Deaza- and deoxyadenosine derivatives: Synthesis and inhibition of animal viruses as human infection models

Article abstract of DOI:10.1081/NCN-120022676

N⁶-Cycloalkyl-2′,3′-dideoxyadenosine derivatives and (2-chloro)-N⁶-cycloheptyl-3-deazaadenosine have been synthesized and tested, along with other (deaza)purine (deoxy)nucleosides from our chemical library, as inhibitors of virus replication against Bovine Herpes Virus 1 (BHV-1) and sheep Maedi/Visna Virus (MVV). Most compounds demonstrated good antireplicative activity against MVV, showing also low cell toxicity.

Full text of DOI:10.1081/NCN-120022676

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Deaza- and Deoxyadenosine Derivatives: Synthesis and
Inhibition of Animal Viruses as Human Infection Models
a c
b
a
b
b
Sauro Vittori
, Daniela Salvatori , Rosaria Volpini , Silvia Vincenzetti , Alberto Vita ,
a
a
a
a
Sara Taffi , Stefano Costanzi , Catia Lambertucci & Gloria Cristalli
a
Dipartimento di Scienze Chimiche , Università di Camerino , Camerino, Italy
Dipartimento di Scienze Veterinarie , Università di Camerino , Camerino, Italy
Universitá di Camerino, Dipartimento di Scienze Chimiche , via S. Agostino 1, 62032,
b
c
Camerino, Italy
Published online: 31 Aug 2006.
To cite this article: Sauro Vittori , Daniela Salvatori , Rosaria Volpini , Silvia Vincenzetti , Alberto Vita , Sara Taffi , Stefano
Costanzi , Catia Lambertucci & Gloria Cristalli (2003) Deaza- and Deoxyadenosine Derivatives: Synthesis and Inhibition of
Animal Viruses as Human Infection Models, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 877-881, DOI: 10.1081/
NCN-120022676
To link to this article: http://dx.doi.org/10.1081/NCN-120022676
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 877–881, 2003
Deaza- and Deoxyadenosine Derivatives: Synthesis and
Inhibition of Animal Viruses as Human
Infection Models
1,*
2
Sauro Vittori, Daniela Salvatori, Rosaria Volpini, Silvia Vincenzetti,
1
2
2
1
1
Alberto Vita, Sara Taffi, Stefano Costanzi, Catia Lambertucci,
1
1
and Gloria Cristalli
1
Dipartimento di Scienze Chimiche and
Dipartimento di Scienze Veterinarie, Universit a` di Camerino,
Camerino, Italy
2
ABSTRACT
6
0
0
6
N -Cycloalkyl-2 ,3 -dideoxyadenosine derivatives and (2-chloro)-N -cycloheptyl-
-deazaadenosine have been synthesized and tested, along with other (deaza)pur-
3
ine (deoxy)nucleosides from our chemical library, as inhibitors of virus replication
against Bovine Herpes Virus 1 (BHV-1) and sheep Maedi=Visna Virus (MVV).
Most compounds demonstrated good antireplicative activity against MVV,
showing also low cell toxicity.
Key Words: Deazaadenosine derivatives; Deoxyadenosine derivatives; Bovine
Herpes Virus 1; Maedi Visna Virus; Antivirals.
*
Correspondence: Sauro Vittori, Universit a´ di Camerino, Dipartimento di Scienze Chimiche,
via S. Agostino 1, 62032 Camerino, Italy; Fax: +39 0737 402295; E-mail: sauro.vittori@
unicam.it.
8
77
DOI: 10.1081/NCN-120022676
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

