Selenoacyclovir and Selenoganciclovir: Discovery of a New Template for Antiviral Agents

Article abstract of DOI:10.1021/acs.jmedchem.5b00804

On the basis of the potent antiviral activity of acyclovir and ganciclovir, selenoacyclovir (2a) and selenoganciclovir (2b) were designed based on bioisoteric rationale and synthesized via the diselenide 7 as the key intermediate. Compound 2a exhibited potent anti-HSV-1 and -2 activities while 2b exerted moderate anti-HCMV activity, indicating that these nucleosides can serve as a novel template for the development of new antiviral agents.

Full text of DOI:10.1021/acs.jmedchem.5b00804

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Brief Article
Seleno-acyclovir and –ganciclovir: A Discovery
of a New Template for Antiviral Agents
Pramod K Sahu, Tamima Umme, Jinha Yu, Akshata Nayak, Gyudong
Kim, Minsoo Noh, Jae-Young Lee, Dae-Duk Kim, and Lak Shin Jeong
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.5b00804 • Publication Date (Web): 13 Oct 2015
Downloaded from http://pubs.acs.org on October 19, 2015
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Seleno-acyclovir and –ganciclovir: A Discovery of a New
Template for Antiviral Agents
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Pramod K. Sahu,†,∧ Tamima Umme,‡,∧ Jinha Yu,† Akshata Nayak,†,‡ Gyudong Kim,† Minsoo Noh,† Jaeꢀ
Young Lee,† DaeꢀDuk Kim,† and Lak Shin Jeong†,*
†Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151ꢀ742, Korea and ‡
College of Pharmacy, Ewha Womans University, Seoul 120ꢀ750, Korea
KEYWORDS Acyclic nucleosides, Seleno-acyclovir, Seleno-ganciclovr, Bioisostere, Antiviral
ABSTRACT: On the basis of the potent antiviral activity of acyclovir and ganciclovir, selenoꢀacyclovir (2a) and selenoꢀ
ganciclovir (2b) were designed based on bioisoteric rationale and synthesized via the diselenide 7 as the key intermediate. Comꢀ
pound 2a exhibited potent antiꢀHSVꢀ1 and ꢀ2 activities, while compound 2b exerted moderate antiꢀHCMV activity, indicating that
these nucleosides can serve as the novel template for the development of new antiviral agents.
quently converted into the diphosphate by cellular guanylate
■ INTRODUCTION
kinase and into the triphosphate by a number of cellular enꢀ
zymes.10 Ganciclovir triphosphate competitively inhibits CMV
Therapy against viral infections still remains one of the subꢀ
stantial challenges to modern medicine because of appearancꢀ
es of resistance, latency, cytotoxicity, and so on.1 The herpesꢀ
viridae family including herpes simplex virus (HSV), varicelꢀ
laꢀzoster virus (VZV), cytomegalovirus (CMV), and Epsteinꢀ
Barr virus (EBV) cause severe viral diseases in humans, which
should be treated with antiviral chemotherapeutic agents.1
Acyclovir (1a),2,3 which is a prototype of acyclic nucleoꢀ
sides, has been a drug of choice for the treatments of herpetic
infections (Figure 1).
polymerase and competes with the natural 2’ꢀdeoxyguanosineꢀ
5’ꢀtriphosphate (dGTP) for incorporation into viral DNA. It
can be also used as a substrate for CMV DNA polymerase and
is incorporated into the viral DNA chain, resulting in the preꢀ
vention of viral DNA synthesis.10 However, this drug is also
associated with high cytotoxicity such as bone marrow supꢀ
pression,11 hepatotoxicity,12 and nephrotoxicity.13 These drawꢀ
backs prompted us to design a new template for acyclic nucleꢀ
oside drug development.
