9-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)guanine, a potential antitumor agent against B-lymphoma infected with Kaposi's sarcoma-associated herpesvirus

Article abstract of DOI:10.1021/jm070032y

Several 9-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)purine derivatives were tested against Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells. The guanine derivative (3, CNDAG), as well as the 2-amino-6-sub

Full text of DOI:10.1021/jm070032y

J. Med. Chem. 2007, 50, 2007-2010
2007
9-(2-C-Cyano-2-deoxy-â-D-arabino-
pentofuranosyl)guanine, a Potential Antitumor
Agent against B-Lymphoma Infected with
Kaposi’s Sarcoma-Associated Herpesvirus
Masaki Ohtawa,† Satoshi Ichikawa,† Yasuhiro Teishikata,‡
Masahiro Fujimuro,‡ Hideyoshi Yokosawa,‡ and
Akira Matsuda*,†
Figure 1. Structures of CNDAC and target compounds.
Department of Medicinal Chemistry and Biological Chemistry,
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity,
Kita-ku, Kita-12, Nishi-6, Sapporo 060-0812, Japan
Scheme 1a
ReceiVed January 9, 2007
Abstract: Several 9-(2-C-cyano-2-deoxy-l-â-D-arabino-pentofuran-
osyl)purine derivatives were tested against Kaposi’s sarcoma-associated
herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells.
The guanine derivative (3, CNDAG), as well as the 2-amino-6-
substituted-purine derivatives 4, 5, and 6, exhibited cell growth
inhibitory activity against KSHV-infected cells, but showed no cyto-
toxicity against KSHV-negative cells at >15 µM concentrations.
Therefore, it was found that compounds 3, 4, 5, and 6 showed selective
cytotoxicity against PEL cells infected with KSHV.
Kaposi’s sarcoma-associated herpesvirus (KSHVa), also
known as human herpesvirus 8, was initially discovered in
acquired immunodeficiency syndrome (AIDS)-associated
Kaposi’s sarcoma (KS), the endothelial cell malignancy KS.1
KSHV is also associated with B-cell malignancies, primary
effusion lymphoma (PEL), and plasmablastic variant multi-
centric Castleman’s disease.2 The neoplastic potentials of KSHV
have been established within the context of immunosuppressed
patients who are undergoing organ (bone marrow) transplant
or AIDS by human immunodeficiency virus (HIV).3 Currently,
cytotoxic chemotherapeutic agents such as doxorubicin are used
in established KS, however, serious side effects and only a
transient tumor response to any chemotherapeutic regimen
render them questionable. Other than in prophylactic antiviral
therapy, the use of antiviral drugs as effective treatment against
KS is still a matter of debate.4-9 At the present time, there is
no definitive chemotherapy to treat KS and PEL. Therefore,
the development of novel antitumor agents against KSHV-
infected transformed cells such as PEL is necessary.
We have developed 9-(2-C-cyano-2-deoxy-1-â-D-arabino-
pentofuranosyl)cytosine (CNDAC, Figure 1, 1)10-17 as an
antitumor nucleoside antimetabolite with a novel mechanism-
based DNA-strand breaking ability, which is currently being
evaluated in clinical trials. The structure-activity relationship
of 1 in terms of a nucleobase revealed that the adenine derivative
(CNDAA, 2) was much less cytotoxic than 1. We anticipated
that the guanine analog (CNDAG, 3) and its derivatives might
exhibit cytotoxicity against tumor cells transformed by virus
infection without toxicity against uninfected cells. Here we
a Reagents and conditions: (a) CrO3, Ac2O, pyridine, MS4A, CH2Cl2,
0 °C; (b) Bu4NCN, 0 °C; (c) PhOC(S)Cl, DMAP, Et3N, CH2Cl2, 0 °C; (d)
Bu3SnH, AIBN, toluene, reflux; (e) TBAF, AcOH, THF, 0 °C; (f) bovine
adenosine deaminase, phosphate buffer (pH 7.0), 37 °C; (g) H2, Pd/C,
MeOH, room temperature.
report the synthesis of 3-7 and their selective cytotoxicity
against PEL caused by infection with KSHV.
The target compounds 3-7 are expected to be prone to
degradation under basic conditions, based on the previous study
of 1.13 Therefore, we planned to synthesize the target nucleosides
using the 2-amino-6-substituted purine ribosides 8,18 9,19 and
1020 and to conduct enzymatic hydrolysis by adenosine deami-
nase (ADA) in the final step.21,22 The synthesis of 3-7 is shown
in Scheme 1. The 2′-hydroxyl groups in the 2-amino-9-[3,5-
O-(tetraisopropyldisiloxane-1,3-diyl)-â-D-ribo-pentofuranosyl]-
6-substituted purine derivatives 8-10 were oxidized using CrO3,
pyridine, and Ac2O to afford the corresponding 2′-ketone
derivatives, which were treated with Bu4NCN23 in CH2Cl2 to
give cyanohydrins. They were further treated with the phenyl
chlorothionoformate in the presence of DMAP in CH2Cl2 to
give thionocarbonates 11-13, respectively. Compounds 11-
13 were heated with Bu3SnH and AIBN in refluxing toluene to
furnish in four steps the desired 2′-â-cyano-2′-deoxy derivative
14-16 in 22-33% yields, respectively. However, the reaction
conditions have to be optimized. Deprotection of the TIPDS
group of each 14-16 was conducted with TBAF in the presence
of AcOH in THF at 0 °C to give the desired 4-6, respectively,
* To whom correspondence should be addressed. Phone: 81 11 706 3228.
Fax: 81 11 706 4980. E-mail: matuda@pharm.hokudai.ac.jp.
† Department of Medicinal Chemistry.
‡ Deparment of Biological Chemistry.
a Abbreviations: KSHV, Kaposi’s sarcoma-associated herpesvirus; KS,
Kaposi’s sarcoma; PEL, primary effusion lymphoma; AIDS, acquired
immunodeficiency syndrome; HIV, human immunodeficiency virus; ADA,
adenosine deaminase; EBV, Epstein-Barr virus; ACV, acyclovir; GCV,
ganciclovir; BVDU, 5-bromovinyl-2′-deoxyuridine; TK, thymidine kinase.
10.1021/jm070032y CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/03/2007

