Synthesis and antiviral properties of arabino and ribonucleosides of 1,3-dideazaadenine, 4-nitro-1,3-dideazapurine and diketopiperazine

Article abstract of DOI:10.1081/NCN-200040614

Different arabinosides and ribosides, viz. Ara-DDA or 9(1-β-D- arabinofuranosyl) 1,3-dideazaadenine (6), Ara-NDDP or 9(1-β-D- arabinofuranosyl) 4-nitro-1,3-dideazapurine (7), Ara-DKP or 1(1-β-D- arabinofuranosyl) diketopiperazine (8), Ribo-DDA or 9(1-β-D-

Full text of DOI:10.1081/NCN-200040614

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Synthesis and Antiviral Properties of Arabino and
Ribonucleosides of 1,3‐Dideazaadenine, 4‐Nitro‐1,
3‐dideazaadenine and Diketopiperazine
Sarika Sinha a , Richa Srivastava a , Prof. Erik De Clercq b & Dr. Ramendra K. Singh a
a Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad,
Allahabad, 211 002, India
b Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, B‐2000,
Belgium
Version of record first published: 17 Aug 2006.
To cite this article: Sarika Sinha , Richa Srivastava , Prof. Erik De Clercq & Dr. Ramendra K. Singh (2004): Synthesis and
Antiviral Properties of Arabino and Ribonucleosides of 1,3‐Dideazaadenine, 4‐Nitro‐1, 3‐dideazaadenine and Diketopiperazine,
Nucleosides, Nucleotides and Nucleic Acids, 23:12, 1815-1824
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 23, No. 12, pp. 1815–1824, 2004
Synthesis and Antiviral Properties of Arabino and
Ribonucleosides of 1,3-Dideazaadenine, 4-Nitro-1,
3-dideazapurine and Diketopiperazine
Sarika Sinha,1 Richa Srivastava,1 Erik De Clercq,2
and Ramendra K. Singh1,
*
1Nucleic Acids Research Laboratory, Department of Chemistry,
University of Allahabad, Allahabad, India
2Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Leuven, Belgium
ABSTRACT
Different arabinosides and ribosides, viz. Ara-DDA or 9(1-b-D-arabinofuranosyl) 1,3-
dideazaadenine (6), Ara-NDDP or 9(1-b-D-arabinofuranosyl) 4-nitro-1,3-dideaza-
purine (7), Ara-DKP or 1(1-b-D-arabinofuranosyl) diketopiperazine (8), Ribo-DDA
or 9(1-b-D-ribofuranosyl) 1,3-dideazaadenine (9) and Ribo-NDDP or 9(1-b-D-
ribofuranosyl) 4-nitro-1,3-dideazapurine (10) have been synthesized as probable
antiviral agents. The arabinosides have been synthesized using the catalyst TDA-1 that
causes stereospecific formation of b-nucleosides while a one-pot synthesis procedure
was adopted for the synthesis of the ribonucleosides where b-anomers were obtained
in higher yields. All the five nucleoside analogs have been screened for antiviral
property against HIV-1 (IIIB), HSV-1 and 2, parainfluenza-3, reovirus-1 and many
others. It was observed that arabinosides had greater inhibitory action than ribosides.
*
Correspondence: Dr. Ramendra K. Singh, Nucleic Acids Research Laboratory, Department of
Chemistry, University of Allahabad, Allahabad 211 002, India; Fax: +91-532-2461005;
E-mail: singhramk@rediffmail.com.
1815
DOI: 10.1081/NCN-200040614
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com
Copyright D 2004 by Marcel Dekker, Inc.

