Synthesis and antiviral evaluation of isatin ribonucleosides

Article abstract of DOI:10.1081/NCN-120016510

A series of novel substituted isatin ribonucleosides 3b-3f were synthesized in good yields by a TMSOTf catalysed coupling reaction between the silylated nitrogenated base (1b-1f) and 1-O-acetyl-2,3,5-tri- O-benzoyl-β-D-ribofuranose (2). Isatin nucleoside 3a previously reported was also prepared using this method giving high yield. From the compounds tested, ribonucleoside 3f proved to be the most active one when assayed for antiviral activitiy on HSV-1 infected cells, leading to 66% of inhibition of virus yield. All the isatin derivatives tested did not inhibit HIV-1 Reverse Transcriptase (RT) activity.

Full text of DOI:10.1081/NCN-120016510

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SYNTHESIS AND ANTIVIRAL EVALUATION OF ISATIN
RIBONUCLEOSIDES
Mara R.P. deOliveira a , José C. Torres a , Simon J. Garden a , Carla Veronica B. dos Santos
b , Thatyana Rocha Alves b , Angelo C. Pinto a , Helena de S. Pereira a , Luiz Roberto Leão
Ferreira c , Nissin Moussatché a , Izabel Christina de P. P. Frugulhetti c , Vitor F. Ferreira b &
Maria Cecília B. V. de Souza d
a Departamento de Química Orgânica , Instituto de Química , Universidade Federal do Rio de
Janeiro , Ilha do Fundão, Rio de Janeiro, CEP 21945-970, Brazil
b Departamento de Química Orgânica , Outeiro de São João Batista s/no, Centro, Niterói ,
Instituto de Química , Rio de Janeiro, CEP 21945-970, Brazil
c Instituto de Biologia , Outeiro de São João Batista s/no, Centro, Niterói , Universidade
Federal Fluminense , Rio de Janeiro, CEP 21945-970, Brazil
d Departamento de Química Orgânica , Outeiro de São João Batista s/no, Centro, Niterói ,
Instituto de Química , Rio de Janeiro, CEP 21945-970, Brazil
Published online: 31 Aug 2006.
To cite this article: Mara R.P. deOliveira , José C. Torres , Simon J. Garden , Carla Veronica B. dos Santos , Thatyana
Rocha Alves , Angelo C. Pinto , Helena de S. Pereira , Luiz Roberto Leão Ferreira , Nissin Moussatché , Izabel Christina de
P. P. Frugulhetti , Vitor F. Ferreira & Maria Cecília B. V. de Souza (2002) SYNTHESIS AND ANTIVIRAL EVALUATION OF ISATIN
RIBONUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 21:11-12, 825-835, DOI: 10.1081/NCN-120016510
To link to this article: http://dx.doi.org/10.1081/NCN-120016510
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©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 21, Nos. 11 & 12, pp. 825–835, 2002
SYNTHESIS AND ANTIVIRAL EVALUATION
OF ISATIN RIBONUCLEOSIDES
1
Mara R. P. de Oliveira, Jose C. Torres, Simon J. Garden, Carla
1
1
´
Veronica B. dos Santos,2 Thatyana Rocha Alves,2 Angelo C. Pinto,1
Helena de S. Pereira,4 Luiz Roberto Leao Ferreira,3
˜
4
3
´
Nissin Moussatche, Izabel Christina de P. P. Frugulhetti,
Vitor F. Ferreira,2 and Maria Cecılia B. V. de Souza2,*
´
1Universidade Federal do Rio de Janeiro, Instituto de Quı
Departamento de Quımica Organica, Ilha do Fundao,
CEP 21945-970, Rio de Janeiro, Brazil
2Instituto de Quı
mica, Departamento de Quımica Organica, and
3Instituto de Biologia, Universidade Federal Fluminense,
Outeiro de Sao Joao Batista s=no, Centro, Niteroi,
CEP 24210-150, Rio de Janeiro, Brazil
4Universidade Federal do Rio de Janeiro, Instituto de Biofı
´
mica,
´
´
´
´
´
sica
Carlos Chagas Filho, Ilha do Fundao, CEP 21941-590,
Rio de Janeiro, Brazil
ABSTRACT
A series of novel substituted isatin ribonucleosides 3b^3f were synthe-
sized in good yields by a TMSOTf catalysed coupling reaction between
the silylated nitrogenated base (1b ^1f) and 1-O-acetyl-2,3,5-tri-O-ben-
zoyl-b-D-ribofuranose (2). Isatin nucleoside 3a previously reported was
also prepared using this method giving high yield. From the compounds
*Corresponding author. Fax: 55 021 21 27193349; E-mail: gqocica@vm.uff.br
825
DOI: 10.1081=NCN-120016510
Copyright # 2002 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

