Synthesis and activity against HBV of novel tetra-seconucleoside analogues of dyphlline having the acyclic chains of ACV and HBG

Article abstract of DOI:10.1080/15257770701845329

Selective alkylation of dyphylline (1) with (2-acetoxyethoxy)methyl bromide (2a) or 4-acetoxybutyl bromide (2b) afforded 3′-O-[(acetoxyethoxy)methyl] dyphylline (3a) and 3′-O-(4-acetoxybutyl)-dyphylline (3b), respectively. A trans esterification process rather than alkylation of the dihydroxy-propyl side chain in 1 had taken place during the reaction with 2-p-toluoyloxy)ethyl chloride (5) to afford the respective 3′-toluoyloxy derivative 7 and not the anticipated 3′-O-[(p-toluoyloxy)ethyl]-dyphylline (6). Deacylation of 3a,b and 7 afforded 4a,b and 1, respectively. Viral screening of selected compounds against HBV has been investigated. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701845329

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Synthesis and Activity Against HBV of
Novel Tetra-Seconucleoside Analogues of
Dyphlline Having the Acyclic Chains of
ACV and HBG
El Sayed H. El Ashry a , Laila F. Awad a , Nagwa Rashed a , Adel
AbdelRahman a & Hana A. Rasheed a
a Department of Chemistry, Faculty of Science, Alexandria
University, Alexandria, Egypt
Published online: 14 Feb 2008.
To cite this article: El Sayed H. El Ashry , Laila F. Awad , Nagwa Rashed , Adel AbdelRahman & Hana
A. Rasheed (2008) Synthesis and Activity Against HBV of Novel Tetra-Seconucleoside Analogues of
Dyphlline Having the Acyclic Chains of ACV and HBG, Nucleosides, Nucleotides and Nucleic Acids,
27:3, 309-317
To link to this article: http://dx.doi.org/10.1080/15257770701845329
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Nucleosides, Nucleotides, and Nucleic Acids, 27:309–317, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701845329
SYNTHESIS AND ACTIVITY AGAINST HBV OF NOVEL TETRA-
SECONUCLEOSIDE ANALOGUES OF DYPHLLINE HAVING THE
ACYCLIC CHAINS OF ACV AND HBG
El Sayed H. El Ashry, Laila F. Awad, Nagwa Rashed, Adel AbdelRahman, and
Hana A. Rasheed
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Selective alkylation of dyphylline (1) with (2-acetoxyethoxy)methyl bromide (2a) or 4-acetoxybutyl
2
bromide (2b) afforded 3ꢁ-O-[(acetoxyethoxy)methyl]dyphylline (3a) and 3ꢁ-O-(4-acetoxybutyl)-
dyphylline (3b), respectively. A trans esterification process rather than alkylation of the dihydroxy-
propyl side chain in 1 had taken place during the reaction with 2-p-toluoyloxy)ethyl chloride (5)
to afford the respective 3ꢁ-toluoyloxy derivative 7 and not the anticipated 3ꢁ-O-[(p-toluoyloxy)ethyl]-
dyphylline (6). Deacylation of 3a,b and 7 afforded 4a,b and 1, respectively. Viral screening of
selected compounds against HBV has been investigated.
Keywords Dyphylline; Tetraseco-Nucleosides; Acylonucleosides; ACV; HBG
INTRODUCTION
Considerable interest in the synthesis of nucleoside analogues resulted
from their pronounced antiviral and antitumoral activities. In recent years
major efforts have been directed toward the synthesis of seco nucleosides
with various side chains and aglycons with the hope to discover new
and effective leads as antiviral agents.[1–6] The skeletal modification of
the heterocyclic portion and/or alkanol side chain of acyclo nucleosides
have provided numerous seco nucleoside analogs possessing a wide variety
of biological activities. Structure-activity relationship studies of acyclo
nucleosides bearing a hydroxypropyl side chain in particular (S)-9-
(2,3-dihydroxypropyl)adenine,[7] 3-(adenin-2-yl)-2-hydroxypropanoic acid
(AHPA)[8,9] and a group of eritadenines[10] attracted our attention. All
Received 14 May 2007; accepted 30 October 2007.
The valuable support from AvH foundation in Germany is highly appreciated.
Address correspondence to E. S. H. El Ashry, Department of Chemistry, Faculty of Science,
Alexandria University, Alexandria, Egypt. E-mail: Eelsahry60@hotmail.com
309