1816
Sinha et al.
The compound 7 or Ara-NDDP has shown maximum inhibition of HIV-1 replication
than the rest of the molecules with an IC50 of 79.4 mg/mL.
Key Words: Antivirals; Arabinosides; Ribosides; Dideazapurines; Diketopiperazine.
INTRODUCTION
Nucleoside analogs act as antitumor and antiviral agents[1–14] via inhibition of the
enzymes, viz. DNA and RNA polymerases, thymidylate synthetase, adenosine deaminase,
adenosine kinase, SAH hydrolase etc. of nucleoside, nucleotide or nucleic acid metabo-
lism of the tumor cells or pathogens.
Arabinosides are known to act as good selective antiviral agents[15] and are
probably the most extensively investigated inhibitors of DNA polymerase.[16,17]
Though it has been difficult to assign a mechanism for their action, these inhibitors
may be said to be rather poor substrates for DNA polymerases, often leading to chain
termination during replication. The best-known inhibitor belonging to the arabinoside
series is Ara-A or Vidarabin.[16–19] It is an important antiviral and antitumor agent but
its activity is restricted by its deamination caused by the enzyme adenosine de-
aminase.[2–5] So, we can see that there is a need for developing adenosine deaminase
resistant analogs of Ara-A and in the same pursuance the compounds 6 and 9 have
been synthesized. The compounds 7, 8, and 10 have been synthesized as broad-
spectrum probable antiviral agents. The compound 8 is expected to have antileukemic
activity and cause inhibition of the enzymes thymidylate synthetase and cytidine
deaminase as well. The results are to be reported elsewhere along with studies on other
structurally similar compounds.
CHEMISTRY
The nucleosides of the purine analog- benzimidazole or 1,3-dideazapurine, with
substitutions at 2 and/or 5, 6 positions, have exhibited good antiviral properties[20–26]
and efforts are on to increase their potency.[7,27] The nucleoside analog 9-(1-b-D-
deoxyribofuranosyl) 1,3-dideazaadenine has been indicated to be resistant to adenosine
deaminase.[28] The molecule 9-(1-b-D-ribofuranosyl) 3-deazaadenine[29–32] has been
found to exhibit a wide range of antiviral properties and is supposed to be adenosine
deaminase resistant. The compounds (6) and (9) can be considered as analogs of
Ara-A or 3-deazaadenosine or 9-(1-b-D-deoxyribofuranosyl) 1,3-dideazaadenine and
this analogy, as we expected, might result in a molecule that has good antiviral
property, particularly against HSV-1 like Ara-A, and is at the same time adenosine
deaminase resistant also. However, these molecules could not show good antiviral
property against HSV-1. The study on adenosine deaminase resistant properties of these
molecules is in progress.
The nucleosides of uracil mimetics have also exhibited antiviral properties.[33–36]
The compound (8) too can be considered as a structural mimetic of uracil and Ara-U.
Another reason for choosing diketopiperazine nucleus for development as nucleoside
analog was that piperazine derivatives have been shown as antagonists of HIV-1.[37]

Ribonucleosides of 1,3-Dideazaadenine
1817
The nucleoside analogs Ara-NDDP (7) and Ribo-NDDP (10) have been synthe-
sized for screening their broad-spectrum antimicrobial properties as well.
For the synthesis of arabinosides 6, 7 and 8, D(À)arabinose was first converted into
2,3,5-tri-O-benzoyl-a-D-arabinosyl chloride (1) which was then coupled with N-
benzoyl-1,3-dideazaadenine (3), 4-nitro-1,3-dideazapurine (4) and bis (trimethylsilyl)
diketopiperazine (5), respectively, at room temperature in the presence of the catalyst
TDA-1. This catalyst has been proved to produce b-anomers selectively.[38]
Ribonucleosides 9 and 10 were synthesized by coupling N-benzoyl-1,3-dideazaadenine
(3) and 4-nitro-1,3-dideazapurine (4), respectively with 1-O-acetyl-2,3,5-tri-O-benzoyl-
b-D-ribofuranose (ABR) (2) at room temperature, in a one-pot synthesis using HMDS,
TCS and SnCl4.[39,40] The nucleosides 6, 7, 8, 9 and 10 were obtained after depro-
tection with 25% ammonia solution and purified by silica gel column chromatography.
Their yields were 40%, 70%, 50%, 40% and 60%, respectively. The synthetic routes
used for the preparation of these compounds are outlined in Schemes 1 and 2.
We have tried to increase the yield of the compound 7 further by coupling the base
4 with 2,3,5-tri-O-benzoyl-a-D-arabinosyl bromide,[41,42] since bromide is supposed to
be a better leaving group than chloride. The catalyst and the reaction conditions were
exactly the same as before but the coupling did not take place. Another set of reaction
˚
was carried out using a mixture of DCM and CH3CN as solvents and 4 A molecular
sieves[6] in the absence of TDA-1. The reaction mixture was stirred at room tem-
perature for about 72 h. However, the yield of the protected nucleoside was not very
significant to proceed further.
Another thing that the authors wish to point out is that a survey of the available
literature has shown that there are only a few reports on arabinosides synthesis by
Scheme 1. Synthesis of arabinosides.