826
DE OLIVEIRA ET AL.
tested, ribonucleoside 3f proved to be the most active one when assayed
for antiviral activitiy on HSV-1 infected cells, leading to 66% of inhibi-
tion of virus yield. All the isatin derivatives tested did not inhibit HIV-1
Reverse Transcriptase (RT) activity.
The synthesis of new ribonucleosides continues to be important for the search
of therapeutically useful agents.[1] Isatin derivatives[2] have been found to
possess a wide variety of pharmacological properties as follows- monoamine
oxidase inhibitor,[3] antibacterial[4] and antiviral activities.[4b,4c,5] However,
the literature reports few studies on the preparation of isatin nucleosides.[6–9]
As part of an ongoing program[10,11] for investigating the trans-
formation of isatins into new derivatives with potential biological activity,
this work describes the synthesis of five new isatin ribonucleosides: 5-methyl-
2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-dione (3b),
5-fluoro-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-dione
(3c), 5-chloro-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-
2,3-dione (3d), 5-iodo-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)
indole-2,3-dione (3e), 4,6-dibromo-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-
ribofuranosyl)indole-2,3-dione (3f) as well as derivative 2,3-dihydro-1-(2,3,5-
tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-dione (3a)[6a] previously repor-
ted. These isatin ribonucleosides were screened for their in vitro antiviral
properties in HSV-1 infected cells. These compounds were also tested on
HIV-1 RT activity. The reaction sequence for the preparation of the target
compounds is outlined in Sch. 1.
RESULTS AND DISCUSSION
Isatin derivatives used in this work (1a–1f) were prepared according to
published procedures.[10,11] The method chosen for the synthesis of the cor-
responding ribonucleosides was the coupling between the previously silylated
nitrogenated base and 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (2)
using Lewis acid catalysis.[12] Heating 1 with bis(trimethylsilyl)trifluoro-
acetamide (BSTFA)[13] containing 1% of trimethylchlorosilane (TMSCl), at
60ꢀC, under nitrogen atmosphere, for 16 h, followed by reaction with 2, in
the presence of trimethylsilyltrifluoroamethanesulfonate (TMSOTf)[14] as
catalyst, at room temperature, for 6 h, gave high yields of the corresponding
ribonucleosides 3a–3f (Sch. 1) (3a: 90%; 3b: 80%; 3c: 82%; 3d: 78%;
3e: 78%; 3f: 80%). The use of a mixture of hexamethyldisilazane=
trimethylchlorosilane as the silylating agent and toluene as solvent led to
clear solutions which failed to give any nucleoside product.
Although the de-O-benzoylation of 3a is successfully reported in the
literature,[6a] all attempts to remove the O-benzoyl groups from 3a–3f using