Selenium is essential for cellular function in many organꢀ
isms as a trace element. This element is a component of the
antioxidant enzymes, glutathione peroxidase and thioredoxin
reductase, which protect the organism from oxidative damꢀ
age.14 In view of new drug developments, selenium possess
several advantages such as the antioxidant properties and high
lipophilicity which might enhance the penetration across the
cell membrane, resulting in higher oral bioavailability. Seleniꢀ
um also exists in a bioisosteric relationship with oxygen and it
is expected to exhibit similar biological activity. Thus, based
on these results, we designed and synthesized selenoꢀacyclovir
(2a) and selenoꢀganciclovir (2b), which replaced the oxygens
of acyclovir (1a) and ganciclovir (1b) with selenium, respecꢀ
tively, using novel selenium chemistry. Herein, we report the
concise and efficient synthesis of the selenoꢀacyclic nucleoꢀ
sides 2a and 2b and their antiꢀHSV activity.
FIGURE 1. The rationale for the design of selenoꢀacyclic nucleoꢀ
sides 2a and 2b
This compound is converted into the triphosphate, which
inhibits viral DNA polymerase.4,5 Compound 1a shows a high
selectivity index because it is monoꢀphosphorylated only by
viral encoded thymidine kinase, but also has many drawbacks
such as low oral bioavailability and poor solubility.4,5 To overꢀ
come these disadvantages, its prodrug, valacyclovir6 has been
developed and clinically used for the treatment of shingles.
Ganciclovir (1b), another prototypical acyclic nucleoside and
its prodrug, valganciclovir have been clinically developed
against CMV infection.7ꢀ9 In CMV infected cell, 1b is convertꢀ
ed to the monophosphate by a virus kinase encoded by the
CMV gene UL97 (phosphotransferase), which is then subseꢀ
■ RESULTS AND DISCUSSION
Chemistry. Scheme 1 illustrates the retrosynthetic analysis
to final nucleosides 2a and 2b. The final compounds can be
synthesized via two routes.
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SCHEME 1. Retrosynthetic analysis of the final nucleo-
sides 2a and 2b
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It is envisaged that route I utilizes the direct SN2 reaction of
the selenium anion 3 with bromomethyl purine 4, which can
be synthesized by reacting purine nucleophile 5 with methꢀ
ylene bromide, whereas route II employs the reaction of purine
nucleophile 5 with selenomethyl bromide 6. The nucleophile 3
and the electrophile 6 can be derived from the same intermediꢀ
ate 7 by treating with reducing agent and methylene bromide
in the presence of reducing agent, respectively. The diselnide
7 can be synthesized by treating Na2Se2 with the bromide 8,
which can be easily modified from the alcohol 9.
SCHEME 3. Synthesis of seleno-acyclovir 2a (route II)
Synthesis began with 2ꢀbromoethanol (10), which could be
easily synthesized from ethylene glycol using the Appel reacꢀ
tion.15 Treatment of 10 with selenium powder in the presence
of hydrazine hydrate and KOH afforded the diselenide 11 in
90% yield.16 The two hydroxyl groups of 11 were protected
with TBDPS to yield 12. Treatment of 12 with methylene
bromide in the presence of NaBH4 produced the selenomethyl
bromide 13,17 which without purification was treated with 2ꢀ
aminoꢀ6ꢀchloropurine anion to afford the inseparable mixture
of the desired N9ꢀisomer 14 and its N7ꢀisomer in 9:1 ratio
1
(measured by H NMR, 45% total yield from 12). After the
removal of TBDPS group of 14 with TBAF, the N9ꢀisomer 14a
was obtained after the purification by silica gel column chroꢀ
matography, but the corresponding N7ꢀisomer could obtain
only in a negligible amount. Compound 14a was further treatꢀ
ed with 2ꢀmercaptoethanol and NaOMe to yield the final seleꢀ
noꢀacyclovir (2a). The N9ꢀ and N7ꢀisomers are generally disꢀ
tinguished by the characteristic 13C NMR chemical shifts of
the C5 signals.18 The C5 signal in the N9ꢀisomer appears at the
chemical shift (δ ~ 116 ppm), whereas the corresponding sigꢀ
nal in the N7ꢀisomer is shifted upfield by ~ 10 ppm. The regioꢀ
chemistry of the final nucleoside 2a was also confirmed by
comparing the 13C NMR chemical shift (δ 116.73 ppm) of C5
with that (δ 116.73 ppm)19 of acyclovir (1a).18
SCHEME 2. Synthetic approach to 4 (route I)
First, route I was attempted, but as shown in Scheme 2, reacꢀ
tion of 2ꢀacetamidoꢀ6ꢀchloropurine (5) with methylene broꢀ
mide under basic conditions did not give the desired comꢀ
pound 4. Thus, we turned our attention into route II, employꢀ
ing selenomethyl bromide 13 (Scheme 3).
