New neplanocin analogues. 12. Alternative synthesis and antimalarial effect of (6′R)-6′-C-methylneplanocin A, a potent AdoHcy hydrolase inhibitor

Article abstract of DOI:10.1021/jm010374i

An improved method for the synthesis of (6′R)-6′-C-methylneplanocin A (RMNPA, 2), a potent S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of MeTiCl₃ to the neplanocin A

Full text of DOI:10.1021/jm010374i

748
J . Med. Chem. 2002, 45, 748-751
New Nep la n ocin An a logu es. 12. Alter n a tive Syn th esis a n d An tim a la r ia l Effect of
(6′R)-6′-C-Meth yln ep la n ocin A, a P oten t Ad oHcy Hyd r ola se In h ibitor 1
Satoshi Shuto,*,† Noriaki Minakawa,† Satoshi Niizuma,† Hye-Sook Kim,‡ Yusuke Wataya,‡ and Akira Matsuda*,†
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, J apan, and
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, J apan
Received August 7, 2001
An improved method for the synthesis of (6′R)-6′-C-methylneplanocin A (RMNPA, 2), a potent
S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, was developed via a chelation-
controlled stereoselective addition of MeTiCl3 to the neplanocin A 6′-aldehyde derivative 6.
Compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo.
The antimalarial EC50 value of 2 against Plasmodium berghei in mice was 1.0 mg/kg/day, which
was superior to that of chloroquine (EC50 ) 1.8 mg/kg/day).
In tr od u ction
important role in interactions with these enzymes,
namely, AdoHcy hydrolase, Ado deaminase, and Ado
kinase.10 We found that (6′R)-6′-C-methylneplanocin A
(RMNPA, 2) effectively inhibits AdoHcy hydrolase and
thus has an efficient antiviral effect comparable to NPA,
yet is significantly less cytotoxic to host cells and
resistant to deamination by Ado deaminase.10a,b Inter-
estingly, the corresponding 6′-diastereomer (6′S)-6′-C-
methylneplanocin A is virtually biologically inactive.10a
On the basis of the above results, we investigated the
antimalarial activity of RMNPA and found that it
significantly inhibited the growth of P. falciparum in
vitro. For an in vivo evaluation of its antimalarial effect,
development of an efficient method of synthesis of
RMNPA was needed. Earlier, less efficient synthesis of
RMNPA had required the separation of a diastereomeric
mixture of 6′-methylneplanocin A derivatives by HPLC10a
or via an enzymatic method with Ado deaminase.12 In
this report, we describe an improved synthesis of
RMNPA and its potent antimalarial activity both in
vitro and in vivo.
The increasing resistance of Plasmodium falciparum
to currently available drugs, such as chloroquine,
presents a challenge in the treatment of malaria,2 which
still remains one of the leading causes of death in the
world. Consequently, new agents are urgently needed
to treat the organism.