ISATIN RIBONUCLEOSIDES
827
Scheme 1. Synthetic route used for the preparation of isatin nucleosides 3a–3f.
different basic or acidic reagents such as methanol=sodium methoxide solu-
tion, methanol=sodium bicarbonate solution and Dowex Hþ=H2O, under
different reaction conditions of time and temperature, led to nucleoside
decomposition products, probably as a result of the initial fragmentation of
N-glycosyl bond. This cleavage, in basic conditions, may be rationalized by
the attack of the alcoxide ion on the most reactive benzoyl group (C-2),
followed by a fast b-attack of the oxygen anion from the ortho-ester to the
anomeric center, eliminating the isatin moiety, which is a good leaving group
due to the vicinal carbonyl, as outlined in Sch. 2. Thus, it seems that this
cleavage reverses the glycosyl bond by the same kind of mechanism of the
regiocontrolled and stereospecific glycoylation of isatin derivatives with 1-O-
acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (2). This cleavage was also
observed in FAB mass spectra.
The structures of the nucleosides were confirmed by IR, UV, 1H and 13
C
NMR experiments [1H (Table 1), 13C (Table 2), DEPT, 1H-1H-COSY, HET-
COR (1JCH andnJCH, n ¼ 2, 3)] and by FAB-high resolution mass spectra which
revealed the molecular-ion peaks (MþH)þas well as the ion m=z 445 attributed
to the riboside fragment resulting from C-N cleavage of glicosyl bond.
1H and 13C spectra of 3a–3f showed very similar chemical shifts for the
riboside moiety in each case (Tables 1 and 2).
The observation of nuclear Overhauser effect (n.O.e.) for the H40 signals
while the anomeric proton was being irradiated (3a: 3.09%; 3b: 2.46%; 3c:
3.72%; 3d: 3.04%; 3e: 3.88%; 3f: 2.97%) confirmed the b-configuration of all
nucleosides.[15] The point of attachment of the sugar to the bases assigned to the

828
DE OLIVEIRA ET AL.
Scheme 2. Cleavage of the N-glycosyl bond of 3a–3f under basic conditions.
nitrogen atom from the isatin nucleus was based upon carbon-13 NMR che-
mical shifts for C2 and C3. These were compared with data for N-alkylated
isatins in the literature.[11] Additionalproof for N1-ribosylation was alsovisible
through the nuclear Overhauser effect in the spectra of the compounds where
the irradiation of the anomeric hydrogen, H10, resulted in an observed n.O.e. on
H7 (3a: 5.45%; 3b: 3.28%; 3c: 6.11%; 3d: 6.89%; 3e: 7.11%; 3f: 5.25%).
BIOLOGICAL STUDIES
HSV-1 infected cells were incubated with the isatins and isatin ribo-
nucleosides at a concentration of 50 mM for 72 h. The antiviral activity was
determined according to the computation of the 50 percent endpoint method
described by Reed and Muench.[5] Among the heterocycles, 1c and 1f were
found to reduce virus yield significantly. Ribonucleosides 3a, 3b and 3f
proved to be more active than the corresponding isatin heterocycles, while
the heterocycle 1c was more active than the corresponding ribonucleoside.
Thus, these five compounds were considered to be the most efficient deri-
vatives, leading to statistically significant inhibition of virus yield (Table 3).
The most efficient isatin derivatives were still less efficient than the potent anti
HSV-1 compound, acyclovir, which reduced virus yield nearly 100% at the
same concentration. Sincitium formation was exclusively observed in infected
cells incubated with ribonucleoside 3c. Compound 3d was toxic to VERO
cells and therefore was not tested.
Further investigation on the antiviral activities of the heterocycles 1a–1f
and the ribonucleosides 3a–3f was assessed by measuring [3H]dTTP incor-
poration in a poly(rA).oligo(dT) template primer by the activity of the

