Synthesis and cytostatic activity of 7-arylsulfanyl-7-deazapurine bases and ribonucleosides

Article abstract of DOI:10.1039/c4md00492b

A series of 7-phenylsulfanyl- or 7-(2-thienyl)sulfanyl-7-deazapurine bases bearing diverse substituents at position 6 was prepared through C-H sulfenylation of 6-chloro-7-deazapurine followed by cross-coupling or nucleophilic substitutions. The corresponding ribonucleosides (as thia-analogues of known nucleoside cytostatics) were prepared by glycosylation of 6-chloro-7-arylsulfanyl-7-deazapurines followed by the same transformations at position 6. The 7-thienylsulfanyl-7-deazapurine bases 2b-2h exerted micromolar cytostatic activities, whereas the nucleosides did not show significant biological effects. This journal is

Full text of DOI:10.1039/c4md00492b

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Synthesis and cytostatic activity of 7-arylsulfanyl-
7-deazapurine bases and ribonucleosides†
Cite this: Med. Chem. Commun.,
2015, 6, 576
Martin Klečka,ab Lenka Poštová Slavětínská,b Eva Tloušťová,b Petr Džubák,c
c
ab
*
Marián Hajdúch and Michal Hocek
A series of 7-phenylsulfanyl- or 7-IJ2-thienyl)sulfanyl-7-deazapurine bases bearing diverse substituents at
position 6 was prepared through C–H sulfenylation of 6-chloro-7-deazapurine followed by cross-coupling
or nucleophilic substitutions. The corresponding ribonucleosides (as thia-analogues of known nucleoside
cytostatics) were prepared by glycosylation of 6-chloro-7-arylsulfanyl-7-deazapurines followed by the
same transformations at position 6. The 7-thienylsulfanyl-7-deazapurine bases 2b–2h exerted micromolar
cytostatic activities, whereas the nucleosides did not show significant biological effects.
Received 30th October 2014,
Accepted 1st December 2014
DOI: 10.1039/c4md00492b
www.rsc.org/medchemcomm
access to 7-arylsulfanyl-7-deazapurine bases,12 which can be
considered extended thia-analogues of 7-aryl-7-deazapurines
1. Introduction
Several base-modified purine nucleosides are important anti-
tumor agents.1 Also diverse substituted purine and deaza-
purine bases exert cytostatic effects, typically through inhibi-
tion of kinases and other ATP- or GTP-dependent enzymes.2
Recently, we have discovered new types of nucleoside cyto-
statics: 6-hetaryl-7-deazapurine,3 7-hetaryl-7-deazaadenine4
and 6-substituted 7-hetaryl-7-deazapurine5 ribonucleosides.
They all showed cytostatic effects at nanomolar concentra-
tions and their mechanism of action is not yet fully under-
stood. They are inhibitors of adenosine kinases,6,7 but they
are substrates at the same time and are phosphorylated to
nucleoside triphosphates which then interfere with RNA
synthesis or are incorporated to DNA and RNA. In all three
series, the most active were derivatives bearing thiophene or
furan (Chart 1).
that are components of the abovementioned nucleoside
cytostatics.4,5 Therefore, we decided to prepare a series of
7-phenylsulfanyl- and 7-IJ2-thienyl)sulfanyl-7-deazapurine bases
and ribonucleosides for screening of their anticancer activity.
These extended analogues should show whether the direct
C–H activation reactions are increasingly popular methods
in organic synthesis8 and were also applied in purines and
deazapurines. In addition to relatively common and useful
C–H arylations of purines reported by us9 and by others,10
we have recently reported C–H borylation11 and C–H
sulfenylation12 of 7-deazapurines. The latter method gave
a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2,
CZ-16610 Prague 6, Czech Republic. E-mail: hocek@uochb.cas.cz;
Tel: +420 220183324
b Department of Organic Chemistry, Faculty of Science, Charles University in
Prague, Hlavova 8, CZ-12843 Prague 2, Czech Republic
c Institute of Molecular and Translational Medicine, Faculty of Medicine and
Dentistry, Palacky University and University Hospital in Olomouc, Hněvotínská 5,
CZ-775 15 Olomouc, Czech Republic
† Electronic supplementary information (ESI) available: Detailed table with all
cytostatic activity data, experimental part and characterization data for all new
compounds. See DOI: 10.1039/c4md00492b
Chart 1 Previously reported nucleoside cytostatics and the design of
thia-analogues under study.