S-Adenosyl-L-homocysteine (AdoHcy) hydrolase, which
is responsible for the hydrolysis of AdoHcy to adenosine
(Ado) and L-homocysteine,3 has been recognized as a
new target for antimalarial agents,4 since the parasite
has a specific AdoHcy hydrolase.4d AdoHcy is a potent
feedback inhibitor of cellular transmethylation reac-
tions, and therefore inhibition of AdoHcy hydrolase
would markedly increase the levels of AdoHcy prevent-
ing transmethylation reactions using S-adenosyl-L-
methionine as the methyl donor, e.g., mRNA methyl-
ations, which are essential for parasite proliferation. In
fact, several AdoHcy hydrolase inhibitors have been
shown to have antimalarial effects.4a-c
The carbocyclic nucleoside antibiotic neplanocin A
(NPA 1),5 one of the most potent AdoHcy hydrolase
inhibitors known,6 has a potent antiviral effect6b as well
as a cytotoxic effect on various cells.7 The extensively
studied mechanism of action7 of the cytotoxic effect can
be attributed mainly to phosphorylation of the primary
hydroxyl group at the 6′-position (the 6′-position of NPA
corresponds to the 5′-position of Ado) by Ado kinase and
subsequent metabolism by cellular enzymes.7 The anti-
viral effect, however, is likely due to the inhibition of
AdoHcy hydrolase via suppression of the virus mRNA
maturation.6a,8 NPA is also known to be rapidly de-
aminated by Ado deaminase to the chemotherapeuti-
cally inactive inosine congener,9,10a which would reduce
the therapeutic potency of NPA. On the basis of these
results, chemical modifications of NPA have been
conducted to develop more efficient AdoHcy hydrolase
inhibitors.10,11 We previously chose the 6′-moiety of NPA
as the target site for the modifications because of its
Ch em istr y
First, we examined, under various conditions, the
stereoselective addition of organometallic reagents, such
as Me3Al, MeLi, MeTiCl3, MeTi(OiPr)3, or MeMgBr to
2′,3′-O-isopropylideneneplanocin A 6′-aldehyde.10a How-
ever, the reactions were not stereoselective and gave the
diastereomeric mixture in moderate yields (data not
shown). Another 6′-aldehyde derivative 6, having bulky
tert-butyldimethylsilyl (TBS) groups on the 2′ and 3′-
hydroxyls, was next selected as a substrate for the
nucleophilic addition (Scheme 1). N6-Benzoylneplanocin
A (3)10a was treated successively with TBSCl/imidazole
in DMF and aqueous AcOH/THF to give the 2′,3′-bis-
O-TBS derivative 5. Compound 5 was oxidized with
10i
BaMnO4 in CH2Cl2 to yield the 6′-aldehyde 6, the
substrate for the addition of organometallics. The al-
dehyde 6 was stable enough to be purified by neutral-
ized silica gel column chromatography. The reactions
were performed with 3 equiv of Me3Al, MeMgBr, MeLi,
MeTiCl3, or MeTi(Oi-Tr)3, in CH2Cl2 (entries 1-5 in
Table 1). Although the desired 6′R-product 7R was not
obtained as the major product in these entries, the 6′S-
* Address correspondence to Akira Matsuda. Phone: +81-11-706-
3228. Fax: +81-11-706-4980. E-mail: matuda@pharm.hokudai.ac.jp.
† Hokkaido University.
‡ Okayama University.
10.1021/jm010374i CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/05/2002

Brief Articles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 749
Sch em e 1a
F igu r e 1.
Ta ble 2. In Vitro Antimalarial Activity and Cytotoxicity of
NPA, RMNPA, and Chloroquine
IC50 (µM)
KATO IIIa
(growing)
Verob
(stationary)
compound
P. falcipruma
NPA (1)
RMNPA (2)
chloroquine
0.20
0.10
0.018
0.22
1.1
580
>1800
ND
NDc
a
Assay was performed by the previously reported method.14
Data were taken from ref 10a. c Not determined.
b
Successive treatment of 5 with BaMnO4 in CH2Cl2,
MeTiCl3 in CH2Cl2, and NH3/MeOH gave 8S in 66%
yield.
Inversion at the 6′-position of 8S was examined using
the Mitsunobu reaction. When 8S was treated succes-
sively with diisopropyl azodicarboxylate (DIPAD), Ph3P,
and ClCH2CO2H in THF and with NH3 in MeOH at
room temperature, the desired 6′R-product 8R was
obtained in 90% yield. Removal of the silyl groups of
8R with NH4F in MeOH finally gave RMNPA (2).
This method, which provides RMNPA without dia-
stereomer separation, is therefore a significant improve-
ment over the previous methods.10a,12
An tim a la r ia l Effect of RMNP A
a
Conditions: (a) TBSCl, imidazole, DMF, rt, quant; (b) AcOH,
The antimalarial activity of NPA, RMNPA, and
chloroquine, a common antimalarial agent used as a
positive control against P. falciparum (FCR-3 strain),
was first evaluated in vitro using the previously re-
ported method.14 The results and cytotoxicity of the two
compounds against human gastric carcinoma cell line
(KATO III) and monkey kidney cell line (Vero) repre-
senting models of hosts are summarized in Table 2.
