Isonucleosides: Design and synthesis of new isomeric nucleosides with antiviral potential

Article abstract of DOI:10.1080/15257770701490639

Isonucleosides discovered in our laboratory have been found to have interesting antiviral activity. The design, development of methodology, and stereochemical synthesis of new isonucleosides of anti-HCV interest are described. Antiviral results are cited.

Full text of DOI:10.1080/15257770701490639

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Isonucleosides: Design and Synthesis of
New Isomeric Nucleosides with Antiviral
Potential
Vasu Nair a , Dorota G. Piotrowska a , Maurice Okello a & Jean
Vadakkan a
a Center for Drug Discovery and the Department of Pharmaceutical
and Biomedical Sciences , University of Georgia , Athens, Georgia,
USA
Published online: 10 Dec 2007.
To cite this article: Vasu Nair , Dorota G. Piotrowska , Maurice Okello & Jean Vadakkan (2007)
Isonucleosides: Design and Synthesis of New Isomeric Nucleosides with Antiviral Potential,
Nucleosides, Nucleotides and Nucleic Acids, 26:6-7, 687-690, DOI: 10.1080/15257770701490639
To link to this article: http://dx.doi.org/10.1080/15257770701490639
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Nucleosides, Nucleotides, and Nucleic Acids, 26:687–690, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701490639
ISONUCLEOSIDES: DESIGN AND SYNTHESIS OF NEW ISOMERIC
NUCLEOSIDES WITH ANTIVIRAL POTENTIAL
Vasu Nair, Dorota G. Piotrowska, Maurice Okello, and Jean Vadakkan
2
Center for Drug Discovery and the Department of Pharmaceutical and Biomedical Sciences,
University of Georgia, Athens, Georgia, USA
Isonucleosides discovered in our laboratory have been found to have interesting antiviral activ-
2
ity. The design, development of methodology, and stereochemical synthesis of new isonucleosides of
anti-HCV interest are described. Antiviral results are cited.
Keywords Isonucleosides; stereochemical synthesis; antiviral activity
INTRODUCTION
Oxetanocin, a natural nucleoside with a surrogate carbohydrate moiety
isolated from bacterial sources, exhibits, anti-HIV activity.[1] In designing
ring-expanded analogues of oxetanocin that would have the potential for
antiviral activity, we focused on a combination of the structural features of
the surrogate carbohydrate moiety of oxetanocin with the sugar component
of another antiviral compound, 4(S)-(adenin-9-yl)-2(S)-hydroxymethyltetra-
hydrofuran [(S, S)-isoddA]. The isomeric nucleoside, (S, S)-isoddA, ex-
hibits potent anti-HIV activity against HIV-1, HIV-2, and HIV- resistant
strains.[2,3] (S,S)-IsoddATP is among the strongest known inhibitors of HIV
reverse transcriptase. (S, S)-IsoddA also showed in vitro anti-HBV activity.
Isonucleosides also have been discovered that show anti-HSV activity.[4,5]
In the course of this work with isomeric nucleoside analogs of ox-
etanocin A, we discovered isonucleoside 6, which exhibited interesting
antiviral activity against HCV (Scheme 1).[6] In this report, we describe
the design, stereochemical approaches and total synthesis of two new
This project was supported by the National Institutes of Health (NIAID). Its contents are solely the
responsibility of the authors and do not necessarily represent the official views of the NIH.
Dorota G. Piotrowska is on leave of absence from the Medical University of Lꢀ o´dz´ Poland
Address correspondence to Vasu Nair, Department of Pharmaceutical and Biomedical Sciences,
University of Georgia, Athens, GA 30602-2352, USA. E-mail: vnair@rx.uga.edu
687

688
V. Nair et al.
isonucleosides related to our anti-HCV compound. Preliminary antiviral
information is mentioned.
SCHEME 1 Synthesis of an anti-HCV compound (6).
RESULTS AND DISCUSSION
The enantiomer of the anti-HCV compound, 6, was a logical extension
of our work. Synthesis of this enantiomer is presented in Scheme 2. The
starting material was 1,2-O-isopropylidene-α-D-glucofuranose (7), which
SCHEME 2 Methodology for synthesis of the enantiomer of the anti-HCV compound 6.

Design and Synthesis of Isomeric Nucleosides
689
SCHEME 3 Synthesis of a 3’-isonucleoside analogue of compound 6.
was tritylated at the primary hydroxyl group and then mesylated at both
secondary hydroxyl groups to give 9. Acid-catalyzed rearrangement of 9
to 10 followed by an intramolecular SN2 reaction led to the epoxide 11.
Cleavage of the epoxide under hydrogenation conditions, protection of
the primary hydroxyl group by tritylation, and mesylation of the secondary
hydroxyl functionality produced the key intermediate 14. Coupling of
14 with sodium adenine and deprotection gave the target enantiomeric
compound 16, which was purified by reversed-phase HPLC. Structures of
this and other target molecules described in this paper were established by
HRMS, UV and multinuclear NMR data including COSY and HMBC data.
The second synthesis involved an analogue with an α-hydroxyl group at
the position adjacent to the base moiety. This synthesis commenced with
ribitol (17),[9] which was treated with TBDMS-Cl in pyridine to give a mix-
ture of 18, 19, and 20. Compound 19 could be converted to the desired in-
termediate 18 by a base-catalyzed rearrangement. The free hydroxyl group
was esterified with triflic chloride and DMAP, and the adenine base was con-
structed using standard methodology as illustrated in Scheme 3. The target
molecule was purified by reversed-phase HPLC.
Finally, it should be stated that while compound 6 exhibited in vitro
anti-HCV activity, its enantiomer, 16, was inactive. Compound 25 also did
not show anti-HCV activity. Other analogues of compound 6 are currently
under investigation.
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immunodeficiency virus by oxetanocin. J . Antibiot. 1987, 40, 1077–1078.

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