetylation of 7 afforded 1 in an overall 45-53% yield from 2.

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The chiral carbocyclic nucleosides 2 and 3 were prepared from aristeromycin. The 4′α-hydroxy compound 2 displays good antiviral activity against HSV-1 and HSV-2 with low toxicity.

A series of HIV-1 proteinase inhibitors was synthesized based upon a single penicillin derived thiazolidine moiety. Reaction of the C-4 carboxyl group with (R)-phenylalaninol gave amide 10 which was a moderately potent inhibitor of HIV-1 proteinase (IC50 = 0.15 microM). Further modifications based on molecular modeling studies led to compound 48 which contained a stereochemically unique statine-based isostere. This was a potent competitive inhibitor (Ki = 0.25 nM) with antiviral activity against HIV-1 in vitro (5 microM). Neither modification to the benzyl group in an attempt to improve interaction with the S2' pocket, nor introduction of a hydrogen bond donating group to interact with residue Gly48' resulted in improved inhibitory or antiviral activity.

The synthesis and enzyme activity of linker modified, dimeric, penicillin derived inhibitors is described. Variation of the linker group enabled beneficial interaction with the catalytic aspartates, however, this was offset by disruption of the original key interactions with the penicillin derived units.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Efficient processes are described for the synthesis of (-)-carbovir 3 and its triphosphate derivative 28 from (-)-aristeromycin 4. The X-ray structure of (-)-carbovir has been determined.

Annals of the New York Academy of SciencesVolume 616, Issue 1 p. 535-537 Improved Synthesis of (−)-Carbovir, GR90352X, a Potent and Selective Inhibitor of HIV-1 in Vitro M. F. JONES, M. F. JONES Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorC. L. MO, C. L. MO Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorP. L. MYERS, P. L. MYERS Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorI. L. PATERNOSTER, I. L. PATERNOSTER Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorR. STORER, R. STORER Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorG. G. WEINGARTEN, G. G. WEINGARTEN Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorC. WILLIAMSON, C. WILLIAMSON Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this author M. F. JONES, M. F. JONES Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorC. L. MO, C. L. MO Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorP. L. MYERS, P. L. MYERS Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorI. L. PATERNOSTER, I. L. PATERNOSTER Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorR. STORER, R. STORER Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorG. G. WEINGARTEN, G. G. WEINGARTEN Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this authorC. WILLIAMSON, C. WILLIAMSON Microbiological Chemistry Department Glaxo Group Research Greenford, Middlesex, United Kingdom UB6 OHESearch for more papers by this author First published: December 1990 https://doi.org/10.1111/j.1749-6632.1990.tb17886.xCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume616, Issue1AIDS: Anti-HIV Agents, Therapies, and VaccinesDecember 1990Pages 535-537 RelatedInformation