RMNPA showed significant antimalarial activity with
an IC50 value of 0.10 µM. The potency was greater than
that of the parent compound NPA (IC50 ) 0.20 µM),
although this value is 5.6-fold higher than that of
chloroquine. On the other hand, RMNPA was shown to
exert lower cytotoxicity against proliferation of KATO
aq THF, 50 °C, 94%; (c) BaMnO4, CH2Cl2, reflux, 63%; (d) see Table
1; (e) NH3, MeOH, rt, 70%; (f) (1) DIPAD, Ph3P, ClCH2CO2H, THF,
rt, (2) NH3, MeOH, rt, 90%; (g) NH4F, MeOH, 74%.
Ta ble 1. Nucleophilic Addition Reactions of Organometallic
Reagents to the NPA 6′-Aldehyde Derivative 6
product,
entry
reagenta
Me3Al
MeMgBr
MeLi
conditions
yield (R:S)b
1
2
3
4
-78 °C, 2 h
no reaction
7, 94% (1:1)
7, 88% (1:3)
7, 30% (1:30<);
8, 60% (1:30<)
7, 31% (1:3)
-78 °C, 2 h
-78 °C, 0.5 h
MeTiCl3
-50 °C, 0.5 hc
5
MeTi(OiPr)3
-0 °C-rt, 2 hc
a
Reactions were performed with 3 equiv of the reagent in
CH2Cl2. Isolated yield. The R/ S ratio was determined by 1H
b
III cells (IC50 ) 1.1 µM) compared with NPA (IC50
)
NMR. c No reaction at -78 °C.
0.22 µM). Furthermore, RMNPA was completely inac-
tive in Vero cells in a stationary phase; no cytotoxic
effect on the cells was observed at concentrations up to
1800 µM of RMNPA.
diastereomer was produced highly selectively when 6
was treated with MeTiCl3 at -50 °C. The reaction gave
the 6′S-diastereomer 7S and its N6-debenzoylated prod-
uct 8S in 30% and 60% yields, respectively, whereas
only a trace of the corresponding diastereomers 7R or
8R was detected in the 1H NMR. Compound 7S was
readily converted into the corresponding debenzoylated
8S on treatment with NH3/MeOH. It is well-known that
addition of MeTiCl3 to â-alkoxyaldehydes proceeds via
a chelation controlled mechanism,13 and therefore in
this case addition from the less hindered si-face might
occur via the chelation intermediate to produce the 6′S-
product with high selectivity, as shown in Figure 1.
In vivo antimalarial activities of NPA and RNMPA
against Plasmodium berghei (NK-65 strain) in mice
were investigated according to the 4 day suppressive
test,14 and the results are shown in Table 3. The widely
used antimalarial drug chloroquine was, as expected,
effective in this system. It is noteworthy that RMNPA
effectively inhibited the growth of P. berghei in mice
with an ED50 value of 1.0 mg/kg/day, which was more
potent than chloroquine (ED50 ) 1.8 mg/kg/day). The
parent compound NPA was less effective than RMNPA,

750 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3
Brief Articles
Ta ble 3. In Vivo Antimalarial Activity of NPA, RMNPA, and Chloroquine in P. berghei in Micea
dose (mg/kg/day)
EC50
compound
untreated
0.1
0.5
1.0
2
5
10
20
(mg/kg/day)b
NPA (1)
>5
1.0
1.8
% parasitemiac
survivald
21
5/5
20
5/5
21
5/5
21
5/5
21
5/5
12
5/5
-
-
0/5
0/5
RMNPA (2)
% parasitemia
survival
chloroquine
% parasitemia
survival
21
5/5
21
5/5
21
5/5
10
5/5
5
5/5
2
5/5
2
5/5
-
2/5
21
5/5
21
5/5
20
5/5
18
5/5
7
5/5
3
5/5
2
5/5
1
5/5
a
In vivo antimalarial activity was assessed using ICR mice infected with P. berghei (NK 65 strain) following the protocol described
previously.14 Various concentrations of the test compounds, prepared in DMSO, were administered daily via intraperitoneal injection to
groups of five mice for four consecutive days beginning on day 0. Five infected, dimethyl sulfoxide-dosed mice were used as a control.