2008 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9
Letters
Table 1. Cytotoxic Effects of Nucleosides on B-Lymphoma Cellsa
IC50 (µM)
cmpd
BC3
BC2
DG75
CNDAC (1)
CNDAG (3)
4
5
6
7
CNDG (17)
CNDAA (2)
acyclovir (ACV)
ganciclovir (GCV)
BVDU
0.23
1.14
0.79
0.47
1.48
>15
1.73
>15
>100
70
0.13
7.61
1.51
1.56
1.73
>15
2.61
>15
>100
81
0.21
>15
>15
>15
>15
>15
>15
>15
>100
>100
>15
>15
>15
a Assay was performed according to the procedures described previously
for activity against herpesvirus-infected lymphoma cells.24 KSHV-positive
PEL cells (BC2 and BC3 cells) and herpesvirus-negative B-lymphoma cells
(DG75 cells) were incubated with nucleoside analogs, varying concentra-
tions, for 120 h and were then subjected to cell viability assay. In each
experiment, viability was assessed in six replicate wells. The optical densities
at 560 nm in untreated respective cells are defined as 100%. The means (
standard deviations were determined in three separate experiments.
Figure 2. Chemical stability of CNDAC (1) and CNDAG (3) and the
structure of glycal 18. Compounds were incubated in Tris HCl buffer
(pH 9.0) at 37 °C, and time profiles of the decrease of CNDAG (3)
and formation of CNDG (17) and guanine were analyzed by HPLC.
without any epimerization at the 2′-position. The configuration
at the 2′-position of these compounds was confirmed to be 2′-
“up” by NOE experiments, in which a correlation with the 4′-
proton was observed upon irradiation at the 2′-proton.
Next, enzymatic deamination of 4 was examined. Compound
4 was incubated with bovine ADA in a phosphate buffer (pH
7.0) at 37 °C for 24 h to furnish 3 along with its 2′-epimer,
9-(2-C-cyano-2-deoxy-â-D-ribo-pentofuranosyl)guanine (17,
CNDG), which was separated by high performance liquid
chromatography (HPLC). Compound 3 was also obtained by
the treatment of 5 and 6 with ADA. Compound 6 was further
treated with Pd/C under a hydrogen atmosphere to give the
2-aminopurine derivative 7.
Figure 3. Cytotoxic effect of 4 (a) and 5 (b) on BC3 cells in the
presence of adenosine deaminase inhibitor. Assay was performed
according to the procedures described previously for BC3 cells in the
presence of 10 µM deoxycoformycin.
against tumor cells infected by KSHV. Clinically used anti-
herpes drugs such as acyclovir (ACV), ganciclovir (GCV), and
5-bromovinyl-2′-deoxyuridine (BVDU) were inactive against
any KSHV-positive PEL cells at 15 µM concentrations. The
2-amino-6-methoxypurine derivative 4, the 2,6-diaminopurine
derivative 5, and the 2-amino-6-chloropurine derivative 6 were
also active against KSHV-infected BC3 cells with IC50 values
of 0.79, 0.47, and 1.48 µM, respectively. The 2-aminopurine
derivative 7 and CNDAA, which is an adenine derivative,
showed no activity. Compound 17 is also effective against BC3
cells similar to 3. The tumor cell growth inhibitory activity of
17 would mainly be related to the epimerized 3.13 The IC50
values for 3 itself should be much lower than the apparent ones,
because 3 should also be epimerized in the cells. It is presumed
that 4, 5, and 6 would be deaminated by a cellular ADA to
produce 3, which would be the active nucleoside. In fact, BC3
cells pretreated with 10 µM deoxycoformycin escaped from the
cytotoxicity of 4-6 (Figure 3). These results clearly showed
that 4-6 themselves exhibited no cytotoxicity and were
metabolized to the active 3 by the action of cellular ADA.
The effect of 3 on the synthesis of DNA (incorporation of
[3H]thymidine), RNA (incorporation of [3H]guanosine), and
protein (incorporation of [3H]leucine) was also examined with
BC3 cells (Figure 4). Contrary to 1, which mainly inhibits DNA