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yield.
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SCHEME 4. Synthesis of diselenide 18 with 1,3-acetonide
Synthesis of selenoꢀganciclovir (2b) began with 1,3ꢀ
diprotectedꢀ2ꢀbromoglycerol 15, which was also synthesized
from glycerol by the Appel reaction15 (Scheme 4). However,
compound 15 could not be converted to the diselenide 16,
regardless of the protection status at the 1,3ꢀdihydroxyl groups,
possibly due to either steric effects or epoxide formation. Thus,
we decided to proceed with another route using 1,3ꢀacetonide
17. Although compound 17 was easily converted to the
diselenide 18, it was too volatile to handle easily. To avoid
this problem, we changed volatile 17 into nonvolatile 21, as
shown in Scheme 5.
SCHEME 6. Synthesis of seleno-ganciclovir 2b
The diselenide 22 was converted to the glycosyl donor 2317 by
treating with NaBH4 followed by treatment with methylene
bromide, which was ready for condensation with a purine base.
The glycosyl donor 23 was condensed with 2ꢀaminoꢀ6ꢀ
chloropurine anion to give the desired N9ꢀisomer 24 (45%) as
a single regioisomer. Removal of the 1,3ꢀbenzylidene of 24
was achieved with I2 in MeOH to give diol 25, which was
converted to the selenoꢀganciclovir (2b) using the same proceꢀ
dure used in the preparation of 2a. The regiochemistry of the
final compound 2b was also confirmed by comparing the 13C
NMR chemical shift (δ 116.56 ppm) of C5 with that (δ 116.40
ppm)22 of ganciclovir (1b).18
The solubility of the synthesized compounds, 2a and 2b in
water was measured and compared with those of the reference
compounds, 1a and 1b (Table S1, Supporting Information). As
expected, the introduction of selenium in place of oxygen deꢀ
creased the water solubility, indicating that selenoꢀacyclic
nucleosides 2a and 2b may penetrate the cell membrane better
than oxaꢀacyclic nucleosides 1a and 1b, resulting in better oral
bioavailability. The water solubility of all compounds is deꢀ
creased in the following order: 1b > 1a > 2b > 2a.
Antiviral activity. The final compounds 2a and 2b were asꢀ
sayed for the antiviral activity against HSVꢀ1 (strain F, VRꢀ
733), HSVꢀ2 (strain MS, VRꢀ540), VZV (Ellen, VRꢀ1367),
and HCMV (Davis, VRꢀ807) and HEL299 (CCLꢀ137) cells
were used for the cytotoxic assay.23 As shown in Table 1,
compound 2a exhibited potent antiviral activities only against
HSVꢀ1 and HSVꢀ2, whereas compound 2b exerted moderate
antiviral activity only against HCMV. It is interesting to note
that 2a and 2b are in bioisosteric relationships with antiꢀHSV
drug 1a and antiꢀHCMV drug 1b, respectively. However,
compounds 2a and 2b were found to be inactive against VZV.
They did not show any cytotoxicity up to 100 µM.
