Synthesis and antiviral evaluation of 3-hydroxy-2-methylpyridin-4-one dideoxynucleoside derivatives

Article abstract of DOI:10.1016/j.bmcl.2003.09.033

We describe the synthesis and the antiviral evaluation of novel α and β dideoxynucleoside derivatives in which the base has been replaced by a 3-hydroxy-2-methylpyridin-4-one. The syntheses were successfully achieved by the use of the standard Vorbrueggen coupling conditions. Moderate activity of these compounds were found on herpes simplex virus (HSV) type 1 and type 2.

Full text of DOI:10.1016/j.bmcl.2003.09.033

Bioorganic & Medicinal Chemistry Letters 13 (2003) 4371–4374
Synthesis and Antiviral Evaluation of 3-Hydroxy-2-methylpyridin-
4-one Dideoxynucleoside Derivatives
Karine Barral,a Robert C. Hider,b Jan Balzarini,c
Johan Neyts,c Erik De Clercqc and Michel Camploa,*
a
´ ´ ´
Laboratoire des Materiaux Moleculaires et des Biomateriaux (UMR-CNRS 6114), Faculte des Sciences de Luminy,
case 901, 13288 Marseille cedex 09, France
´
bKing’s College London, Department of Pharmacy, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK
cRega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received 30 June 2003; revised 8 September 2003; accepted 16 September 2003
Abstract—We describe the synthesis and the antiviral evaluation of novel a and b dideoxynucleoside derivatives in which the base
has been replaced by a 3-hydroxy-2-methylpyridin-4-one. The syntheses were successfully achieved by the use of the standard
Vorbruggen coupling conditions. Moderate activity of these compounds were found on herpes simplex virus (HSV) type 1 and
type 2.
# 2003 Elsevier Ltd. All rights reserved.
3-Hydroxypyridin-4-ones (HPOs) are currently one of
the main candidates for the development of orally active
iron chelators.1 Indeed, the 1,2-dimethyl derivative
(Deferiprone, Fig. 1), with an associated pFe3+ value of
19.4 is the only active iron chelator currently available
for clinical use (marketed by Apotex Inc., Toronto,
Canada as FerriproxTM).2 It has been shown that iron
chelation, which would make iron unavailable for redox
reactions, could influence HIV replication in two possi-
ble ways:
Figure 1.
in which the base has been changed to a 3-hydroxy-
ꢀ by inactivation of the iron-dependent cellular
enzyme ribonucleotide reductase which is
responsible for generating the building blocks for
viral DNA.3
pyridin-4-one. Moreover, the base modification of these
new nucleosides could confer activity against other viru-
ses than HIV. For a start, the synthesised nucleosides
contain sugar moieties similar to that of two currently
FDA approved anti-HIV 20,30-dideoxynucleosides: ddC
and 3TC (Fig. 2).
ꢀ via reduction of nuclear factor-kB (NF-kB)
activation.4
Recently, a clear synergism in HIV-1 inhibition was
observed by combining iron chelators with the anti-HIV
nucleoside analogue ddI and it was suggested that in
combination with existing antivirals, iron chelation could
have a beneficial effect on HIV disease.5 These findings
prompted us to synthesise several 20,30-dideoxynucleosides
Results and Discussion
3-Hydroxybenzyl-2-methylpyridin-4-one is a requisite
for the Vorbruggen conditions in the sugar-base coupl-
ing. It was obtained starting from maltol which was
benzylated with benzyl bromide in a basic media
(Scheme 1). Reaction of adduct 1 with ammonia was
performed by reflux in 50% aqueous ethanol. The ben-
zylated pyridinone 2 was isolated in a crystalline form
*Corresponding author. Tel.:+33-4-9182-9586; fax:+33-4-9182-9580;
e-mail: camplo@luminy.univ-mrs.fr
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.09.033

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K. Barral et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4371–4374
as a free base in 58% yield.6 The primary alcohol func-
tion of the commercially available precursor (S)-(+)-
dihydro-5-(hydroxymethyl)-2-(3H)-furanone was pro-
tected with TBDPSCl in THF to give the lactone 3
(Scheme 2). This latter compound was then reduced
with diisobutylaluminium (DIBAL-H), followed by
trapping of the resulting lactol with acetic anhydride to
give 4 in 78% yield. 3-Benzyloxy-2-methylpyridin-4-one
2 was silylated under reflux for 2 h with hexamethyldi-
silazane (HMDS) in the presence of a catalytic amount
of ammonium sulfate. After the removal of the excess of
HMDS, the base was solubilised in 1,2-dichloroethane
and a mixture of 4 and trimethylsilyltriflate (TMSOTf)7
in 1,2-dichloroethane was slowly added at room tem-
perature to afford compounds 5 and 6 in 47% yield. The
b/a ratio generally was around 1, and separation of
both isomers was successfully accomplished by flash
silica gel chromatography. The relative stereochemistry
Figure 2.
1
of these compounds was assigned by 1D and 2D H
Scheme 1. (a) BnBr, NaOH, MeOH, reflux, 16 h; (b) NH3, EtOH,
reflux, 24 h.
NMR studies (Fig. 3). NOE interactions were observed
between H-10 and H-40 suggesting the cis orientation of
the less polar compound 5. The trans configuration was
then assigned to the more polar isomer 6. Compounds 5
Scheme 2. (a) TBDPSCl, imidazole, dry DMF, rt, 18 h; (b) DIBAL, dry DCM, ꢁ90 ꢂC then Ac2O, pyridine, DMAP, rt, 72 h; (c) silylated 2, dry
DCE, TMSOTf, rt, 20 h; (d) TBAF, dry THF, rt, 72 h; (e) H2, Pd/C, MeOH, rt, 16 h.