synthesis, RNA synthesis was inhibited by 80% at 10 µM
concentration of 3, although 3 has a deoxyribonucleoside
structure. It may be suggested that the mode of action of 3 in
exhibiting tumor cell growth inhibitory activities might not be
the same as the known deoxyribonucleoside antimetabolites.
Most of the nucleoside antimetabolites have to be phospho-
rylated at the 5′-hydroxyl group by a nucleoside and nucleotide
kinases, and its efficiency sometimes plays an important role
Compound 1 is chemically labile in alkaline solution, leading
to epimerization and degradation via the E1cB mechanism to
give cytosine.13 Therefore, we examined the chemical stability
of 3 in alkaline solution in comparison with 1. Compounds 3
or 17 were incubated in Tris HCl buffer (pH 9.0) at 37 °C, and
time profiles of the decrease of 3 and formation of 17 and
guanine were examined. The results are shown in Figure 2.
1
Indeed, the concentration ratio of 3 to 17 is approximately /3
in the slow phase, confirming that 17 is thermodynamically more
stable than 3. Compared with 1, compound 3 is, as expected,
more susceptible to the epimerization. However, interestingly,
the formation of guanine and 1,4-anhydro-2-C-cyano-2-deoxy-
D-erythro-pent-l-enitol (18, glycal), which were â-elimination
products of 3, was more suppressed than that of 1. Both 3 and
17 were stable under neutral conditions (pH ) 7.0) and no
epimerization or degradation was observed. Using the same
experiments, we found that other 6-modified analogs 4-7 had
similar chemical properties by the same experiments (data not
shown).
Cytotoxic effects of the above synthesized compounds were
evaluated on B-cell lines isolated from a patient suffering from
KSHV infection (BC3 cells), from a patient suffering both
KSHV and Epstein-Barr virus (EBV) infections (BC2 cells),
and from a patient with no known KSHV infections (DG75
cells).24 The results are summarized in Table 1. Compound 3
exhibited cell growth inhibitory activity against KSHV-infected
BC3 and BC2 cells with IC50 values of 1.14 and 7.61 µM,
respectively. On the other hand, 3 did not show any cytotoxicity
against KSHV-negative DG75 cells at >15 µM concentrations.
Compound 1, which is currently in a phase I clinical trial as an
anticancer drug, was toxic against all the cells tested in this
assay, and thus, 3 was revealed to be a selective cytotoxic agent

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 9 2009
Culture, Sports, Science and New Energy and Industrial
Technology Development Organization (NEDO) of Japan. We
thank Ms. M. Kiuchi and Ms. A. Tokumitsu (Center for
Instrumental Analysis, Hokkaido University) for elemental
analysis and Ms. S. Oka (Center for Instrumental Analysis,
Hokkaido University) for measurement of mass spectra. This
paper constitutes Part 248 of Nucleosides and Nucleotides: for
part 247 in this series, see ref 28.
Supporting Information Available: Synthetic procedures of
compounds 3-17 and procedures for cell viability assays. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 4. Effect of CNDAG (3) on the synthesis of DNA, RNA, and
protein. After BC3 cells (2.5 × 105 cells/mL) were incubated for 24 h,
3 was added to the culture and incubated for 1 h. Before cell harvest,
cells were pulse-labeled for 30 min with [3H]thymidine, [3H]uridine,
or [3H]leucin. The radioactivity of the acid-insoluble fractions was
measured by a liquid scintillation counter.
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aid for scientific research from the Ministry of Education,

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