1818
Sinha et al.
Scheme 2. Synthesis of ribosides.
direct coupling of the sugar arabinose with natural/non-natural bases. In most cases,
arabinosides have been synthesized by post-coupling modification of ribosides, which
leads to increased number of synthetic steps. The authors, therefore, have tried to
synthesize arabinosides by direct coupling of appropriately protected and activated
D-arabinose with base analogs and have thereby been able to produce these nucleosides
in considerably shorter time with significant yields in some cases like that of Ara-
NDDP or compound 7.
The compounds 1,3-dideazaadenine (3a), 4-nitro-1,3-dideazapurine (4) and di-
ketopiperazine (5a) were prepared using standard procedures.[43,44] The compound 3a was
N-benzoylated with 1.5 equivalents of benzoyl chloride following the usual benzoylation
procedure to get 3. The compound 5a was silylated with HMDS and TCS to get 5.
Prior to coupling of silylated base 5 with halogenose (1), HMDS and TCS were
completely removed at pump. This was done after taking lead from the work of Kotick
et al.[45] where it has been pointed out that trimethylsilyl chloride might cause
anomerization of the halogenose during the coupling reaction, presumably by chloride
exchange. Since the method we have used for nucleoside synthesis involves TDA-1, a
phase transfer catalyst, which causes specific formation of b-anomers as major
products, removal of HMDS and TCS seemed necessary. On the basis of the
observations of Kotick et al., if the coupling reaction proceeds by nucleophilic attack
of the silylated base on the glycosyl halide, with a single Walden inversion (SN2
mechanism), then the reaction of a pure a halogenose should lead to the formation of a
b nucleoside. In the coupling procedure we have followed, TDA-1 is already causing
stereospecific formation of b-anomers. The presence of HMDS and TCS may lead to a
double Walden inversion and as a result an undesired major product, i.e., a nucleoside
will be obtained. Hence removal of HMDS and TCS completely from the reaction
mixture was an essential requirement prior to the coupling step.