SCHEME 5. Synthesis of diselenide 22 with 1,3-
benzylidene acetal
Glycerol (19) was converted to the 1,3ꢀbenzylideneacetal 2020
by treating with benzaldehyde in the presence of pꢀTsOH to
produce a 90% yield after recrystallization. After mesylation,
the resulting mesylate 2121 was treated with selenium, hydraꢀ
zine hydrate, and KOH to give the diselenide 22 in a 90%
TABLE 1. Antiviral activities of 2a and 2b
CC50
EC50 (µM)a
(µM)b
Comꢀ
pound
HSVꢀ1
HSVꢀ2
VZV HCMV HEL299
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filtered, and evaporated. The residue was purified by silica gel
2a
2b
1a
1.47
>100
0.66
0.90
6.34
>100
1.02
1.40
> 100
> 100
6.4
> 100
53.1
18.9
2.14
> 100
> 100
> 100
> 100
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column chromatography (hexane : ethyl acetate = 1 : 1) to give
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14 (2.71 g, 45%) as a white solid. H NMR revealed the prodꢀ
uct was mixed with inseparable N7 isomer in 9: 1 ratio: mp
1b
11.1
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aThe concentration required to inhibit virusꢀinduced cytopathic effect by 50%
bThe concentration of compound responsible for 50% reduction of cell viability
115ꢀ120 C; UV λmax 219, 310 nm; H NMR (400 MHz,
CDCl3) δ 7.81 (s, 1H), 7.68ꢀ7.65 (m, 4H), 7.46ꢀ7.37 (m, 6H),
5.22 (s, 2H), 3.92 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H),
1.05 (s, 9H); MS (ESI) found m/z 546.0995 [calcd for
C24H29ClN5OSeSi (M+H)+ 546.0995]; Anal. Calcd for
C24H28ClN5OSeSi: C, 52.89; H, 5.18; N, 12.85. Found: C,
52.99; H, 4.98; N, 12.45.
■ CONCLUSION
We have synthesized the bioisosteric selenoꢀacyclovir (2a)
and selenoꢀganciclovir (2b) from acyclovir and ganciclovir,
respectively, by condensing the glycosyl donor, the selenomeꢀ
thyl bromide, prepared by treating the diselenide with NaBH4
and CH2Br2, with 2ꢀaminoꢀ6ꢀchloropurine. The regioisomeric
configurations of 2a and 2b were easily confirmed by the 13C
NMR chemical shifts of the C5 signals. Compound 2a exhibitꢀ
ed potent antiviral activities against HSVꢀ1 andꢀ2, while comꢀ
pound 2b showed moderate antiꢀHCMV activity, indicating
that selenium can serve as a bioisostere of oxygen. The mechꢀ
anism study about if their antiviral activities are related to their
conversions to the triphosphates, thereby inhibiting viral polꢀ
ymerases is underway and will be reported in due course.
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2-((2-Amino-6-chloro-9H-purin-9-yl) methylselanyl) etha-
nol (14a). To a solution of 14 (2.20 g, 4.036 mmol) in THF
(40 mL), TBAF (2.06 mL, 2.06 mmol, 1 M solution in THF)
was added under N2, and the reaction mixture stirred at room
temperature for 1 h and evaporated. The residue was purified
by column chromatography (hexane : ethyl acetate = 1 : 9) to
o
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give 14a (588 mg, 49%) as a white solid: mp 150ꢀ152 C; H
NMR (400 MHz, DMSOꢀd6) δ 8.22 (s, 1H), 6.95 (br s, 2H,
exchangeable), 5.35 (s, 2H), 3.59 (t, J = 6.4 Hz, 2H), 2.83 (t, J
= 6.8 Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6): δ 159.8,
153.6, 149.5, 142.7, 123.4, 61.4, 33.8, 27.7; MS (ESI) found
m/z 307.9807 [calcd for C8H11ClN5OSe (M+H)+ 307.9817];
UV λmax 310 nm.