310
E. S. H. El Ashry et al.
FIGURE 1
these compounds inhibit SAH hydrolases[11] and hence exert effect on pro-
liferative processes. In the course of our ongoing research program devoted
to the synthesis of carboacyclonucleosides containing 2,3-dihydroxypropyl
chain,[12,13] novel acyclonucleoside analogs were synthesized by modifica-
tion of the hydroxypropyl moiety.
Dyphlline (1) is effective in treatment bronchial asthma and we had
modified, in an earlier publication, the glycerolyl side chain via its periodate
oxidation.[13] Attracted by the discovery of acyclovir (I) and the carboacyclic
analogue HBG (II),[14,15] as potent and selective antiherpetic agents, the
insertion of the (2-hydroxyethoxy)methyl and the 4-hydroxybutyl moieties,
which are the side chains in ACV and HBG, respectively, to the 3ꢁ-O-
position of dyphylline became our objective in this work. Moreover, selected
compounds were found to exhibit interesting ant-HBV activity.
RESULTS AND DISCUSSIONS
Alkylation of dyphylline (1) with either (2-acetoxyethoxy)methyl bro-
mide (2a) or 4-acetoxybutyl bromide (2b) in the presence of silver oxide
as catalyst and chloroform as solvent resulted in a selective introduc-
tion of the (2-acetoxyethoxy)methyl and 4-acetoxybutyl moieties on the
3ꢁ-hydroxy group of 1 to give 3ꢁ-O-(acetoxyethoxy)methyl- and 3ꢁ-O-(4-
acetoxybutyl)dyphyllines (3a) and (3b) in 58 and 60% yield, respectively
(Scheme 1). On the other hand an attempt to perform the reaction using
sodium hydride in DMF did not lead to a significant improvement in the
yield. The structures of both compounds were assigned from their elemental
1
analyses and H NMR spectra. The introduction of the acyclic residue was
confirmed by the presence of signals at δ 2.08 or 2.14 assigned for one acetyl
group in each of 3a and 3b, respectively (Scheme 1).
The methylene protons signals of the acyclic ethoxy moiety of 3a were
assigned as a doublet of doublet at δ 3.66 (AcOCH2-CH2O) while the second
one was appeared under a multiplet in the range of δ 4.16–4.36 together
with both of H-2ꢁ and H-3ꢁꢁ of dyphylline. The singlet corresponding to
OCH2O protons was assigned at δ 4.76. The methylene protons of the butyl
moiety of 3b were resonated as three multiplets at δ 1.26–1.44, 1.71–1.75,

HBV of Novel Tetra-Seconucleoside Analogues
311
SCHEME 1
and 4.15–4.35. These data confirmed the introduction of only one alkyl
moiety on 1. The deprotected products 4a and 4b were obtained in good
yield by treatment of 3a and 3b, respectively with sodium methoxide in
methanol. The structures of both compounds were based on their elemental
analyses and spectral data which showed the absence of the acetyl signals.
On the other hand, attempted alkylation of 1 with 2-(p-toluoyloxy)ethyl
chloride (5) in the presence of sodium hydride in DMF gave 3ꢁ-O-(p-
toluoyloxy)ethyl derivative 6, the 3ꢁ-O-p-toluoyl derivative 7. Combustion
analysis and mass spectrum of the product (Scheme 2) were characteristic
for the structure of 7 which showed a molecular ion peak at m/z 372
in agreement with the molecular formula C18H20N4O5. The 1H NMR
spectrum of 7 indicated the absence of signals due to the methylene protons
of the ethyl moiety anticipated in 6 and the presence of a tolyl group
which appeared as a singlet (δ 2.40) and two doublets (δ 7.23 and 7.89)
corresponding to the methyl and aromatic protons, respectively. These data
confirmed the introduction of one p-toluoyl group on 1 rather than the
p-toluoyloxyethyl group. The location of the p-toluoyl on the O-C-3ꢁ was
indicated by the appearance of the signals of protons of C-3ꢁ (δ 4.10 and
4.37) in a downfield region compared to that of 1 (δ 3.36–3.45). On the
other hand, carrying out the same reaction using silver oxide as catalyst to
avoid such unexpected result led to the recovery of the starting material 1.