The dose required to cause 50% suppression of P. berghei growth in mice. c To evaluate the antimalarial activity of the compounds,
b
blood smears from the tails were taken and stained with Giemsa. A total of 1 × 104 erythrocytes per one thin blood film was examined
d
under microscopy. On day 4, parasitemia of the control mice was between 18 and 22%. Survival was monitored as a symptom indicative
of toxicity on day 4.
in CH2Cl2 (15 mL) at -78 °C. The mixture was warmed to
-50 °C, and the crude 6 in CH2Cl2 (13 mL) was added to the
resulting brown solution via a cannula over 10 min. The
mixture was stirred for 30 min at the same temperature. The
reaction was quenched by addition of saturated aqueous
NH4Cl, and the mixture was partitioned between CHCl3 and
H2O. The organic layer was washed with H2O and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was dis-
solved in NH3/MeOH (20 mL, saturated at 0 °C), and the
mixture was kept at room temperature overnight. The solvent
was removed in vacuo, and the residue was purified on a silica
gel column with EtOH in CHCl3 (0-8%) to give 8S (446 mg,
66% from 5 as a white solid): MS m/z 505 (M+); 1H NMR
(CDCl3) 8.33 and 7.76 (each s, each 1 H, H-2 and 8), 5.73 (m,
1 H, H-5′), 5.57 (br s, 2 H, NH2), 5.44-5.41 (m, 1 H, H-1′),
4.77 (d, 1 H, H-3′, J ) 4.6 Hz), 4.49-4.41 (m, 2 H, H-2′and 6′),
2.73 (br s, 1 H, OH), 1.43 (d, 3 H, 6′-Me, J ) 6.6 Hz), 0.91 and
0.74 (each s, each 9 H, tert-butyl), 0.13, (s, 6 H, Me x 2), -0.17,
-0.56 (each s, each 3 H, Me).
having an ED50 of >5.0 mg/kg/day, 57% growth of P.
berghei at 5.0 mg/kg/day, and toxic against mice at 10
mg/kg/day (survival 0/5). During administration of
RMNPA (5.0 mg/kg/day), growth of the parasites was
inhibited as shown in Table 3, whereas malaria para-
sites were still observed in circulating blood even after
the 4 day suppressive test. All of the mice infected with
P. berghei with and without RMNPA treatment died
after 8-10 days of infection. However, no side effects
such as diarrhea, body weight loss, or mortality were
observed during the treatment with RMNPA at doses
of 5.0 mg/kg/day. Therefore, mortality may not be due
to toxicity caused by RMNPA but to P. berghei infection.
While the inhibitory effect of RMNPA against AdoHcy
hydrolase is weaker than that of NPA in vitro,10a its
antimalarial activity in vivo is superior to that of NPA.