Ribonucleosides of 1,3-Dideazaadenine
Table 1. Anti-viral screening results of compounds 6–10.
IC50 (mg/ml)
1819
Virus/cells
6
7
8
9
10
HIV-1(IIIB)/MT-4 cells
>125
>40
>40
= 79.4
>80
>80
>125
>80
>80
>125
>40
>40
>125
>40
>40
Vesicular stomatitis virus/HeLa cells
Coxsackie virus B4/HeLa cells
Respiratiory syncytial virus/HeLa cells
Parainfluenza-3 virus/Vero cells
Reovirus-1/Vero cells
>40
>40
>80
>80
>40
>120
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>40
>40
Sindbis virus/Vero cells
Coxsackie virus B4/Vero cells
Punta Toro virus/Vero cells
>40
>40
Herpes simplex virus-1 (KOS)/HEL cells
Herpes simplex virus-2/HEL cells
Vaccinia virus/HEL cells
>200
>200
>200
>200
>200
Vesicular stomatitis virus/HEL cells
Herpes simplex virus-1 TK-KOS ACVr/HEL cells
BIOLOGY
All the five nucleoside analogs 6–10 have been evaluated for their antiviral and
enzyme inhibition properties. The anti-HIV-1 screening was done in MT-4 cells using
the MTT method.[46] Similarly, these molecules were screened for their antiviral
properties against a number of viruses using different cell cultures : compound 6 has
shown good inhibitory action against vesicular stomatitis virus, coxsackie virus,
respiratory syncytial virus, parainfluenza-3 and reovirus-1; compound 7 against HIV-1,
vesicular stomatitis virus, coxsackie virus and respiratory syncytial virus; compound
8 against vesicular stomatitis virus, coxsackie virus and respiratory syncytial virus;
compound 9 against vesicular stomatitis virus, coxsackie virus and respiratory syncytial
virus and compound 10 against vesicular stomatitis virus and coxsackie virus.
However, these molecules have shown little inhibitory effect in the case of
other viruses.
The results have been shown in Table 1 in the form of IC50 values for
these compounds.
The evaluation of all the five nucleoside analogs against HIV-2 is also in progress.
EXPERIMENTAL SECTION
Silica gel G for TLC and silica gel (60–120 mesh) for column chromatogra-
phy were obtained from E-Merck India Ltd. Hexamethyldisilazane (HMDS),
chlorotrimethylsilane (TCS), tris [2-(methoxyethoxy)ethyl]amine (TDA-1), arabinose
and 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose (ABR) (2) were purchased from
Aldrich Chemical Co. USA. UV measurement was carried out on Hitachi 220S

1820
Sinha et al.
1
spectrophotometer. H NMR was recorded using DRX 300 instrument with DMSO as
solvent. All solvents were dried and distilled prior to use.
2,3,5-Tri-O-benzoyl-a-D-arabinosyl chloride (1). The compound 1 was synthe-
sized starting from D-arabinose (10 g) which was first converted into methyl-a-D-
arabinofuranoside-tri-O-benzoate (15 g). The latter was then dissolved in glacial acetic
acid (75 mL) and to this was added glacial acetic acid saturated with dry HCl gas
(75 mL) to get a clear solution. The mixture was stirred at room temperature for