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conjugation of the (het)aryl group at position 7 is needed for
the cytostatic activity of this class of 7-deazapurine
nucleosides,4,5 and in principle, they can also be metabolized
to other sulfur-containing nucleosides.
coupling. Thus the Stille reactions of 1a or 2a with thienyl- or
furylIJtributyl)stannanes under standard conditions in the
presence of PdCl2IJPPh3)2 in DMF proceeded smoothly to give
desired 6-hetaryl derivatives 1b–1c and 2b–2c in good yields
(57–87%) (Scheme 2, Table 1, entries 1, 2, 7, and 8). A methyl
group was introduced through Pd-catalysed cross-coupling of
1a or 2a with Me3Al to give 1d and 2d in good yields (entries
3 and 9). Finally, dimethylamino, methylamino and amino
groups were introduced through aromatic nucleophilic
substitution of 6-chloro-derivative 1a or 2a with amines or
ammonia to give 1e–1f and 2e–2f in good yields (58–85%,
entries 4–6, 10–12).
On the other hand, direct methoxylation of 1a–2a by reac-
tion with NaOMe in MeOH was not successful. Therefore, we
first protected the NH at position 9 by a SEM group and then
the methoxylation of 5a or 6a by MeONa proceeded quantita-
tively to give intermediates 5h and 6h. Final cleavage of
the SEM groups by TFA afforded the desired 6-methoxy-7-
deazapurines 1h and 2h in high yields (Scheme 3).
2. Results and discussion
2.1. Chemistry
The proposed synthetic approach to our target 7-arylsulfanyl-
7-deazapurines was based on recently developed direct C–H
sulfenylation12 of 6-chloro-7-deazapurine (correct IUPAC
name: 4-chloro-7H-pyrroloij2,3-d]pyrimidine) catalysed by CuI
and 4,4-di-tert-butyl bipyridine (dtbpy) under oxygen atmo-
sphere. This modified procedure (oxygen atmosphere and
dtbpy) gave better results than previously published methods
developed for related heterocycles.13 By the reaction with
diphenyldisulfide and bisIJ2-thienyl)disulfide, two modified
7-IJhet)arylsulfanyl-7-deazapurines 1a and 2a were synthesized
in excellent yield (90% or 95%) (Scheme 1). After one-pot
silylation by N,O-bisIJtrimethylsilyl)acetamide (BSA) of 1a
followed by glycosylation using commercially available
1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, in analogy to
the modified Vorbrüggen procedure,14 the desired protected
7-phenylsulfanyl-7-deazapurine ribonucleoside intermediate
3a was obtained in good yield of 49% (Scheme 1). In case of
7-thienylsulfanyl-7-deazapurine 2a, the silylation was not
completed under standard conditions and therefore 2 equiv.
of BSA were used to fully dissolve the starting material, even
though the yield of the following glycosylation to 4a was only
30%, which was still sufficient to make multigram amounts
of this key intermediate.
The target nucleoside analogues were prepared by ana-
logous modifications of 6-chloro-7-IJhet)aryl-7-deazapurine
nucleoside intermediates 3a and 4a (Scheme 4, Table 2). The
Stille coupling reactions with thienyl- or furylstannanes gave
the corresponding benzoylated 6-hetaryl-7-deazapurine nucleo-
sides 3b and 3c and 4b and 4c, whereas the coupling with
In order to synthesize a series of target 6-substituted
7-deazapurine nucleobase analogues, 6-chlorodeazapurine
intermediates 1a and 2a were modified at position 6. The
first goal was to introduce thiophene and furan substituents
(previously reported3 in cytostatic nucleosides). Since
attempted Suzuki–Miyaura cross-coupling reactions with the
corresponding thienyl- or furylboronic acids gave very low
conversions (<10%), we further focused on the Stille
Scheme 2 Reagents and conditions, A: 2-thienylSnBu3 (1.2 equiv.),
PdCl2IJPPh3)2 (5%), DMF, 100 °C, 18 h; B: 2-furylSnBu3 (1.2 equiv.),
PdCl2IJPPh3)2 (5%), DMF, 100 °C, 18 h; C: Me3Al (3 equiv.), PdIJPPh3)4
(5%), THF, 70 °C, 12 h; D: Me2NH in THF (3 equiv.), propan-2-ol, 70 °C,
24 h; E: aq. methylamine (40% [w/w]), dioxane, 120 °C, 18 h; F: aq.
ammonia (25% [w/w]), dioxane, 120 °C, 18 h.
