Synthesis and in vitro evaluation of novel anti-varicella-zoster virus (VZV) nucleosides

Article abstract of DOI:10.1081/NCN-100002343

A series of alkyl-aryl, -phenoxy, and -thiophenoxy bicyclic furo pyrimidine nucleosides have been successfully synthesised by Pd-coupling of 5-iodo-2′-deoxyuridine (IDU) with terminal alkynes, followed by in situ copper-cyclisation. Synthesised compounds (4a-i) showed an anti-VZV activity at low μM concentration, comparable to that of current treatment acyclovir.

Full text of DOI:10.1081/NCN-100002343

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SYNTHESIS AND IN VITRO EVALUATION OF NOVEL
ANTI-VARICELLA-ZOSTER VIRUS (VZV) NUCLEOSIDES
Antonella Carangio a , Christopher McGuigan b , D. Cahard c , Graciela Andrei d , Robert
Snoeck d , Erik De Clercq d & Jan Balzarini d
a Welsh School of Pharmacy, Cardiff University , King Edward VII Avenue, Cardiff, CF10
3XF, United Kingdom
b Welsh School of Pharmacy, Cardiff University , King Edward VII Avenue, Cardiff, CF10
3XF, United Kingdom
c Université de Rouen, UFR des Sciences , 76821, Mont Saint Aignan Cedex, Rouen,
France
d Rega Institute for Medical Research , Minderbroedersstraat 10, Leuven, B-3000,
Belgium
Published online: 07 Feb 2007.
To cite this article: Antonella Carangio , Christopher McGuigan , D. Cahard , Graciela Andrei , Robert Snoeck , Erik De
Clercq & Jan Balzarini (2001) SYNTHESIS AND IN VITRO EVALUATION OF NOVEL ANTI-VARICELLA-ZOSTER VIRUS (VZV)
NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 653-656, DOI: 10.1081/NCN-100002343
To link to this article: http://dx.doi.org/10.1081/NCN-100002343
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 653–656 (2001)
SYNTHESIS AND IN VITRO EVALUATION
OF NOVEL ANTI-VARICELLA-ZOSTER
VIRUS (VZV) NUCLEOSIDES
Antonella Carangio,1 Christopher McGuigan,1,∗ D. Cahard,2
Graciela Andrei,3 Robert Snoeck,3 Erik De Clercq,3
and Jan Balzarini3
1Welsh School of Pharmacy, Cardiff University, King Edward VII
Avenue, Cardiff, CF10 3XF, United Kingdom
2Universite´ de Rouen, UFR des Sciences, 76821 Mont Saint Aignan
Cedex, Rouen, France
3Rega Institute for Medical Research, Minderbroedersstraat 10,
Leuven B-3000, Belgium
ABSTRACT
A series of alkyl-aryl, -phenoxy, and -thiophenoxy bicyclic furo pyrimidine
nucleosides have been successfully synthesised by Pd-coupling of 5-iodo-2ꢀ-
deoxyuridine (IDU) with terminal alkynes, followed by in situ copper-cyclisa-
tion. Synthesised compounds (4a-i) showed an anti-VZV activity at low µM
concentration, comparable to that of current treatment acyclovir.
We have recently reported on the discovery of a new class of anti-VZV nucle-
osides with unusual bicyclic furo pyrimidine structures (1). Preliminary evaluation
pointed out the structural requirement of a long alkyl side-chain on the base moiety
for biological activity, with an optimal length of C8-C10 (1) (structure 1, Fig. 1).
Most recently, we observed that introduction of a phenyl group in the side chain of
these compounds leads to further significant enhancement of antiviral potency (2)
(structure 2, Fig. 1). Following this extraordinary result, we sought to investigate
SARs regarding the aromatic moiety in the lead structure 2 by synthesising a broad
series of alkyl-aryl chain-modified analogues.
∗Corresponding author.
653
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
654
CARANGIO ET AL.
R
Ph(R)
O
O
N
O
N
O
N
N
O
O
R = alkyl (C8-C10)
R = alkyl (C4-C6)
HO
HO
OH
OH
1
2
Figure 1.
Effect of introduction of a heteroatom (O, S) on the antiviral activity was also
investigated, through the synthesis and in vitro evaluation of phenoxy and thiophe-
noxy analogues.
Chemistry. Target structures have been synthesised in good yield following
the previously reported procedure for this family of molecules (1). Thus, we treated
5-iodo-2ꢀ-deoxyuridine with the corresponding terminal alkynes in the presence of
a catalytic amount of Pd(0). As previously observed (1), the resulting alkynyl-
deoxyuridine may be easily cyclised in situ, by treatment with copper(I) and Et3N.
The terminal alkynes (3a-h) used in the coupling step were synthesised in good
yields from the appropriate halides, by treatment with lithium acetylide, ethylene-
diamine complex (3). The whole process is reported in Scheme 1.
Bearing in mind previous observation regarding derivatives with p-alkylaryl
side-chains, where an alkyl chain of 4–6 carbon atoms was optimal for antivi-
ral activity (2), we synthesised compounds 4a and 4b, with 4 and 5 methylene
groups between the furo-system and the phenyl moiety. Following previous studies
on derivatives bearing an oxygen along the alkyl side chain (4), we synthesised
phenoxy-derivatives 4c and 4d. Since we previously observed that introduction
of an oxygen atom in the side chain, whilst being extremely successful in en-
hancing water solubility, was detrimental for antiviral activity (4), we replace the
oxygen by the more lipophilic sulphur (compounds 4e and 4f). Compounds 4g (5),
4h and 4i have been synthesised in order to investigate the effect of a substitu-
tion on the phenyl ring, as well as increase the ClogP of the phenoxy-derivatives
(Table 1).
Antiviral Activity. The target bicyclic compounds 4a-i were evaluated for
their ability to inhibit the replication of VZV in vitro, according to previously
described methodology (6). Data are shown in Table 1 for the activity of these
compounds versus two strains of thymidine kinase-competent, and also two strains