30 minutes. After passing additional amounts of dry HCl gas through it for another
20 minutes, CH2Cl2 (300 mL) was added to the reaction mixture. Finally, the whole
mixture was poured into ice-cold water (1000 mL). Dichloromethane fraction, sep-
arated immediately, was washed quickly with saturated aqueous solution of NaHCO3,
dried over Na2SO4, filtered and its volume reduced at pump to get crystalline 1. Yield
9.5g (63%); m.p. 65°C.
9-(1-b-D-Arabinofuranosyl) 1,3-dideazaadenine (6). For the synthesis of Ara-
DDA, 3 (3.8 mmol), dried overnight over P2O5 in a vacuum desiccator, was first
dissolved in dry actetonitrile (100 mL) and then to it were added TDA-1 (0.3 mmol)
and powdered KOH (9.5 mmol) and the mixture was stirred at room temperature for 30
minutes. Subsequently, 1 (4 mmol) was added and the reaction mixture was again
stirred for 2 h at room temperature. The solid separated was filtered out and the filtrate
was evaporated at the pump to get crystals of impure protected nucleoside. The latter
was deprotected by dissolving it in minimum amount of acetonitrile and heating the
resulting solution with ammonia (25%) for 5 h at 60°C. After deprotection, TLC
indicated the presence of two isomers, which were actually the N-7 and N-9
regioisomers of the nucleoside. The yield of N-9 isomer or the title compound (6) was
higher than that of the N-7 isomer. The nucleoside also gave positive ninhydrin test
indicating the presence of a free primary amino group that is actually present at
position 4 in the 1,3-dideazaadenine molecule (the aglycone). The nucleoside was
purified by silica gel column chromatography. Compound 6 eluted between 9–11%
CH3OH in CH2Cl2. Rf = 0.2 (DCM/MeOH, 9.2:0.8). UV (MeOH) lmax 220, 263, 315
1
nm. H NMR (DMSO- D6) d 3.37–3.42 (m, 1H, H2’); 3.54–3.57 (m, 2H, H5’); 3.64–
3.67 (m, 1H, H4’); 4.12–4.14 (m, 1H, H3’); 4.6 (s, 2H, NH2); 5.3–5.5 (d, 1H, H1’);
7.52–7.69 (m, 4H, aro). MS (EI) m/z 265 (M+). Anal. Calcd for C12H15N3 : C, 54.33;
H, 5.66; N, 15.84. Found: C, 54.28; H, 5.64; N, 15.80.
9-(1-b-D-Arabinofuranosyl) 4-nitro-1,3-dideazapurine (7).
The nucleoside 7
was synthesized following the same procedure and molar ratios as that for 6. TLC
indicated the formation of 7 as the only regioisomer. After the coupling reaction the
solid separated was filtered, the filtrate was evaporated at pump and the residue was
recrystallized with ethanol to get crystals of pure protected nucleoside. The protected
nucleoside was stirred with methanolic ammonia (25%) for 5 h at room temperature
and after deprotection, the reaction mixture was partitioned between water and ether
and 7 was obtained in the water fraction. The latter was evaporated at pump and
recrystallized from ether-ethanol. Rf = 0.78 (DCM /MeOH, 8:2). UV (MeOH) lmax
1
240, 274, 316 nm. H NMR (DMSO- D6) d 3.36–3.41 (m, 1H, H2’); 3.53–3.56 (m,
2H, H5’); 3.63–3.67 (m, 1H, H4’); 4.12–4.14 (m, 1H, H3’); 4.59 (s, 2H, NH2); 5.4–5.5