Table 1 Yields of the transformations of 7-deazapurine bases
Product
Entry Procedure Reagent
X–
R–
(yield %)
1
2
3
4
5
6
A
B
C
D
E
F
2-ThienylSnBu3 2-Thienyl- Ph–
1b (80%)
1c (87%)
1d (73%)
1e (84%)
1f (83%)
1g (85%)
2-FurylSnBu3
Me3Al
2-Furyl-
Me–
Ph–
Ph–
Ph–
Ph–
Ph–
Me2NH
MeNH2
NH3
Me2N–
MeNH–
NH2–
7
8
9
10
11
12
A
B
C
D
E
F
2-ThienylSnBu3 2-Thienyl- 2-Thienyl- 2b (57%)
2-FurylSnBu3
Me3Al
2-Furyl-
Me–
2-Thienyl- 2c (72%)
2-Thienyl- 2d (66%)
2-Thienyl- 2e (63%)
2-Thienyl- 2f (58%)
2-Thienyl- 2g (85%)
Scheme 1 Reagents and conditions: i) RS-SR (1 equiv.), CuI (10%),
dtbpy (20%), O2, DMF, 110 °C, 18 h. ii) 1. BSA (1 or 2 equiv.), MeCN,
15 min, rt, 2. TMSOTf (2 equiv.), sugar (1 equiv.), 80 °C, 6 h.
Me2NH
MeNH2
NH3
Me2N–
MeNH–
NH2–
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trimethylaluminum afforded 6-methyl derivatives 3d and 4d.
The reactions with trimethylamine furnished 6-IJdimethylamino)-
7-deazapurine nucleosides 3e and 4e. Final Zemplén depro-
tection using sodium methoxide in methanol furnished free
6,7-disubstituted nucleosides 7b–7e and 8b–8e in 59–87%
yields (Scheme 4, Table 2). Nucleophilic substitutions of
protected nucleoside intermediate 3a or 4a with methyl-
amine, ammonia or NaOMe proceeded with concomitant
de-benzoylation to give directly unprotected 6-methylamino-,
6-amino or 6-methoxy-7-IJhet)arylsulfanyl-7-deazapurine ribo-
nucleosides 7f–7h and 8f–8h in good yields.
2.2. Biological activity profiling
Scheme
3 Reagents and conditions: i) NaH (60 wt%, 1.1 equiv.),
The in vitro cytotoxic/cytostatic activities of all final nucleo-
bases 1b–1h and 2b–2h, as well as nucleosides 7b–7h and
8b–8h, were initially evaluated against seven cell lines derived
from human solid tumors including lung (A549 cells) and
colon (HCT116 and HCT116p53−/−) carcinomas, as well as
leukemia cell lines (CCRF-CEM, CEM-DNR, K562 and
K562-TAX) and, for comparison, non-malignant BJ and MRC-5
fibroblasts. Concentrations inhibiting the cell growth by
50% (IC50) were determined using a quantitative metabolic
staining with 3-IJ4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT)15 following a 3-day treatment. In addition,
the anti-proliferative effect was tested against a human
hepatocarcinoma Hep G2, human T-lymphoblastic promyelocytic
leukemia HL-60 and cervical carcinoma HeLa S3 growing in
liquid suspension. Cell viability was determined following a
3-day incubation using 2,3-bis-IJ2-methoxy-4-nitro-5-sulfophenyl)-
2H-tetrazolium-5-carboxanilide (XTT) assay.16
SEM-Cl (1.1 equiv.), DMF, 0 °C to rt, 30 min; ii) 1 M MeONa in MeOH
(2 equiv.), acetone, rt, 18 h; iii) 1.CF3COOH, rt, 18h, 2. aq. ammonia
(25% [w/w]), rt, 18 h.
Selected results are summarized in Table 3 (for complete
data including standard deviations, see Table S1 in the ESI†).
Surprisingly, most of the nucleosides, 7 and 8, were entirely
inactive in these assays with the exception of 6-amino-7-
deazapurine nucleosides 7g and 8g showing moderate cyto-
toxic activities at >20 μM concentrations. Also none of
the 7-phenylsulfanyl-7-deazapurine bases 1b–1h exerted any
significant cytostatic activity. On the other hand, all the
7-IJ2-thienyl)sulfanyl-7-deazapurine bases bearing diverse
Scheme 4 Reagents and conditions, A: 2-thienylSnBu3 (1.2 equiv.),
PdCl2IJPPh3)2 (5%), DMF, 100 °C, 18 h; B: 2-furylSnBu3 (1.2 equiv.),
PdCl2IJPPh3)2 (5%), DMF, 100 °C, 18 h; C: Me3Al (3 equiv.), PdIJPPh3)4
(5%), THF, 70 °C, 12h; D: Me2NH in THF (3 equiv.), propan-2-ol, 70 °C,
24 h; E: aq. methylamine (40% [w/w]), dioxane, 120 °C, 18 h; F: aq.
ammonia (25% [w/w]), dioxane, 120 °C, 18 h; G: 1 M MeONa in MeOH
(1.5 equiv.), MeOH, rt, 18 h.