RMNAP is effective presumably because the compound
is (1) completely resistant to Ado deaminase,10a,12 keep-
ing it at relatively higher concentrations in vitro as well
as in vivo, and (2) it is less toxic to host cells, because
it is not phosphorylated by Ado kinase, a possible toxic
mechanism of NPA.7
(6′R )-2′,3′-Di-O-(t er t -b u t yld im e t h ylsilyl)-6′-m e t h yl-
n a p la n ocin A (8R ). Diisopropyl azodicarboxylate (514 µL,
2.61 mmol) was added to a mixture of 8S (440 mg, 0.87 mmol),
Ph3P (686 mg, 2.61 mmol), and ClCH2CO2H (247 mg, 2.61
mmol) in THF (18 mL) at 0 °C, and the mixture was stirred
for 50 min at room temperature. The reaction was quenched
by addition of ice, and the mixture was partitioned between
AcOEt and saturated aqueous NaHCO3. The organic layer was
washed with H2O and brine, dried (Na2SO4), and concentrated
in vacuo. The residue in NH3/MeOH (20 mL, saturated at 0
°C) was kept at room temperature overnight. The solvent was
removed in vacuo, and the residue was purified on a silica gel
column with EtOH in CHCl3 (0-16%) to give 8R (398 mg, 90%
as a white solid). An analytical sample was crystallized from
AcOEt-hexane to give white crystals: mp 211 °C; MS m/z 505
Exp er im en ta l Section
Melting points were measured on a Yanagimoto MP-3
micromelting point apparatus (Yanagimoto, J apan) and are
uncorrected. Fast atom bombardment mass spectrometry
(FAB-MS) was done on a J EOL J MS-HX110 instrument at an
1
ionizing voltage of 70 eV. The H NMR spectra were recorded
on a J EOL J NM-GX 270 (270 MHz) or Bruker ARX 500 (500
MHz) spectrometer with tetramethylsilane as an internal
standard. Chemical shifts are reported in parts per million
(δ), and signals are expressed as s (singlet), d (doublet), t
(triplet), m (multiplet), or br (broad). All exchangeable protons
were detected by disappearance on the addition of D2O. TLC
was done on Merck Kieselgel F254 precoated plates (Merck,
Germany). The silica gel used for column chromatography was
YMC gel 60A (70-230 mesh) (YMC Co., Ltd., J apan). Reac-
tions were carried out under an argon atmosphere.
P r a ct ica l Syn t h esis of (6′S)-2′,3′-Di-O-(ter t-b u t yld i-
m eth ylsilyl)-6′-m eth yln a p la n ocin A (8S). A mixture of 5
(800 mg, 1.34 mmol) and BaMnO4 (3.44 g, 13.4 mmol) in
CH2Cl2 (80 mL) was heated under reflux. After 11 h, an
additional BaMnO4 (3.44 g, 13.4 mmol) was added, and the
reaction mixture was heated overnight. The reaction mixture
was cooled to room temperature and filtered through a Celite
pad, which was washed with hot CHCl3. The filtrate and
washings were combined and concentrated in vacuo to give
crude aldehyde 6. An Et2O solution of MeLi (1.03 M, 4.5 mL,
4.7 mmol) was added to a solution of TiCl4 (510 µL, 4.7 mmol)
1
(M+); H NMR (CDCl3) 8.31 and 7.72 (each s, each 1 H, H-2
and 8), 5.83 (m, 1 H, H-5′), 5.57 (br s, 2 H, NH2), 5.44-5.42
(m, 1 H, H-1′), 4.58 (d, 1 H, H-3′, J ) 5.0 Hz), 4.43-4.38 (m,
1 H, H-6′), 4.41 (t, 1 H, H-2′, J ) 5.0 Hz), 2.64 (br s, 1 H, OH),
1.42 (d, 3 H, 6′-Me, J ) 6.6 Hz), 0.91 and 0.76 (each s, each 9
H, tert-butyl), 0.12, 0.10, -0.15, -0.48 (each s, each 3 H, Me).
Anal. (C24H43N5O3Si2) C, H, N.
(6′R)-6′-Meth yln a p la n ocin A (RMNP A, 2). A solution of
8R (395 mg, 0.78 mmol) and NH4F (303 mg, 8.4 mmol) in
MeOH (15 mL) was heated for 18 h under reflux. The solvent
was removed in vacuo, and the residue was purified on a silica
gel column with EtOH in CHCl3 (10-40%) to give 2 (160 mg,
74% as a white solid, which was crystallized from EtOH-
H2O): mp 210 °C (lit.10a 211 °C); 1H NMR (DMSO-d6) 8.10 and
8.01 (each s, each 1 H, H-2 and 8), 7.15 (br s, 2 H, NH2), 5.66
(s, 1 H, H-5′), 5.30 (m, 1 H, H-1′), 5.10, 4.88, and 4.83 (each d,
each 1 H, 2′, 3′, and 5′-OH), 4.49 (m, 1 H, H-3′), 4.43-4.32 (m,
1 H, H-6′), 4.24 (m, 1 H, H-2′), 1.24 (d, 3 H, 6′-Me, J ) 6.6
Hz). Anal. (C12H15N5O3) C, H, N.

