Bicyclic nucleoside inhibitors of varicella-zoster virus (VZV): Effect of terminal unsaturation in the side-chain

Article abstract of DOI:10.1081/NCN-100002425

As part of an ongoing research program, we have prepared novel bicyclic nucleoside inhibitors bearing long alkyl side-chains for evaluation against VZV. In particular, we report the synthesis of analogues with terminal unsaturation in the side-chain. Terminal alkenyl derivatives were found to be potent antivirals whereas the terminal alkynyls displayed poor activity.

Full text of DOI:10.1081/NCN-100002425

This article was downloaded by: [University of Michigan]
On: 18 March 2013, At: 05:42
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic Acids
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lncn20
BICYCLIC NUCLEOSIDE INHIBITORS OF VARICELLA-
ZOSTER VIRUS (VZV): EFFECT OF TERMINAL
UNSATURATION IN THE SIDE-CHAIN
a
b
c
c
Sheila Srinivasan , Christopher McGuigan , Graciela Andrei , Robert Snoeck , Erik
c
c
De Clercq & Jan Balzarini
a
Welsh School of Pharmacy, Cardiff University, King Edward VII Ave, Cardiff, CF10 3XF,
United Kingdom
b
Welsh School of Pharmacy, Cardiff University, King Edward VII Ave, Cardiff, CF10 3XF,
United Kingdom
c
Rega Institute for Medical Research, Minderbroederstraat 10, Leuven, B-3000, Belgium
Version of record first published: 07 Feb 2007.
To cite this article: Sheila Srinivasan , Christopher McGuigan , Graciela Andrei , Robert Snoeck , Erik De Clercq &
Jan Balzarini (2001): BICYCLIC NUCLEOSIDE INHIBITORS OF VARICELLA-ZOSTER VIRUS (VZV): EFFECT OF TERMINAL
UNSATURATION IN THE SIDE-CHAIN, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 763-766
To link to this article: http://dx.doi.org/10.1081/NCN-100002425
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 763–766 (2001)
BICYCLIC NUCLEOSIDE INHIBITORS
OF VARICELLA-ZOSTER VIRUS (VZV): EFFECT
OF TERMINAL UNSATURATION
IN THE SIDE-CHAIN
1
1,∗
2
Sheila Srinivasan, Christopher McGuigan, Graciela Andrei,
2
2
2
Robert Snoeck, Erik De Clercq, and Jan Balzarini
1Welsh School of Pharmacy, Cardiff University, King Edward VII Ave,
Cardiff CF10 3XF, United Kingdom
2
Rega Institute for Medical Research, Minderbroederstraat 10,
Leuven, B-3000, Belgium
ABSTRACT
As part of an ongoing research program, we have prepared novel bicyclic nu-
cleoside inhibitors bearing long alkyl side-chains for evaluation against VZV.
In particular, we report the synthesis of analogues with terminal unsaturation in
the side-chain. Terminal alkenyl derivatives were found to be potent antivirals
whereas the terminal alkynyls displayed poor activity.
We have recently identified an entirely new family of extremely potent and
selective antiviral nucleosides bearing a highly unusual bicyclic furo base moiety
(1). The lead compounds have long alkyl side-chains at the 6-position of the furo
ring and preliminary investigative studies have indicated that this structural feature
is an absolute requirement for antiviral activity, with optimal activity observed for
compounds with chain lengths of C -C (1).
8
10
We have also recently noted the effects of structural modifications within the
alkyl side-chain of the lead compounds. Terminal substitution with halogen atoms
is well tolerated and full retention of antiviral potency, down the group F, Cl, Br, I,
is observed (2). However, although attempts to increase the overall water solubility
∗
Corresponding author.
763
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
7
64
SRINIVASAN ET AL.
n = 2, 1a (76%)
n = 3, 1b (97%)
n = 5, 1c (99%)
n = 7, 1d (71%)
i
Br
n
n
o
i lithium acetylenide EDA complex, DMSO, 8 C-r.t.
Figure 1.
of the lead compounds by ether substitution along the side-chain proved successful,
the resulting derivatives displayed a significant reduction in antiviral potency (3),
suggesting that substitution along the side-chain, perhaps with particularly polar
groups, is not tolerated.
Bearing this in mind, we sought to make alternative structural modifications
at the terminus of the side-chain: in particular, we wanted to probe the effect on
antiviral activity of unsaturation at the terminus and now report the preparation and
evaluation of terminal (ω) alkenyl and alkynyl derivatives (4).
Theω-alkyn-1-enes(1a–d, Fig. 1), usedinthepreparationofω-alkenylderiva-
tives, were synthesised from the corresponding bromoalk-1-enes in good yields
(
2
71–99% ) (5). Using established methodology (1–3), coupling of 1a–d with 5-iodo-
-deoxyuridine, followed by cyclisation afforded the target bicyclic nucleosides
ꢁ
2
a–d (Fig. 2) in variable yields (8–73%). The ω-alkynyl derivatives (3a–d, Fig. 2),
ꢁ
prepared from 5-iodo-2 -deoxyuridine and commercially available 1,ω-di-alkynes,
were obtained in lower yields than the ω-alkenyl derivatives (4–20%). The variable
yields noted for 2a–d and 3a–d are probably due to the presence of the unsatu-
rated moieties at the terminus of the side-chain, which provide extra sites for metal
chelation and thus, result in unwanted side-reactions and possible polymerisation.
R
O
N
2a, R = [CH2]3CH=CH2 (73%)
O
2
2
2
b, R = [CH ] CH=CH ( 9%)
I
2 4 2
HN
O
c, R = [CH ] CH=CH (39%)
N
O
2 6
2
i
d, R = [CH ] CH=CH ( 8%)
2
8
2
O
O
N
HO
ii
HO
3a, R = [CH2]3C CH ( 4%)
3
b, R = [CH ] C CH (14%)
2 4
3
c, R = [CH ] C CH (16%)
2
5
OH
OH
3d, R = [CH ] C CH (20%)
2 6
i ω-alkyne, Pd(PPh ) , CuI, iPr NEt, DMF, r.t., 19h
3
4
2
ii NEt , MeOH, CuI, reflux
3
Figure 2.