Table 2 Yields of the transformations of 7-deazapurine nucleosides
Procedure
Reagent
X–
R–
Product (yield %)
Deprotection product (yield %)
A
B
C
D
E
F
G
A
B
C
D
E
F
ThienylSnBu3
FurylSnBu3
Me3Al
Me2NH
MeNH2
2-Thienyl-
2-Furyl-
Me–
Me2N–
MeNH–
NH2–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
Ph–
2-Thienyl-
2-Thienyl-
2-Thienyl-
2-Thienyl-
2-Thienyl-
2-Thienyl-
2-Thienyl-
3b (72%)
3c (92%)
3d (55%)
3e (88%)
—
7b (75%)
7c (78%)
7d (87%)
7e (87%)
7f (90%)
7g (86%)
7h (75%)
8b (59%)
8c (57%)
8d (64%)
8e (65%)
8f (75%)
8g (70%)
8h (77%)
NH3
—
—
NaOMe
ThienylSnBu3
FurylSnBu3
Me3Al
Me2NH
MeNH2
MeO–
2-Thienyl-
2-Furyl-
Me–
Me2N–
MeNH–
NH2–
4b (78%)
4c (41%)
4d (67%)
4e (88%)
—
NH3
NaOMe
—
—
G
MeO–
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Table 3 Cytostatic activities of selected compounds
IC50 (μM)
A549
CCRF–CEM
CEM–DNR
HCT116
HCT116p53–
K562
K562-TAX
HepG2
HL60
HeLa S3
BJ
MRC-5
2b
2c
2d
2e
2f
2g
2h
7g
8g
16.19
11.43
>50
19.80
28.58
22.82
21.47
22.91
43.76
10.55
7.73
>50
14.63
14.72
16.68
18.23
33.96
64.66
17.67
20.83
>50
35.25
26.15
20.34
>50
13.03
6.75
5.06
5.14
4.26
13.99
3.83
4.95
17.88
>50
23.09
23.43
21.664
18.90
>50
22.14
21.00
17.92
43.95
29.62
55.77
>25
>25
>25
>25
>25
>25
>25
>25
>25
21.1
7.63
>25
>25
13.5
13.9
>25
>25
>25
>25
8.49
>25
>25
17.6
17.9
23.9
>25
>25
23.38
22.06
>150
144.56
132.24
>150
122.60
67.88
93.59
54.48
32.87
19.53
29.10
27.54
45.30
>50
>50
22.41
23.18
38.12
11.01
18.98
22.79
17.15
20.80
36.72
135.50
>150
148.21
135.71
148.13
67.70
>50
>100
138.24
substituents at position 6 showed significant cytostatic effects
at micromolar concentrations. The most active were 6-hetaryl-
(2b and 2c) and 6-methylamino and -dimethylamino (2e and
2f) derivatives having IC50 values in the low micromolar
range. Compounds 2e and 2f were non-toxic to BJ and MRC-5
fibroblasts showing a promising therapeutic index.
(Palacky University) for antimicrobial screening and Dr. Gina
Bahador and Dr. Joy Feng (Gilead Sciences, Inc.) for anti-HCV
testing.
Notes and references
Since the nucleosides 7 and 8 were inactive with the excep-
tion of moderately active adenosine analogues 7g and 8g
(thia-analogues of cytostatic 7-aryl-7-deazaadenosines4), it can
be concluded that replacement of the (het)aryl group at
position 7 by the extended (het)arylsulfanyl group is not
tolerated by the biological target(s) of the previously devel-
oped nucleoside cytostatics.3–5 Further studies will be neces-
sary to explain the significant cytostatic effect of the
7-IJthienylsulfanyl)-7-deazapurine bases which is apparently
caused by a different mechanism (presumably by kinase
inhibition).
In addition, all compounds were also tested on antiviral
activity (HCV 1B and 2A replicon and RSV), antimicrobial
activity (panel of gram-positive and gram-negative bacteria)
and antifungal activity (several strains of Candida species)
but did not show any significant activity in these assays.
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In conclusion, we have developed a facile methodology for
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This work was supported by the institutional support of the
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