Brief Articles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 751
(8) Ransohoff, R. M.; Narayanan, P.; Ayes, D. F.; Rottaman, F. M.;
Nilsen, T. W. Antiviral Res. 1987, 7, 17-327.
Ack n ow led gm en t. This work was supported by
grants for Scientific Research (12307007 and 13672286)
from the Ministry of Education, Culture, Sports, Science
and Technology of J apan and also by Grant-in-Aid for
Creative Scientific Research (13NP0401) from the J apan
Society for Promotion of Science. We are grateful to Ms.
H. Matsumoto, A. Maeda, S. Oka, and N. Hazama
(Center for Instrumental Analysis, Hokkaido Univer-
sity) for technical assistance with NMR, MS, and
elemental analysis.
(9) Tsujino, M.; Yaginuma, S.; Fujii, T.; Hayano, K.; Matsuda, T.;
Watanabe, T.; Abe, J . Curr. Chemother. Infect. Dis. 1981, 3, 1559.
(10) (a) Shuto, S.; Obara, T.; Toriya, M.; Hosoya, M.; Snoeck, R.;
Andrei, G.; Balzarini, J .; De Clercq, E. New neplanocin ana-
logues. I. Synthesis of 6′-modified neplanocin A derivatives as
broad-spectrum antiviral agents. J . Med. Chem. 1992, 35, 324-
331. (b) Shigeta, S.; Mori, S.; Baba, M.; Ito, M.; Honzumi, K.;
Nakamura, K.; Oshitani, H.; Numazaki, Y.; Matsuda, A.; Obara,
T.; Shuto, S.; De Clercq, E. Antiviral activities of ribavirin,
EICAR, and (6′R)-6′-C-methylneplanocin
A against several
ortho- and paramyxoviruses. Antimicrob. Agents Chemother.
1992, 36, 435-439. (c) Shuto, S.; Obara, T.; Kosugi, Y.; Toriya,
M.; Yaginuma, S.; Shigeta, S.; Matsuda, A. New neplanocin
analogues. III. 6′R-Configuration is essential for the antiviral
activity of 6′-C-methyl-3-deazaneplanocin A's. BioMed. Chem.
Lett. 1993, 4, 605-608. (d) Shuto, S.; Obara, T.; Itoh, H.; Kosugi,
Y.; Saito, Y.; Toriya, M.; Yaginuma, S.; Shigeta, S.; Matsuda, A.
New neplanocin analogues. IV. An adenosine deaminase-
resistant equivalent of neplanocin A. Chem. Pharm. Bull. 1994,
42, 1688-1690. (e) Obara, T.; Shuto, S.; Saito, Y.; Toriya, M.;
Ogawa, K.; Yaginuma, S.; Shigeta, S.; Matsuda, A. New nep-
lanocin analogues. V. A potent adenosylhomocysteine hydrolase
inhibitor lacking antiviral activity. Synthesis and antiviral
activity of 6′-carboxylic acid derivatives of neplanocin A. Nucleo-
sides Nucleotides 1996, 15, 1157-1167. (f) Shuto, S.; Obara, T.;
Saito, Y.; Andrei, G.; Snoeck, R.; De Clercq, E.; Matsuda. A. New
neplanocin analogues. 6. Synthesis and potent antiviral activity
of 6′-homoneplanocin A. J . Med. Chem. 1996, 39, 2392-2399.
(g) Obara, T.; Shuto, S.; Saito, Y.; Snoeck, R.; Andrei, G.;
Barzarini, J .; De Clercq, R.; Matsuda, A. New neplanocin
analogues. 7. Synthesis and antiviral activity of 2-halo deriva-
tives of neplanocin A. J . Med. Chem. 1996, 39, 3847-3852. (h)
Shuto, S.; Obara, T.; Saito, Y.; Yamashita, K.; Tanaka, M.;.