ORDER
REPRINTS
ANTI-VARICELLA-ZOSTER VIRUS NUCLEOSIDES
655
Scheme 1.
Table 1.
a
a
a
a
c
EC50 (µM) EC50 (µM) EC50 (µM) EC50 (µM) MCCb CC50
Cpd
TK+ YS
TK+ OKA
TK−d 07/1
TK− d YS/R
(µM)
(µM) ClogPe
4a
4b
4c
4d
4e
N.D.f
N.D.f
92
N.D.f
N.D.f
77
N.D.f
N.D.f
>200
>200
>50
N.D.f
>50
>50
>20
74
N.D.f
N.D.f
>200
>200
>50
N.D.f
N.D.f
>200
≥200
200
N.D.f
N.D.f
>200
>200
>200
N.D.f
>200
165
1.76
2.29
0.65
1.18
1.29
1.82
1.15
1.68
2.21
–
13
25
0.67
N.D.f
11
10.8
2.8
0.90
N.D.f
5
8.4
3.2
4f
N.D.f
>50
N.D.f
200
4g
4h
4i
>50
>20
125
200
≥50
>200
>200
ACV
1.0
2.9
>200
aEC50, effective concentration (µM), required to reduce virus plaque formation by 50%.
bMCC, minimal cytotoxic concentration (µM), required to alter microscopically detectable cell
morphology.
cCC50, 50% cytotoxic concentration, required to inhibit Hel cell growth by 50%.
dTK; thymidine kinase-deficient.
eValues calculated using ClogP version 1.0.0.. Biobyte, P.O. Box 517, Claremont, CA 91711, USA.
fN.D., not determined: data awaited (Sept. 2000).