878
Vittori et al.
INTRODUCTION
Viral infections are life threatening and among the most common diseases both
in developing and wealthy countries. Furthermore, emerging of new viral strains and
increasing of resistance to known drugs push the needs for new antivirals.
In the last two decades the class of retrovirus has gained much attention, mostly
because of human immunodeficiency virus (HIV), causative agent of acquired immu-
nodeficiency disease (AIDS). Recently, it has been proposed that other viruses of the
same class, in particular Maedi-Visna Virus (MVV), can be in vitro ed in vivo models
[
1,2]
for testing anti-HIV potential drugs.
Another class of widespread viruses is that of herpes virus (HV), which cause
severe infections both in humans and animals. Animal HV shows high degree of
similarity to human one, being suitable models to study molecular biology and effec-
[3]
tive therapies of HV. In particular, Bovine Herpes Virus type 1 (BHV-1), a neuro-
tropic HV causing infectious rhinotracheitis in cattle, can be a suitable animal model
for studying human HV.
Taking into account all the above, and also our long expertise in nucleoside
medicinal chemistry, we started a program aimed at testing compounds on BHV
and MVV.
6
0
0
In the present study we report on the synthesis of N -cycloalkylamino-2 ,3 -
dideoxyadenosine derivatives, bearing or not a chlorine atom in 2 position (1–6),
6
and of 2-chloro-N -cyclopentyl-3-deazaadenosine (18).
Synthesized compounds, along with other purine nucleoside analogues pre-
[
4–6]
viously prepared in our laboratory,
have been tested for their antiviral activity
against BHV-1 and MVV, and for their cytotoxicity on the cell lines used for virus
replication. Structures of tested compounds are shown in Fig. 1.
RESULTS AND DISCUSSION
Chemistry
6
The synthesis of the N -cycloalkyl-2 ,3 -dideoxadenosine derivatives 1–6 was
0
0
accomplished as reported in Sch. 1.
[
7]
2,6-Dichloro-9-(2,3-dideoxy-b-D-glyceropentofuranosyl)-9H-purine (33) was
treated with the appropriate cycloalkylamine, and then deprotected with
NH =MeOH, to give nucleosides 1, 3, and 5. Dechlorination of the purified products
3
0
0
6
with Pd=C under hydrogen atmosphere gave the corresponding 2 ,3 -dideoxy-N -
cycloalkyladenosine derivatives 2, 4, and 6.
Synthesis of the 3-deazaadenosine derivative 18 was accomplished according to
Scheme 2. 2,6-Dichloro-3-deazapurine (34) was fused with tetraacetylribose (35) to
give about 90% yield of the protected nucleoside 36. This nucleoside has been already
[
prepared, but with a different procedure and a much lower yield. Treatement of
[
8]
9]
3
6 with cyclopentylamine at high temperature gave the desired nucleoside 18.
Structures of synthesized compounds were confirmed using spectroscopic techni-
ques; in particular, assignment of glycosilation site and anomeric configuration of
1
compound 36 was performed using UV, [ H] NMR and n.O.e. data.

Deaza- and Deoxyadenosine Derivatives
879
Figure 1. Structure of tested compounds.
Scheme 1. Synthesis of dideoxyadenosine derivatives.

880
Vittori et al.
Scheme 2. Synthesis of 2-chloro-3-deazacyclopentyladenosine.
Table 1. AntiMVV activity and cytotoxicity of selected compounds.
a
b
c
Cp
CD50, mM
Viral titre
EC50, mM
3-TC=Cp
CD50=EC50
2
5
7
280
125
234
100
145
>400
>300
2.50
3.50
3.75
6.50
3.50
3.50
<1
0.15
0.027
0.15
0.15
0.15
0.15
5
33
185
33
33
33
33
1
1867
4630
1560
667
967
> 2667
> 60
1
1
2
3
3
9
7
-TC
Virus control
6.50
a
Concentration of compound able to give 50% of the maximal cytotoxic effect.
b
Maximal dilution (negative log of concentration) at which the virus is still able to give cyto-
pathic effect.
c
Concentration of compound able to lower virus effects by 50%.
Biology
All compounds showed moderate activity against BHV-1, with EC50 averaging
around 50 mM. Cytotoxicity of compounds ranged, with few exceptions, between 100
and 400 mM.
Regarding MVV, Table 1 shows data of compounds that are at least 20-fold
more potent than the reference compound 3-thiacytidine (3-TC). In addition to
the fact that 6 compounds out of 29 showed such a high activity, it is worth to note
6
that a cycloheptyl substituent on N (5, 13, 19) and a chlorine atom in 2 position
(5, 7, 13, 19, 27) are important for high activity.
ACKNOWLEDGMENTS
Work supported by the European Community (COST action no. D13=0009=00)
and by the University of Camerino (Fondo di Ricerca di Ateneo).

Deaza- and Deoxyadenosine Derivatives
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