312
E. S. H. El Ashry et al.
SCHEME 2
The formation of the ester 7 could be attributed to the high electrophilicity
of the carbonyl carbon of 5 rather than that of the methylene group
linked to the chlorine atom. This led to its preferential attack by the anion
generated from 1 and sodium hydride to give 7. Thus, a trans esterification
process proceeded more likely than the alkylation one. Deacylation of 7 with
sodium methoxide in methanol afforded the starting dyphylline (1) which
also unequivocally proved the structure of the ester 7; otherwise 6 would
afford a different compound than 1.
BIOLOGICAL EVALUATION
The results of the viral screening against HBV of the selected com-
pounds 3a,b and 4a,b indicated that compound 4b showed moderate viral
replication inhibition and mild cytotoxicity with selective index >227.3.
On the other hand, the effective concentration of compounds 3a, 3b and
4a was 10.0 µM which showed weak antiviral activity with low cytotoxicity
with selective index >10.50, >12.50 and >140.80, respectively. These results
indicated that the unacetylated derivatives showed better inhibition than the
respective acetyl derivatives. Moreover, the presence of oxygen in the side

HBV of Novel Tetra-Seconucleoside Analogues
313
TABLE 1 Cytotoxic effect (CC50), inhibitory concentration (IC50) and selective
index (SI) of compounds 3 and 4
Compdound No. HBV DNA IC50 (µM) Hep G2 2.2.15 CC50 (µM)
SI
Lamivudine
<0.10
9.50
8.00
0.71
0.44
>100
>100
>100
>100
>100
>1000
>10.50
>12.50
>140.8
>227.3
3a
3b
4a
4b
chain of 4a which is a characteristic feature in ACV is not necessary in this
series of compounds where the carbo analogue showed a better inhibition.
EXPERIMENTAL
Melting points were determined on a Mel-Temp apparatus and are
uncorrected. IR spectra were recorded with a unicam SP1025 spectrometer.
1
EI mass spectra were recorded on a Varian MAT 311A spectrometer. H
NMR spectra were recorded with a Bruker AC 300 NHz. The chemical shifts
are expressed on the δ scale using Me4Si as a standard. J-values are given
in Hz. TLC was performed on Merck Silica Gel 60 F254 with detection by
UV light. Microanalyses were performed in the unit of Microanalysis at the
Faculty of Science, Cairo University.
( )-3ꢁ-O-Substituted-dyphylline (3a,b)
Method A
A mixture of compound 1 (0.25 g, 1.0 mmol), silver oxide (1.0 g) and
molecular sieves (1.0 g) was stirred for 1 hour. in dry chloroform (10 ml)
at room temperature and then a solution of 2a (0.197 g, 1.0 mmol) or
2b (0.15 g, 1.0 mmol) in dry chloroform (5 ml) was added over 2 hours.
The stirring was continued for overnight. The mixture was filtered, washed
with chloroform, and the filtrate was evaporated under reduced pressure.
The residue was purified by flash column chromatography using petroleum
ether : ethyl acetate (5:1) to afford 3a (58% yield) and 3b (60% yield).
Method B
A stirred solution of 1 (0.25 g, 1.0 mmol) in dry DMF (5 ml) was
treated with sodium hydride (0.024 g, 1.0 mmol). After complete evolution
of hydrogen gas, the mixture was heated at 80◦C for 1 hour and then treated
with compound 2a or 2b (1.0 mmol) with stirring at room temperature for
overnight. The reaction mixture was diluted with cold water (20 ml) and
extracted with ethyl acetate (3 × 20 ml). The organic layers were collected,
washed with water, dried and evaporated under reduced pressure. The