K. Barral et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4371–4374
4373
presence of pyridine and 4-(dimethylamino)pyridine to
give the corresponding acetate 12 in 64% yield. The
heterocycle base 2 was silylated and reacted with 12 in
1,2-dichloroethane and TMSOTf as catalyst. The rela-
tive stereochemistry of these compounds was assigned
by NOESY and COSY experiments (Fig. 3). NOE
interactions were observed between H-10 and H-40 sug-
gesting the cis configuration of the less polar 13 and the
trans configuration of the more polar 14. The racemic
cis nucleoside 13 and the racemic trans nucleoside 14
were then deprotected by treatment with TBAF in THF,
to give 15 and 16 in quantitative yields. Since the sul-
phur atom, contained in the oxathiolane ring, poisons
the Pd catalyst, debenzylation of the heterocycle base
was successfully achieved with the use of iodo-
trimethylsilane10,11 to afford the racemic cis nucleoside
17 and the racemic trans nucleoside 18 in modest yields.
Figure 3.
and 6 were converted to compounds 7 and 8 by
treatment with TBAF in THF. Catalytic hydrogena-
tion in MeOH over 10% palladium on carbon gave
the cis nucleoside 9 and the trans nucleoside 10 in
quantitative yields.8 In order to prepare the oxathio-
lane derivatives 17 and 18 (Scheme 3) the racemate
thialactone 11 previously described by Choi et al.9 was
reduced with DIBAL-H and acetylated by Ac2O in
Evaluation of antiviral activity was done as described
previously.12 The compounds were evaluated against
HIV-1 and HIV-2, herpes simplex virus type 1 (HSV-1)
Scheme 3. (a) DIBAL, dry DCM, ꢁ90 ꢂC then Ac2O, pyridine, DMAP, rt, 72 h; (b) silylated 2, dry DCE, TMSOTf, rt, 24 h; (c) TBAF, dry THF, rt,
3 h; (d) NaI, TMSCl, dry CHCl3, rt, 18 h.

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K. Barral et al. / Bioorg. Med. Chem. Lett. 13 (2003) 4371–4374
Table 1. Anti-HIV and anti-HSV activities of compounds 9, 10, (ꢃ)-17, and (ꢃ)-18
Compd
Anti-HIV activity
Anti-HSV activity
EC50 (mM)
HIV-1
in CEM cells
EC50 (mM)
HIV-2
in CEM cells
CC50 (mM)
EC50 (mM)
HSV-1 (KOS)
in HEL cells
EC50 (mM)
HSV-2 (G)
in HEL cells
EC50 (mM)
HSV-1 TK neg
in HEL cells
CC50 (mM)
9
10
(ꢃ)-17
(ꢃ)-18
ACV
>50
>50
>80
>80
>50
>50
>80
>80
101ꢃ6.2
>50
203ꢃ2.5
203ꢃ11.9
>200
40
177
32
40
0.32
>900
500
81
500
500
80
95
88
>900
>900
>100
>400
>1700
90
1.3
>200
>200
(acyclovir)
DHPG
(ganciclovir)
HPMPC
(cidofovir)
>200
>200
>200
>200
>200
>200
—
0.06
—
—
—
>400
>350
0.57
EC50, effective concentration or concentration required to inhibit 50% of virus induced cytopathicity; CC50, cytotoxic concentration or concen-
tration required to reduce cells viability by 50%; —not determined.
References and Notes
and type 2 (HSV-2), vaccinia virus and vesicular stomatitis
virus in HEL cells, parainfluenza-3 virus, reovirus-1,
Sindbis virus, coxsackie B4 virus, Punta Toro virus in
Vero cells and respiratory syncytial virus in HeLa cell
cultures. The anti-HIV and HSV activities of com-
pounds 9, 10, 17 and 18 are represented in Table 1.
None of these compounds were active against any of the
tested viruses except for herpes simplex virus (Table 1).
Compound 10, 17 and 18 displayed moderate activity
against both wild-type HSV-1 and HSV-2, as well as
against a thymidine kinase deficient strain of HSV-1
that has a 270 fold reduced sensitivity for acyclovir than
the wild-type virus. The weak but consistent activity of
these compounds against HSV-1 and HSV-2 is
encouraging and may suggest that these new nucleosides
are metabolised to their 50-triphosphates or as such
recognised by the viral DNA polymerases. The (moder-
ate) activity of an form of a nucleoside (10 and 18) is
quite unusual, few such molecules have been reported.
Further work is needed both to design analogues with
an improved anti-herpes virus activity and to unravel
their mechanism of action.
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Acknowledgements
We wish to thank Dr. Robert Faure (St. Jerome Uni-
versity, Marseilles) for his expertise in conducting NMR
experiments and Mrs. Miette Stuyck, Mrs. Ann Absillis,
Mrs. Anita Vankierde and Mrs. Frieda De Meyer for
excellent technical assistance.