■
EXPERIMENTAL SECTION
Chemistry. Elemental analyses (C, H, and N) were used to
determine the purity of all unknown compounds, and the reꢀ
9-((2-Hydroxyethylselanyl)methyl)-2-amino-1H-purin-
6(9H)-one (2a). A solution of 14a (110 mg, 0.34 mmol), 2ꢀ
mercaptoethanol (0.091 mL, 1.30 mmol), and sodium methoxꢀ
ide (97 mg, 1.80 mmol) in methanol (15 mL) was refluxed at
sults were within ± 0.4% of the calculated values, confirming
≥ 95% purity.
o
70 C for 48 h. The reaction mixture was cooled down, neuꢀ
tralized with acetic acid, and evaporated. The residue was
purified by column chromatography (CH2Cl2 : methanol = 22 :
Bis-((O-tert-butyl-diphenylsilylhydroxylethyl)-diselenide
(12). To a stirred solution of 1111 (15.0 g, 60.439 mmol) in
CH2Cl2 (600 mL), tertꢀbutylchlorodiphenylsilane (39.314 mL,
151.186 mmol), triethylamine (42.1734 mL, 302.369 mmol),
and 4ꢀdimethylaminopyridine (0.739 g, 5.985 mmol) were
added, and the reaction mixture was stirred at room temperaꢀ
ture for 8 h, quenched with aqueous NaHCO3 (200 mL), and
extracted with CH2Cl2 (300 mL x 3). The organic layer was
dried (MgSO4), filtered, and evaporated. The residue was puriꢀ
fied by silica gel column chromatography (100% hexane) to
o
3) to give 2a (102 mg, 94%) as white solid: mp 266ꢀ268 C;
1H NMR (400 MHz, DMSOꢀd6): δ 10.60 (br s, 1H, exchangeꢀ
able with D2O), 7.78 (s, 1H), 6.49 (br s, 2H), 5.23 (s, 2H), 4.86
(t, J = 5.3 Hz, 1H), 3.58 (q, J = 6.5 Hz, 2H), 2.79 (t, J = 6.8
Hz, 2H); 13C NMR (100 MHz, DMSOꢀd6): δ 156.7, 153.7,
150.9, 137.1, 116.6, 61.4, 33.4, 27.3; MS (ESI) found m/z
290.0152 [calcd for C8H12N5O2Se (M+H)+ 290.0156]; UV λmax
259 nm; Anal. Calcd for C8H11N5O2Se: C, 33.34; H, 3.85; N,
24.30. Found: C, 33.14; H, 4.15; N, 24.01.
1
give 12 (38.06 g, 91%) as a yellow colored oil: H NMR (400
MHz, CDCl3): δ 7.68ꢀ7.64 (m, 4H), 7.43ꢀ7.34 (m, 6H), 3.86 (t,
J = 6.8 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 1.05 (s, 9H). The
product was contaminated with monoselenide in 4:1 ratio
judged by 1H NMR.