Ribonucleosides of 1,3-Dideazaadenine
1821
(d, 1H, H1’); 7.42–7.87 (m, 4H, aro). MS (EI) m/z 295 (M+). Anal. Calcd for
C12H13N3: C, 48.81; H, 4.41; N, 14.24. Found: C, 48.72; H, 4.38; N, 14.20.
1-(1-b-D-Arabinofuranosyl) diketopiperazine (8). Ara-DKP was synthesized by
coupling 5 (3.8 mmol) with 1 (4 mmol) following the same procedure used for the
synthesis of 6 and 7. After deprotection of the nucleoside with methanolic ammonia
(25%), TLC showed the presence of two isomers, 1 and 2 with Rf = 0.7 and 0.4 (DCM/
MeOH, 9.6:0.4), respectively. The title compound (isomer 2) was purified by silica gel
column chromatography using 4% CH3OH in CH2Cl2. The pure nucleoside could not
be crystallized from ether-ethanol and had the appearance of brown colored jelly. UV
1
(MeOH) lmax 268 nm. H NMR (DMSO-D6) d 3.19–3.26 (m, 1H, H2’); 3.30–3.32
(m, 2H, H5’); 3.77–4.00 (m, 1H, H4’); 4.26–4.48 (m, 1H, H3’); 5.36–5.45 (d, 1H,
H1’); 7.4–7.97 (m, 5H, aro). MS (EI) m/z 246 (M+). Anal. Calcd for C9H14N2: C,
44.26; H, 5.74; N, 11.48. Found: C, 44.15; H, 5.68; N, 11.4
9-(1-b-D-Ribofuranosyl) 1,3-dideazaadenine (9). Synthesis of Ribo-DDA was
achieved by following the one pot synthesis method proposed by Vorbru¨ggen and
Bennua.[39] N-benzoyl-1,3-dideazaadenine (5 mmol) and 2 (5 mmol) were dissolved in
dry acetonitrile (75 mL) and stirred for a few minutes to get a clear solution. After
this HMDS (4 mmol) and TCS (4 mmol) were added. Finally, the catalyst SnCl4 (6
mmol) in dry acetonitrile (25 mL) was added to the reaction vessel. The reaction
mixture was stirred overnight at room temperature, filtered and the filtrate dried
completely under vacuum (40°–50°C). The residue was dissolved in CH2Cl2 (30 mL)
and this organic fraction was washed consecutively with saturated solutions of
NaHCO3 (20 mL) and NaCl (20 mL), dried on Na2SO4, filtered and reduced at the
pump. The residue was recrystallized from ethanol to get white crystals of one isomer
of the resulting nucleoside while the mother liquor contained the second isomer. Both
isomers were contaminated with unreacted ABR and were purified by silica gel
column chromatography. The first isomer of the nucleoside eluted out between 2.5–
4% CH3OH in CH2Cl2. The second isomer of the nucleoside present in the mother
liquor along with unreacted sugar was eluted with 2% CH2Cl2 in hexane. Rf = 0.65
and 0.39 (DCM/MeOH, 9.8:0.2) for isomers 1 and 2 respectively. Both the isomers
were separately deprotected by first dissolving them in a very small volume of
CH2Cl2-CH3OH mixture and then stirring them with methanolic ammonia (25%) for
5 h at room temperature. Pure nucleoside 9 was obtained by partitioning the de-
protection reaction mixture of isomer 1 between ether and water followed by drying
of the water fraction at the pump; though the yield of pure nucleoside was not
satisfactory. The formation of 9 was also confirmed by positive ninhydrin test for the
amino group present in the aglycone at position 4. Rf = 0.3 (DCM/MeOH, 9.2:0.8).
1
UV (MeOH) lmax 235, 240, 317 nm. H NMR (DMSO-D6) d 1.85–2.5 (m, 1H, H 2’);
3.34–3.46 (m, 1H, H5’); 4.36–4.46 (m, 2H, H4’); 4.59 (s, 2H, NH2); 4.67–4.81
(m, 1H, H3’); 5.66–5.68 (d, 1H, H1’); 7.79–8.01 (m, 4H, aro). MS (EI) m/z 265
(M+). Anal. Calcd for C12H15N3 : C, 54.33; H, 5.66; N, 15.84. Found: C, 54.25; H,
5.60; N, 15.75.
9-(1-b-D-Ribofuranosyl) 4-nitro-1,3-dideazapurine (10). The nucleoside 10 was
synthesized following the same procedure and molar ratios as that for 9. TLC indicated

1822
Sinha et al.
the formation of a single isomer which was separated from unreacted ABR by
recrystallizing with ethanol. After deprotection with methanolic ammonia (25%), the
reaction mixture was partitioned between water and ether whereby 10 was obtained in
the water fraction. Rf = 0.25 (DCM/CH3OH, 9.5:0.5). UV (MeOH) lmax 235, 292, 305
1
(sh) nm. H NMR (DMSO-D6) d 1.85–2.5 (m, 1H, H 2’); 3.34–3.46 (m, 1H, H5’);
4.36–4.46 (m, 2H, H4’); 4.59 (s, 2H, NH2); 4.67–4.81 (m, 1H, H3’); 5.66–5.68 (d, 1H,
H1’); 7.79–8.01 (m, 4H, aro). MS (EI) m/z 295 (M+). Anal. Calcd for C12H13N3: C,
48.81; H, 4.41; N, 14.24. Found: C, 48.80; H, 4.35; N, 14.00.
ACKNOWLEDGMENTS
Financial assistance from the Department of Science and Technology (DST), New
Delhi, is sincerely acknowledged and we thank RSIC, CDRI, Lucknow for spectral data.
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Received May 12, 2004
Accepted August 5, 2004