ISATIN RIBONUCLEOSIDES
829

830
DE OLIVEIRA ET AL.

ISATIN RIBONUCLEOSIDES
Table 3. Antiviral Activity of Isatins 1a–1f and Isatin Ribonucleosides
831
3a–3f (50 mM) on HSV-1 Yield
Herpes Simplex Type 1
Virus (% of Inhibition of
Virus Yield)
Compounds
1a
1b
1c
1d
1e
1f
0
ꢁ 16
60*
28
28
46*
3a
3b
3c
3d
3e
3f
61*
46*
15
N.D.
37
66*
N.D. ¼ not determined.
Vero cells (106 cells=well) were infected with HSV-1 at 1PFU=cell for 2 h.
At zero time post-infection, virus inocullum was replaced by culture
medium containing or not isatin derivatives. After 72 h post-infection, virus
yield of each sample was determined by 50% tissue culture infective dose
(TCID50=mL). The data are mean values from one of the representative
experiments.
*P values < 0.05 for comparing drug-treated and non-treated cells.
recombinant HIV-1 reverse transcriptase (HIV-1 RT), as already descri-
bed.[17] Our results showed that none of the isatin derivatives reduced the
RNA-dependent DNA polymerase activity of the recombinant HIV-1 RT.
In conclusion, the modest but significant anti-HSV-1 activities of the
isatin derivatives described here suggests that these compounds may be
selectively targeted to HSV-1 replication, since they were not cytotoxic to
VERO cells at the concentration tested.
EXPERIMENTAL
General Procedures
Melting points were determined on a Fisher-Johns apparatus and
are uncorrected. The IR spectra were recorded on a Perkin-Elmer 1420
spectrometer as potassium bromide pellets and frequencies are expressed in
cmꢁ1. Ultraviolet (UV) spectra were obtained on a Schimadzu spectro-
photometer; l are in nm and e in molꢁ1 cmꢁ1. Mass spectra analysis

832
DE OLIVEIRA ET AL.
(FABHRMS) were recorded in a 3-nitrobenzylalcohol matrix in the positive
ion mode on a VG ZAB-E mass spectrometer, by Department of Chemistry
and Biochemistry, University of Oklahoma. NMR spectra were recorded on
a Varian Unity Plus 300 spectrometer operating at 300.00 MHz (1H) and
75.0 MHz (13C), in specified solvents. Chemical shifts are reported in ppm (d)
relative to tetramethylsilane. Proton and carbon spectra were typically
obtained at room temperature. The two dimensional experiments were
acquired using standard Varian Associates automated programs for data
acquisition and processing.
General Procedure for the Preparation of 2,3-Dihydro-1-(2,3,5-tri-O-
benzoyl-b-D-ribofuranosyl)indole-2,3-dione (3a), 5-Methyl-2,3-dihydro-1-
(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-dione (3b), 5-Fluoro-2,3-
dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-dione (3c), 5-
Chloro-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-dione
(3d), 5-Iodo-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)indole-2,3-
dione (3e) and 4,6-Dibromo-2,3-dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofur-
anosyl)indole-2,3-dione (3f). A mixture of isatin 1a–1f (2.0 mmol) and
bis(trimethylsilyl)trifluoroacetamide (BSTFA, 7.46 mmol) containing 1% of
trimethylchlorosilane, in acetonitrile (4 mL) was stirred at 60ꢀC, under
nitrogen atmosphere, for 16 h. The reaction mixture was allowed to cool to
room temperature and a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-
ribofuranose (2.1 mmol) in 15 mL of acetonitrile was added. This procedure
was followed by the dropwise addition of a solution of TMSOTf (2.1 mmol)
in 10 mL of acetonitrile. After stirring for 6 h. the resulting mixture was
poured into ice-cold water (20 g). Afterwards, it was neutralized with a
saturated aqueous solution of sodium bicarbonate and extracted with ethyl
acetate (3630 mL). The combined organic phases were dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using hex-
ane:methylenechloride gradient (up to 40%) as the eluant, to give:
3a: as orange crystals (1.08 g, 90%), m.p. 73ꢀC; UV lmax (CHCl3) 411
(e 426), 244 (e 35,449); IR 1730 (C¼O), 1260 (C-O); FABHRMS m=z calcd
1
for C34H26NO9 (MþH)þ 592.1619, found 592.1607; H NMR (300.00 MHz,
CDCl3) see Table 1; 13C NMR (75.0 MHz, CDCl3) see Table 2.
3b: as orange crystals (0.97 g, 80%), m.p. 78ꢀC; UV lmax (CHCl3) 424
(e 406), 244 (e 17,939); IR 1730 (C¼O), 1260 (C-O); FABHRMS m=z calcd
1
for C35H28NO9 (MþH)þ 606.1715, found 606.1171; H NMR (300.00 MHz,
CDCl3) see Table 1; 13C NMR (75.0 MHz, CDCl3) see Table 2.
3c: as orange crystals (1.00 g, 82%), m.p. 86ꢀC; UV lmax (CHCl3) 411
(e 633), 245 (e 25,443); IR 1725 (C¼O), 1260 (C-O); FABHRMS m=z calcd