2-Phenyl-5-(2-(2-phenyl-1,3-dioxan-5-yl)diselanyl)-1,3-
dioxane (22). To a solution of KOH (9.0 g, 160.811 mmol),
hydrazine hydrate (4.012 mL, 82.548 mmol,) and water (4.132
o
mL, 299.556 mmol) at 0 C, selenium powder (12.271 g,
153.548 mmol) was added and the reaction mixture was stirred
9-((2-O-tert-Butyldiphenylsilyloxyethylselanyl)methyl)-6-
chloro-9H-purin-2-amine (14). To a stirring solution of 12
(5.0 g, 5.52 mmol, 80% purity) in ethanol (25 mL), NaBH4
o
at 85 C for 3 h. To this solution, a solution of mesylate 2121
(40.0 g, 258.06 mmol) in THF (10 mL) was added at room
o
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temperature and the mixture was stirred at 65 C for 11 h,
(1.78 g, 46.88 mmol) was added at 0 C, followed by addition
quenched with water (100 mL), and extracted with CH2Cl2 (3
x 200 mL). The combined organic layers were dried (MgSO4),
filtered, and evaporated to give crude residue, which was puriꢀ
fied by silica gel column chromatography (hexane : ethyl aceꢀ
tate = 9 : 1) to give 22 (32 g, 90%) as yellow fluffy solid. The
product was contaminated with monoselenide product (5:1,
of a solution of CH2Br2 (47.96 mL, 683.47 mmol) in ethanol
(100 mL), and the reaction mixture was stirred at room temꢀ
perature for 1 h and evaporated. The residue was treated with
aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3
x 150 mL). The organic layer was dried (MgSO4), filtered, and
evaporated to give crude bromide 13. A suspension of K2CO3
(3.82 g, 27.68 mmol), 18ꢀcrownꢀ6 (2.74 g, 10.36 mmol), and
2ꢀaminoꢀ6ꢀchloropurine (2.34 g, 13.81 mmol) in N,Nꢀ
1
o
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judged by H NMR): mp 90ꢀ92 C, H NMR (400 MHz,
CDCl3) δ 7.46ꢀ7.45 (m, 4H), 7.36ꢀ7.35 (m, 6H), 5.51 (s, 2H),
4.48ꢀ4.35 (m, 4H), 3.88 (t, 4H, J = 11.5 Hz), 3.53ꢀ3.43 (m,
2H).
o
dimethylformamide (100 mL) was stirred under N2 at 85 C
for 3 h. To this mixture, a solution of 13 in DMF (10 mL) was
added and the reaction mixture was stirred at 55 C for 7 h,
o
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This work was supported by the grant from Midꢀcareer Research
9-((2-Phenyl-1,3-dioxan-5-ylselanyl)methyl)-6-chloro-9H-
purin-2-amine (24). Compound 22 (8.0 g, 16.461 mmol) was
converted to 24 (3.5 g, 45%) as a white solid, according to the
same procedure used in the preparation of 14: mp 164ꢀ166 oC;
1H NMR ( 400 MHz, CDCl3) δ 7.88 (s, 1H), 7.43ꢀ7.40 (m,
2H), 7.36ꢀ7.32 (m, 3H), 5.44 (s, 1H), 5.27 (s, 2H), 5.24 (s,
2H), 4.32 (dd, J = 4.5 and 11.4 Hz, 2H), 3.82ꢀ3.76 (m, 2H),
3.69ꢀ3.63 (s, 1H); 13C NMR (125 MHz, CD3OD): 159.3,
153.4, 151.8, 141.4, 137.6, 129.1, 128.3, 125.9, 125.2, 101.4,
71.4. 35.4, 33.4; MS (FAB) found m/z 426.0117 [calcd for
C16H17ClN5O2Se (M+H)+ 426.0236]; UV λmax 223, 310 nm;
Anal. Calcd for C16H16ClN5O2Se: C, 45.24; H, 3.80; N, 16.49.
Found: C, 45.33; H, 4.10; N, 16.55.
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Program (370Cꢀ20130120) of National Research Foundation,
Korea. Antiviral assay by Dr. ChongꢀKyo Lee (KRICT, Korea) is
greatly appreciated.
■ ABBREVIATIONS USED
HSV, herpes simplex virus; VZV, varicellarꢀzoster virus; HCMV,
human cytomegalovirus; EBV, EpsteinꢀBarr virus; HEL, human
embryonic lung fibroblast.
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o
1
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changeable with D2O), 5.25 (s, 2H), 4.84 (t, J = 5.3 Hz, 2H,
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■ ASSOCIATED CONTENT
1
Supporting Information. Antiviral assay procedure and H and
13C NMR copies of unknown compounds. This material is availaꢀ
ble free of charge via the Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresponding Author
*Phone: +82 2 880 7850. Fax: +82 2 888 0649. Eꢀmail:
lakjeong@snu.ac.kr.
Author Contributions
∧These authors contributed equally.
■ ACKNOWLEDGMENT
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