Modified cyclobutane carbonucleosides: Synthesis and evaluation of their antiviral activity

Article abstract of DOI:10.1081/NCN-100002504

The synthesis of some 9-(2-cyclobutylethyl)guanine derivatives and analogous carbonucleosides from 1 S-α-pinene is here presented. None of them showed detectable selectivity when assayed in the performed anti-viral tests.

Full text of DOI:10.1081/NCN-100002504

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MODIFIED CYCLOBUTANE CARBONUCLEOSIDES:
SYNTHESIS AND EVALUATION OF THEIR ANTIVIRAL
ACTIVITY
F. Fernández a , A. R. Hergueta a , C. López a , E. De Clercq b & J. Balzarini b
a Universidad de Santiago , Dpto. Química Orgínica, Facultad de Farmacia, Santiago de
Compostela, E-15706, Spain
b Rega Institute for Medical Research, Katholieke Universiteit Leuven , Leuven, B-3000,
Belgium
Published online: 07 Feb 2007.
To cite this article: F. Fernández , A. R. Hergueta , C. López , E. De Clercq & J. Balzarini (2001) MODIFIED CYCLOBUTANE
CARBONUCLEOSIDES: SYNTHESIS AND EVALUATION OF THEIR ANTIVIRAL ACTIVITY, Nucleosides, Nucleotides and Nucleic
Acids, 20:4-7, 1129-1131, DOI: 10.1081/NCN-100002504
To link to this article: http://dx.doi.org/10.1081/NCN-100002504
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1129–1131 (2001)
MODIFIED CYCLOBUTANE
CARBONUCLEOSIDES: SYNTHESIS AND
EVALUATION OF THEIR ANTIVIRAL ACTIVITY
F. Ferna´ ndez,1,∗ A. R. Hergueta,1 C. Lo´pez,1 E. De Clercq,2
and J. Balzarini2
1Dpto. Qu´ımica Orga´nica, Facultad de Farmacia, Universidad
de Santiago. E-15706 Santiago de Compostela, Spain
2Rega Institute for Medical Research, Katholieke Universiteit Leuven.
B-3000-Leuven, Belgium
ABSTRACT
The synthesis of some 9-(2-cyclobutylethyl)guanine derivatives and analogous
carbonucleosides from 1S-α-pinene is here presented. None of them showed
detectable selectivity when assayed in the performed anti-viral tests.
Carbocyclic nucleosides with a cyclobutane ring linked to a purine base, such
as Lubocavir (1) (1) and Cyclobut A (2) (2), are known to present interesting
antiviral properties. In a search to explore structural variations on the pseudo-sugar
moiety which might improve or retain antiviral activity, a series of carbocyclic
=
=
nucleosides of type 3 (Z CH, N; X Cl, OH, NH2) was studied.
The synthesis of compounds 3 in enantiomerically pure form was carried out
starting from easily available 1S-α-pinene (4). Permanganic oxidation of 4 yielded
pinonic acid 5, which was reduced by NaBH4 mainly to the pinolic acid 6. Acetyla-
tion of 6 by Ac2O/Pyr was followed by successive treatments with ClCO2Et/Et3N
and NH3, to obtain the acetoxy amide 7. Finally, reduction of 7 by LiAlH4 gave the
amino alcohol 8, in a 26% overall yield.
∗Corresponding author.
1129
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
´
1130
FERNANDEZ ET AL.
X
N
N
N
NH2
O
N
N
Z
3a (Z = CH, X = Cl)
3b (Z = CH, X = OH)
3c (Z = CH, X = NH2)
N
N
N
N
N
NH
NH2
OH
N
H2
HO
HO
N
3d (Z = N, X = Cl)
3e (Z = N, X = OH)
3f (Z = N, X = NH2)
HO
HO
1
2
3
Scheme 1.
OH
OH
O
O
OH
O
b
a
50%
95%
6
4
5
84%
c
NH 2
O
NH2
OAc
OH
d
64%
7
8
Scheme 2. a) KMnO4/H2O; b) NaBH4/EtOH; c) 1:Ac2O/Pyr; 2: CICO2Et/Et3N/NH3; d) LiAlH4/
THF.
Cl
N
Cl
N
H2N
HN
Cl
N
N
N
N
HN
OH
NH2
OH
NH2
c
68%
11
10
8
Cl
N
d
f
55%
g
76%
3b
b
87%
75%
a
N
3a
HN
OH
NH2
e
72%
60%
e
70%
f
76%
3b
3c
3e
3f
9
Scheme 3. a) 4,6-Dichloropyrimidin-2-amine/Et3N/1-butanol; b) 4-CIC6H4N2/H2O; c) Zn/AcOH;
d) CH(OEt)3/12N HCl; e) 0.33N NaOH; f) 14M NH4OH; g) NaNO2/1N HCl; h) 0.33N NaOH;
i) 14M NH4OH.

ORDER
REPRINTS
MODIFIED CYCLOBUTANE CARBONUCLEOSIDES
1131
Condensation of 8 with 4,6-dichloropyrimidin-2-amine afforded 9, which
was further condensed with 4-chlorophenyldiazonium chloride to give the 5-azo-
pyrimidine derivative 10. The hydrogenation of the azo group of 10 with Zn/AcOH
yielded the 2,5-diaminopyrimidine derivative 11. This key intermediate was then
used to construct the guanine or 8-azaguanine derivatives using well stablished
procedures (3).
Compounds 3(a–f) were assayed against a variety of viruses, including
HIV-1 and HIV-2, cytomegalovirus, TK+ and TK− varicella zoster virus, influenza
[H2N2 A2 Japan/305/57, H3N2 (X31) and B Hong Kong/51/72] virus, herpes sim-
plex virus type 1 and type 2, vaccinia virus, vesicular stomatitis virus, reovirus-1,
sindbis virus and Punta Toro virus. No antiviral activity at concentrations ≥ 5-fold
below the corresponding cytotoxicity thresholds could be discerned with any of the
compounds against any of the viruses evaluated.
REFERENCES
1. Ireland, C.; Leeson, P. A.; Castan˜er, J. Drugs of the Future, 1997, 22, 259.
2. Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham, H.; Herrin, T.; Plattner,
J. J.; Erickson, J.; Clement, J.; Swanson, R.; Shipkowitz, N.; Hardy, D.; Marsh, K.;
Arnett, G.; Shannon, W.; Broder, S.; Mitsuya, H. J. J. Med. Chem., 1990, 33, 1281.
3. Borges, J. E. R.; Ferna´ndez, F.; Garc´ıa, X.; Hergueta, A. R.; Lo´pez, C.; Andrei, G.;
Snoeck, R.; Witvrounw, M.; Balzarini, J.; De Clercq, E. Nucleosides & Nucleotides,
1998, 17, 1237.

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