ORDER
REPRINTS
BICYCLIC NUCLEOSIDE INHIBITORS
765
Table 1. Antiviral Activity and Cytotoxicity Data for 2a–d and 3a–d and Reference Compounds
Cf1369 and Acyclovir (ACV)
EC50 (µM)a EC50 (µM)a EC50 (µM)a EC50 (µM)a
−
d
−
d
MCCb
(µM)
CC50c
(µM)
VZV
VZV
TK VZV TK VZV
07/1 Strain YS/R Strain
Cpd
ClogP7 OKA Strain YS Strain
2
2
2
2
a
b
c
0.4
0.9
2.0
3.0
>200
14
0.27
0.09
>200
13
0.06
0.1
>200
>200
>200
>200
>200
>200
>50
>200
>200
≥200
≥50
>200
>200
>200
>200
>200
>200
>200
>200
d
>200
3
3
3
3
a
b
c
−0.5
8
25
79
5
10
33
37
4
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
0.0
0.6
1.1
d
Cf1369
ACV
3.5
0.015
2.9
0.008
1.0
>50
>4
>50
>50
>50
–
125
>200
>200
a
EC50, 50% effective concentration, required to reduce plaque formation by 50%.
MCC, minimal cytotoxic concentration, required to alter microscopically detectable cell morphol-
b
ogy.
c
CC50, 50% cytotoxic concentration, required to inhibit He1 cell growth by 50%.
TK , thymidine kinase-deficient.
d
−
Compounds 2a–d and 3a–d were evaluated for antiviral activity and cytoxi-
city (1,6) (data presented in Table 1, along with reference data for the lead parent
C -alkyl compound Cf1369, and acyclovir, ACV). Within the ω-alkenyl series,
1
0
potency increases from C to C with full retention of potency for the C analogue.
5
8
10
Compounds 2c and 2d are notably more active than ACV but are less active than
their corresponding n-alkyl counterparts (4). The ω-alkynyls 3a–d, however are
much less effective as antivirals, with no apparent trend arising with increasing
chain length. We previously noted that the most active bicyclic nucleosides have
calculated octanol-water ClogP (7) values in the range 2.5–3.5, indicating a possible
correlation between activity and optimal compound lipophilicity (1). Thus, it is
interesting to note the significantly negative impact that the ω-alkynyl functionality
has on overall compound lipophilicity (∼30-fold reduction compared to parent
n-alkyl analogues), which may possibly account for the observed loss of activity.
In agreement with earlier observations (1–3), no antiviral activity is observed
in thymidine kinase-deficient VZV strains, implying a need for thymidine kinase-
mediated activation of these types of compounds. Furthermore, compounds 2a–d
and 3a–d display low in vitro cytotoxicity, resulting in selectivity index values for
2c and 2d exceeding 3000.
REFERENCES
1.
McGuigan, C.; Yarnold, C.J.; Jones, G.; Vel a´ zquez, S.; Barucki, H.; Brancale, A.;
Andrei, G.;Snoeck, R.;DeClerrcq, E.;Balzarini, J. J. Med. Chem. 1999, 42, 4479–4484.

ORDER
REPRINTS
7
66
SRINIVASAN ET AL.
2.
3.
4.
Brancale, A.;McGuigan, C.;Andrei, G.;Snoeck, R.;DeClercq, E.;Balzarini, J. BioOrg.
Med. Chem. Lett. 2000, 10, 1215–1217.
Brancale, A.; Srinivasan, S.; McGuigan, C.; Andrei, G.; Snoeck, R.; De Clercq, E.;
Balzarini, J. Antiviral Chem. & Chemother. in press, 2000.
Srinivasan, S.; McGuigan, C.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.
BioOrg. Med. Chem. Lett., submitted 2000.
5
6
.
.
Smith, W.N.; Beumel, O.F. Jr. Synthesis, 1974, 441–442.
De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maudgal, P.C. Nature,
1
986, 324, 464–467.
Values calculated using ClogP version 1.0.0; Biobyte, P.O. Box 517, Claremont, CA
1711 USA.
7.
9

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081NCN100002425