ISATIN RIBONUCLEOSIDES
833
for C34H25NO9F (MþH)þ 610.1525, found 610.1513; 1H NMR
(300.00 MHz, CDCl3) see Table 1; 13C NMR (75 MHz, CDCl3) see Table 2.
3d: as orange crystals (0.98 g, 78%), m.p. 86ꢀC; UV lmax (CHCl3) 419
(e 609), 245 (e 25,749); IR 1730 (C¼O), 1260 (C-O); FABHRMS m=z calcd
for C34H25NO935Cl (MþH)þ 626.5229; found 626.1217; 1H NMR
(300.00 MHz, CDCl3) see Table 1; 13C NMR (75.0 MHz, CDCl3) see Table 2.
3e: as orange crystals (1.10 g, 78%), m.p. 83ꢀC; UV lmax (CHCl3) 424
(e 989), 243 (e 22,198); IR 1730 (C¼O), 1260 (C-O); FABHRMS m=z calcd
1
for C34H25NO9I (MþH)þ 718.0585, found 718.0574; H-NMR (CDCl3) see
Table 1; 13C-NMR (CDCl3) see Table 2.
3f: as yellow crystals (1.20 g, 80%), m.p. 223ꢀC; UV lmax (CHCl3) 406
(e 922), 243 (e 19,324); IR 1730 (C¼O), 1260 (C-O); FABHRMS m=z calcd
for C34H24NO981Br2 (MþH)þ 751.9790, found 751.9788; 1H NMR
(300.00 MHz, CDCl3) see Table 1; 13C NMR (75.0 MHz, CDCl3) see Table 2.
Cells. VERO epithelial cell line derived from monkey kidney cells
obtained from the American tissue culture Collection (Rockville, MD) were
grown in monolayer cultures in Dulbecco’s modified Eagle’s medium (Gibco
laboratories) containing 2% heated-inactivated fetal bovine serum (FBS;
Pigue Farm), 8% calf serum (CS; Pan-American Center of aftose fever),
2.25% sodium bicarbonate, 500 U=mL penicilin, 100 mg=mL streptomycin,
50 mg=mL gentamycin, 2.5 mg=mL fungison. Cell cultures were incubated at
37ꢀC in humidified air containing 5% CO2. For passaging, confluent
monolayers (6.56105 cells) were washed with phosphate-buffered saline
solution (NaCl, 0.8 g%, KCl, 0.02 g%, Na2HPO4, 0.15 g%, NaH2PO4,
0.02 g%, EDTA, 1 mM PBS pH 7.2), and after a short trypsinisation
(Trypsin at 0.25 g%) the cells were suspended in the culture medium.
Virus. HSV-1 were kindly provided by Dr. Marcia Wigg (Uni-
versidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil), propagated in
Hep-2-cells and stored at ꢁ70ꢀC until use.
Antiviral Activity. Antiviral activity on HSV-1 virus infection was
assessed by virus yield assay. Briefly, sub-confluent VERO cells, grown in 96-
well plates (106 cells=well), were infected with HSV-1 at 1 PFU (plaque
forming unity)=cell for 120 min at 37ꢀC in 100 mL of DMEM. After this
period, virus inocullum was replaced by culture medium, containing isatin
derivatives or not. We defined this point as the zero time post-infection. After
72 h post-infection, culture medium was harvested and virus titer of each
sample was quantified in terms of the 50% tissue culture infective dose
(TCID50=mL) by endpoint dilution, according to Reed and Muench.[16]

834
DE OLIVEIRA ET AL.
ACKNOWLEDGMENTS
Fellowship granted to M.R.P.O. from CNPq (Brazil) is gratefully
acknowledged. A.C.P., S.J.G., M.C.B.V.S. and V.F.F. are grateful to CNPq
for their individual research fellowships. This work was partially supported
by CNPq (National Council of Research from Brazil) and FAPERJ.
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Received February 8, 2002
Accepted August 26, 2002