Synthesis of unusual bicyclic nucleosides bearing an unsaturated side-chain, as potential inhibitors of varicella-zoster virus (VZV)

Full text of DOI:10.1081/NCN-120022661

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Synthesis of Unusual Bicyclic Nucleosides Bearing
an Unsaturated Side-Chain, as Potential Inhibitors of
Varicella-Zoster Virus (VZV)
O. Bidet a c , C. McGuigan a , G. Andrei b , R. Snoeck b , E. De Clercq b & J. Balzarini b
a Welsh School of Pharmacy, Cardiff University , Cardiff, UK
b Rega Institute for Medical Research , K.U. Leuven, Leuven, Belgium
c Welsh School of Pharmacy , King Edward VII Avenue, Cardiff, CF10 3XF, UK
Published online: 31 Aug 2006.
To cite this article: O. Bidet , C. McGuigan , G. Andrei , R. Snoeck , E. De Clercq & J. Balzarini (2003) Synthesis of Unusual
Bicyclic Nucleosides Bearing an Unsaturated Side-Chain, as Potential Inhibitors of Varicella-Zoster Virus (VZV), Nucleosides,
Nucleotides and Nucleic Acids, 22:5-8, 817-819, DOI: 10.1081/NCN-120022661
To link to this article: http://dx.doi.org/10.1081/NCN-120022661
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 817–819, 2003
Synthesis of Unusual Bicyclic Nucleosides Bearing an
Unsaturated Side-Chain, as Potential Inhibitors of
Varicella-Zoster Virus (VZV)
1
2
2
2
O. Bidet,1, C. McGuigan, G. Andrei, R. Snoeck, E. De Clercq,
*
and J. Balzarini2
1Welsh School of Pharmacy, Cardiff University,
Cardiff, UK
2Rega Institute for Medical Research, K.U. Leuven,
Leuven, Belgium
We have previously reported a novel class of unusual bicyclic furano pyrimidine
nucleosides bearing p-alkyl phenyl side-chains[1] that showed an outstanding potency
and highly selective activity against varicella-zoster virus (VZV). The p-pentyl phenyl
analogue displayed an EC50 value of 0.3 nM against the TKþ strain of VZV,
representing an inhibitory activity 10,000 times more potent than that of acyclovir
(ACV).
In an effort to further explore the structure-activity relationship in this series, we
decided to introduce a more rigid side chain by inclusion of an alkene unsaturation
*Correspondence: O. Bidet, Welsh School of Pharmacy, King Edward VII Avenue, Cardiff,
CF10 3XF, UK; Fax: þ44 2920 874537; E-mail: sphob@cf.ac.uk.
817
DOI: 10.1081/NCN-120022661
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

818
Bidet et al.
to the a-phenyl unit. The substitution of the side-chain on the phenyl group at the
meta position 1a–c was carried out to probe the shape and size of the presumed lipo-
philic pocket of the target enzyme.
As previously reported by Robins and Barr,[2] the target molecules were
synthesized by the Pd(0) -catalyzed coupling of the alkenylphenyl iodide (5a–c)
with 5-ethynyl-20-deoxyuridine[3] to yield 5-alkenylphenyl nucleosides which were
finally cyclized in presence of CuI (1a–c). Compound 3 was prepared from the
coupling of 5-iodo-20-deoxyuridine with trimethylsilylacetylene, followed by desilyla-
tion. Alkenylphenyl iodide was the product of a two step reaction involving
an Aldol-Grob[3] reaction on the bromobenzaldehyde and a reverse halogen
exchange.[4]
The target bicyclic compounds were evaluated for their ability to inhibit the
replication of VZV in human embryonic lung (HEL) fibroblasts. The results showed
a severe reduction of activity by more than 40,000-fold compared to the p-pentyl
phenyl nucleoside. Thus, it is noticed the lipophilic pocket does not tolerate any
alkenyl extension at the meta position of the aromatic system.
REFERENCES
1. McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.; Erichsen, J.T.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Highly potent and selective
inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing
an aryl side chain. J. Med. Chem. 2000, 43, 4993–4997.
2. Robins, M.J.; Barr, P.J. Nucleic-Acid related-compounds. Efficient conversion
of 5-iodo to 5-alkynyl and derived 5-substituted uracil bases and nucleosides.
J. Org. Chem. 1983, 48, 1854–1862.

Bicyclic Nucleosides with an Unsaturated Side-Chain
819
3. Kabalka, G.W.; Li, N.-S.; Tejedor, D.; Malladi, R.R.; Trotman, S. Synthesis of
(E)-1-aryl-1-alkenes via a novel BF3.OEt2-catalyzed Aldol-Grob reaction
sequence. J. Org. Chem. 1999, 64, 3157–3161.
4. Suzuki, H.; Kondo, A.; Ogawa, T. Preparation of aromatic iodides from bro-
mides via the reverse halogen exchange. Chem. Lett. 1985, 411–412.