Sasaki, T.; Andrei, G.; Snoeck, R.; Neyts, J .; Padalko, E.;
Barzarini, J .; De Clercq, E.; Matsuda, A. New neplanocin
analogues. VIII. Synthesis and biological activity of 6′-C-ethyl,
ethenyl, and ethynyl derivatives of neplanocin A. Chem. Pharm.
Bull. 1997, 45, 1163-1168. (i) Shuto, S.; Niizuma, S.; Matsuda,
A. One-pot conversion of R,â-unsaturated alcohols into the
corresponding carbon-elongated dienes with a stable phosphorus
ylide-BaMnO4 system. Synthesis of 6′-methylene derivatives of
neplanocin A as potential antiviral nucleosides. New neplanocin
analogues. 11. J . Org. Chem. 1998, 63, 4489-4493.
Su p p or tin g In for m a tion Ava ila ble: Experimental Sec-
tion to synthesize the compounds 4, 5, and 6, and the reactions
of 6 with MeTiCl3, MeLi, and MeMgBr described in Table 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Refer en ces
(1) This report constitutes part 211 of Nucleosides and Nucleotides;
for part 210, see: Karino, N.; Ueno, Y.; Matsuda, A. Synthesis
and properties of oligonucleotides containing 5-formyl-2′-deoxy-
cytidine. In vitro DNA polymerase reactions on DNA templates
containing 5-formyl-2′-deoxycytidine. Nucleic Acids Res. 2001,
29, 2456-2463.
(2) (a) Peters, W. Antimalarial drug resistance: an increasing
problem. Br. Med. Bull. 1982, 38, 187-192. (b) Cowman, A. F.;
Foote, S. J . Chemotherapy and drug resistance in malaria. Int.
J . Parasitol. 1990, 20, 503-513. (c) Slater, A. Chloroquine:
mechanism of drug action and resistance in Plasmodium falci-
parum. Pharmacol. Ther. 1993, 57, 203-235. (d) Latel, D, F.;
Mangou, F.; Tribouley-Duret, J . High-level chloroquine resist-
ance of Plasmodium berghei is associated with multiple drug
resistance and loss of reversal by calcium antagonists. Int. J .
Parasitol. 1998, 28, 641-51.
(3) (a) Ueland, P. M. Pharmacological and biochemical aspects of
S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase.
Pharmacol. Rev. 1982, 34, 223-253. (b) Wolfe, M. S.; Borchardt.
R. T. S-Adenosyl-L-homocysteine hydrolase as
a target for
antiviral chemotherapy. J . Med. Chem. 1991, 34, 1521-1530.
(4) For examples, see: (a) Trager, W.; Robert-Gero, M.; Lederer, E.
Antimalarial activity of S-isobutyladenosine against Plasmo-
dium falciparum in culture. FEBS Lett. 1980, 85, 264-266. (b)
Whaun, J . M.; George, G. A.; Brown, N. D.; Gordon, R. K.;
(11) For examples, see: (a) Borcherding, D. R.; Narayanan, S.;
Hasobe, M.; McKee, J . G.; Keller, B. T.; Borchadt, R. T. Potential
inhibitors of S-adenosylmethionine-dependent methyltrans-
ferases. 11. Molecular dissections of neplanocin A as potential
inhibitors of S-adenosylhomocysteine hydrolase. J . Med. Chem.
1988, 31, 1729-1738. (b) Tsend, C. K. H.; Marquez, V. E.; Fuller,
R. W.; Goldstein, B. M.; Arnett, G.; Hollingshead, M.; Driscoll,
J . S. Synthesis of 3-deazaneplanocin A, a powerful inhibitor of
S-adenosylhomocysteine hydrolase with potent and selective in
vitro and in vivo antiviral activities. J . Med. Chem. 1989, 32,
1442-1446. (c) Hasobe, M.; McKee, J . G.; Borcherding, D. R.;
Borchardt, R. T. 9-(trans-2′,trans-3′-Dihydroxycyclopent-4′-enyl)-
adenine and 3-deazaadenine: analogs of neplanocin A which
retain potent antiviral activity but exhibit reduced cytotoxicity.