314
E. S. H. El Ashry et al.
residue was purified by column chromatography using petroleum ether :
ethyl acetate (5:1) to give 3a (55% yield) and 3b (29% yield). They were
identical with those obtained from method a.
( )-3ꢁ-O-[(2-Acetoxyethoxy)methyl]dyphylline (3a)
1
Colorless syrup; Rf 0.15 (petroleum ether : ethyl acetate 1:1); H NMR
(CDCl3, 300 NHz) δH: 2.08 (s, 3 H, OAc), 3.40, 3.59 (2 s, 6 H, 2 NMe),
ꢁ
ꢁ
3.66 (dd, 2 H, J 4.1 Hz, J 6.1 Hz, CH2-CH2-O), 3.80 (t, 1 H, J 2 ,3 8.0 Hz,
H-3ꢁ), 4.16–4.36 (m, 4 H, H-2ꢁ, H-3ꢁꢁ, CH2-OAc), 4.59 (dd, 1 H, J 1 ,2 3.3 Hz,
ꢁ
ꢁ
H-1ꢁ), 4.68 (t, 1 H, J 1 ,1 11.3 Hz, H-1ꢁꢁ), 4.76 (s, 2 H, OCH2O), 4.83 (bs, 1 H,
D2O exchangeable, OH), 7.69 (s, 1 H, H-8). Anal. calcd. For C15H22N4O7
(370.15): C, 48.64; H, 5.99; N, 15.13; found: C, 48.92; H, 6.21; N, 15.44.
ꢁ
ꢁꢁ
( )-3ꢁ-O-(4-Acetoxybutyl)dyphylline (3b)
1
Yellow syrup; Rf 0.32 (petroleum ether : ethyl acetate 1:1); H NMR
(CDCl3, 300 NHz) δH: 1.26–1.44, 1.71–1.75 (2 m, 4 H, 2CH2), 2.14 (s, 3 H,
ꢁ
OAc), 3.40, 3.59 (2 s, 6 H, 2 NMe), 3.69 (d, 1 H, D2O exchangeable, J2 ,OH
4.1 Hz, OH), 4.15–4.35 (m, 8 H, H-1ꢁ, H-2ꢁ, H-3ꢁ, H-3ꢁꢁ, 2 CH2), 4.58 (dd,
1 H, J1 ,2 2.2 Hz, J1 ,1 11.4 Hz, H-1ꢁꢁ), 7.66 (s, 1 H, H-8), Anal. calcd. for
C16H24N4O6 (368.17): C, 52.17; H, 6.57; N, 15.21; found: C, 52.36; H, 6.63;
N, 15.51.
ꢁ
ꢁ
ꢁ
ꢁꢁ
( )-Deprotection of the acetylated nucleosides 3a,b
General Method
Compounds 3a,b (0.30 mmol) in absolute methanol (3 ml) were treated
with sodium methoxide in methanol (0.15 M, 3 ml) with stirring at room
temperature for 2 hours (TLC). The reaction mixture was neutralized
with Amberlite IR-120(H+) resin, filtered, and the resin was washed with
methanol. The combined filtrates were evaporated under reduced pressure
and the residue was purified by column chromatography using petroleum
ether : ethyl acetate (1:1) to afford 4a and 4b.
( )-3ꢁ-O-[(2-Hydroxyethoxy)methyl]dyphylline (4a)
Colorless syrup (94% yield); 1H NMR (CD3OD+D2O) δH: 3.33, 3.57 (2 s,
6 H, 2 NMe), 3.66–3.70 (m, 4 H, OCH2CH2O), 4.13–4.16 (m, 1 H, H-2ꢁ),
4.30 (m, 2 H, H-3ꢁ,3ꢁꢁ), 4.59 (m, 2 H, H-1ꢁ,1ꢁꢁ), 4.77 (s, 2 H, O-CH2-O), 7.91
(s, 1 H, H-8). Anal. calcd. for C13H20N4O6 (328.14): C, 47.56; H, 6.14; N,
17.06; found: C, 48.22; H, 5.98; N, 16.96.