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656
CARANGIO ET AL.
of thymidine kinase-deficient VZV, with data also included for the reference anti-
herpetic agent acyclovir (ACV).
A preliminary evaluation shows that target nucleosides retain an anti-VZV
activity comparable to that of acyclovir, although their antiviral activity is con-
siderably less pronounced than that of our previously reported analogues (1,2).
No cytotoxicity is detectable in vitro at the concentration required for antiviral
activity.
The clear absence of antiviral activity against thymidine kinase-deficient
VZV strains remains a constant characteristic of this family of compounds (7),
and strongly suggests the absolute requirement for a thymidine kinase-mediated
phosphorylation for antiviral activity.
REFERENCES
a). McGuigan, C.; Yarnold, C.J.; Jones, G.; Vela´zquez, S.; Barucki, H.; Brancale, A.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J., J. Med. Chem, 1999, 42, 4479–
4484.
a). McGuigan, C.; Barucki, H.; Carangio, A.; Blewett, S.; Andrei, G.; Snoeck, R.;
De Clercq, E.; Balzarini, J., J. Med. Chem, 2000, submitted.
a). Nystro¨m, J.E., McCanna, T.D., Helquist, P., Amouroux, R., Synthesis, 1988, 1, 56.
a). Brancale, A., Srinivasan, S., McGuigan, C., Andrei, G., Snoeck, R., De Clercq, E.,
and Balzarini, J., Antiv. Chem & Chemother., in press, 2000.
5-. 3[4-hydroxy-5-(hydroxymethyl)tetrahydrofuro-2-furanyl]-6-(3-p-methyl-phen-
oxypropyl)-2,3-dihydrofuro[2,3,d]pyrimidin-2-one (4g). 1H-nmr (d6-DMSO;
3
3
300 MHz): 9.00 (1H, s, H-4), 7.07 (2H, d, J = 7.9 Hz., m-Ph), 6.80 (2H, d, J =
7.9 Hz., o-Ph), 6.49 (1H, s, H-5), 6.17 (1H, dd, J = 5.6 Hz, H-1ꢀ), 5.30 (1H, d,
3
3J = 4.1 Hz, 3ꢀ-OH), 5.13 (1H, t, 3J = 4.9 Hz, 5ꢀ-OH), 4.23 (1H, m, H-3ꢀ), 3.98 (2H,
t, 3J = 5.9, OCH2), 3.91 (1H, m, H-4ꢀ), 3.63 (2H, m, H-5ꢀ), 2.82 (2H, t, 3J = 6.9 Hz,
α-CH2), 2.38 and 2.16 (2H, m, H-2ꢀ), 1.38 (2H, m, CH2). 13C-nmr (d6-DMSO;
75 MHz): 19.2 (CH3) 24.6, 26.65 (2 × CH2) 41.5 (C-2ꢀ), 61.1 (C-5ꢀ), 66.6 (OCH2),
70.0 (C-3ꢀ), 87.7 (C-4ꢀ), 88.4 (C-1ꢀ), 100.4 (C-5), 106.7 (C-4a), 114.6 (o-Ph), 129.5
(p-Ph), 130.1 (m-Ph), 137.2 (C-4), 154.1 (ipso-Ph), 156.7 (C-6), 157.9 (C-2), 171.5
(C-7a). MS (ES+) m/e 423 (MNa+, 100%), 307 (baseNa+, 10%). Accurate mass:
C21H24N2O6Na requires: 423.1532. Found: 423.1534.
6-. De Clercq, E.; Holy, A; Rosenberg, I; Sakuma, T.; Balzarini, J.; Maudgal, P.C.; Nature,
1986, 324, 464–467.
McGuigan, C., Brancale, A., Barucki, H., Srinivasan, S., Jones, G., Pathirana, R.,
Blewett, S., Alvarez, R., Yarnold, C.J., Carangio, A., Vela´zquez, S., Andrei, G.,
De Clercq, E, and Balzarini, J., Drugs of the Future, 2000, 25, in press.

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