Antimicrob. Agents Chemother. 1987, 31, 1849-1851.
(12) Shuto, S.; Obara, T.; Yaginuma, S.; Matsuda, A. New neplanocin
analogues. IX. A practical preparation of (6′R)-6′-C-methylne-
planocin A (RMNPA), a potent antiviral agent, and the deter-
mination of its 6′-configuration. Diastereoselective deamination
by adenosine deaminase. Chem. Pharm. Bull. 1997, 45, 138-
142.
(13) Petasis, N. A.; Akritopoulou-Aanze, I. In Encyclopedia of Re-
agents for Organic Synthesis; Paquette, L. A., Ed.; 1995; Vol 5
(L-M), pp 3598-3601.
Chiang, P. K. Antimalarial activity of neplanocin
A with
perturbations in the metabolism of purines, polyamines and
S-adenosylmethionine. J . Pharmacol. Exp. Ther. 1986, 236,
277-283. (c) Bitonti, A. J . R.; Baumann, J .; J arvi, E. T.;
McCarthy, J . R.; McCann, P. P. Antimalarial activity of 4′,5′-
unsaturated 5′-fluoroadenosine mechanisms-based inhibitor of
S-adenosyl-L-homocysteine hydrolase. Biochem. Pharm. 1990,
40, 601-606. (d) Creedon, K. A.; Rathod, P. K.; Wellems, T. E.
Plasmodium falciparum S-adenosylhomocysteine hydrolase.
cDNA identification, predicted protein sequence, and expression
in Escherichia coli. J . Biol. Chem. 1994, 269, 16364-16370.
(5) (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. Studies on neplanocin A, new antitumor antibiotic.
I. Producing organism, isolation, and characterization. J . Anti-
biot. 1981, 34, 359-366. (b) Hayashi, M.; Yaginuma, S.; Yoshio-
ka, H.; Nakatsu, K. Studies on neplanocin A, new antitumor
antibiotic. II. Structure determination. J . Antibiot. 1981, 34,
675-680.
(6) (a) Borchardt, R. T.; Keller, B. T.; Patel-Thombre, U. Neplanocin
A. A potent inhibitor of S-adenosylhomocysteine hydrolase and
of vaccinia virus multiplication in mouse L-020 cells. J . Biol.
Chem. 1984, 259, 4353-4358. (b) De Clercq, E. Antiviral and
antimetabolic activities of neplanocins. Antimicrob. Agents
Chemother. 1985, 28, 84-89.
(7) (a) Glazer, R. I.; Knode, M. C. Neplanocin A. A cyclopentenyl
analog of adenosine with specificity for inhibiting RNA meth-
ylation. J . Biol. Chem. 1984, 259, 12964-12969. (b) Inaba, M.;
Nagashima, S.; Tsukagoshi, S.; Sakurai, Y. Biochemical mode
of cytotoxic action of neplanocin A in L 1210 leukemic cells.
Cancer Res. 1986, 46, 1063-1067. (c) Hoshi, A.; Yoshida, M.;
Iigo, M.; Tokuzen, R.; Fukukawa, K.; Ueda, T. Antitumor activity
of derivatives of neplanocin A in vivo and in vitro. J . Pharma-
cobio-Dyn. 1986, 9, 202-206.
(14) (a) Kim, H.-S.; Shibata, Y.; Wataya, Y.; Tsuchiya, K.; Masuyama,
A.; Nojima, M. Synthesis and antimalarial activity of cyclic
peroxides, 1,2,4,5,7-pentoxocanes and 1,2,4,5-tetroxanes. J . Med.
Chem. 1999, 42, 2604-2609. (b) Kim, H.-S.; Nagai, Y.; Ono, K.;
Begum, K.; Wataya, Y.; Hamada, Y.; Tsuchiya, K.; Masuyama,
A.; Nojima, M.; McCullough, K. J . Synthesis and antimalarial
activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes. J .
Med. Chem. 2001, 44, 2357-2361.
J M010374I