HBV of Novel Tetra-Seconucleoside Analogues
315
( )-3ꢁ-O-(4-Hydroxybutyl)dyphylline (4b)
1
Yellow syrup (81% yield); H NMR (CD3OD) δH: 1.27–1.36 (m, 4 H,
2CH2), 3.21 (s, 3 H, NMe), 3.29–3.31 (m, 4 H, 2CH2), 3.41(s, 3 H, NMe),
3.80 (bs, 1 H, H-2), 4.03–4.13 (m, 2 H, H-3ꢁ,3ꢁꢁ), 4.44 (dd, 2 H, J 1 ,2 3.2 Hz,
ꢁ
ꢁ
J 1 ,1 13.5 Hz, H-1ꢁ,1ꢁꢁ), 4.78 (bs, 1 H, D2O exchangeable, OH), 5.03 (d, 1 H,
D2O exchangeable, OH), 7.96 (s, 1 H, H-8). Anal. calcd. for C14H22N4O5
(326.16): C, 51.52; H, 6.79; N, 17.17; found: C, 51.32; H, 6.32; N, 16.87.
ꢁ
ꢁꢁ
( )-3ꢁ-O-(p-Toluoyl)dyphylline (7)
To a stirred solution of 1 (0.25 g, 1.0 mmol) in dry DMF (5 ml), NaH
(0.024 g, 1.0 mmol) was added. After complete evolution of hydrogen gas,
the mixture was heated at 80◦C for 1 hour, then compound 5 (0.19 g,
1.0 mmol) was added. The reaction mixture was stirred for overnight at
room temperature and then diluted with cold water (20 ml) whereby a
white precipitate was formed. It was filtered and recrystallized from ethanol
1
to afford 7 (0.29 g, 70% yield) as white crystals mp.198–200◦C; HNMR
(CDCl3, 300 NHz) δH: 2.40 (s, 3 H, Me), 3.35, 3.52 (2 s, 6 H, 2 NMe), 4.10
(bs, 1 H, H-3ꢁ), 4.37–4.39 (m, 4 H, H-3ꢁꢁ, H-2ꢁ, H-1ꢁ, OH), 4.63 (d, 1 H, J 1,1
11.1 Hz, H-1), 7.23 (d, 2 H, J 8.1 Hz, Ar-H), 7.68 (s, 1 H, H-8), 7.89 (d, 2 H,
J 8.1 Hz, Ar-H).MS : m/z (%): 372 (M+• , 15), 236(M+• -p-CH3C6H4CO2H,
13), 194 (7-methyltheophyline+, 60), 119 (p-CH3C6H4CO• , 76) and 91
•
(CH3C6H4 , 48).
( )-Treatment of 7 with sodium methoxide, dyphylline (1)
Compound 7 (0.1 g, 0.27 mmol) was treated with sodium methoxide in
absolute methanol (3ml, 0.43 mmol). The reaction mixture was processed
as in the general method for deprotection to afford 1 (0.062 g, 86% yield) as
white crystals, mp 160◦C, lit mp 162◦C [16]; 1H NMR (DMSO-d6, 300 NHz)
δH: 3.28 (s, 3 H, NMe), 3.36–3.45 (m, 2 H, H-3ꢁ, H-3ꢁꢁ), 3.48 (s, 3 H,
NMe), 3.87–3.90 (m, 1 H, H-2ꢁ), 4.17 (dd,1 H, J
8.4 Hz, J
1ꢁ,2ꢁ
1ꢁ,1ꢁꢁ
13.5 Hz,
H-1ꢁ), 4.50 (dd, 1 H, J 1 ,2 3.6 Hz, J 1 ,1 13.5 Hz, H-1 ), 4.80 (t,1 H, D2O
exchangeable,OH), 5.05 (d, 1 H, D2O exchangeable, OH), 8.01 (s,1 H,
H-8).
ꢁꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁꢁ
Preparation and culture of Hep G2 2.2.15 cells
The required cell line was made by transfection of Hep G2-cells with
a plasmid containing multiple tandem copies of HBV genome (subtype
ayw).[17] The 2.2.15 cell line was maintained in RPMI-1640 (Glutamax) cul-
ture media containing 100 IU/ml nystatin +380 µg/ml G418 (geneticin).
The transferred HEP G2-2.2.15 cell line was kept in tissue culture flask at
37◦C + 5% CO2. Subcultures were set up after a week by aspiration of

316
E. S. H. El Ashry et al.
the media from culture flask and washing the cells twice by PBS. A 10%
versene/trypsin was added and the cells were incubated for 1 minutes at
37 ◦C.
The drug Lamivudine which is a potent selective inhibitor of HBV
replication [18] has been used as a standard for the compartive studies.
PCR-ELLISA
The PCR reaction mixture was 14 µL extracted supernatant, 4 mmol/L
MgCl2, 10 µmol/L DIG-11-dUTP, 190 µmol/L dTTP, 200 µmol/L dATP,
dGTP, dCTP, 1.5 U Taq polymerase, 20 mmol/L HCI (pH 8.4), 50 mmol/L
KCI, 1 µmol/L HCID-1 primer (5ꢁ GGA AAG AAG TCA GAA GGC A3),
and 1 µmol/L HCID-2 (5TTG GGG GAG GAG ATT AGG TT3), in total
volume 50 µL. PCR reaction conditions were 32 cycles of 1 minute at 94◦C,
30 seconds at 58◦C and 30 seconds at 72◦C +3 seconds for each cycle in a
thermal circler as described in literature.[19]
Cytotoxicity Assay
A colorimetric assay for living cells should utilize a colorless substrate
that is modified to a colored product by any living cells, but not by dead
cells or tissue culture medium. 3-(3,5-Dimethylthiazol-2-yl)-2,5-diphenyl-
tetrazolium bromide (MTT) is the candidate for this purpose. The cytotoxic
effect of the compounds was accessed by culturing the Hep G2-2.2.15 cells
in the presence of compounds using a MTT-assay.[20]
Calculation of IC50, CC50 and SI
The 50% inhibitory concentration of antiviral drugs (IC50) was de-
termined by interpolation from the plots of the amounts of DNA copies
versus antiviral drug concentrations. The 50% cytotoxic effect (CC50) was
calculated from the average viability of the cells with concentration of drugs.
The selective index (SI) could be calculated as CC50/IC50.
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