Synthesis and adenosine deaminase inhibitory activity of 3'-deoxy-1- deazaadenosines

Article abstract of DOI:10.1002/(SICI)1522-2675(19991215)82:12<2112::AID-HLCA2112>3.0.CO;2-2

New 1-deazapurine nuclcosides were synthesized by coupling 2,6-dichloro- 1-deaza-9H-purine (= 5,7-dichloro-3H-imidazo[4,5-b]pyridine) with a 3- deoxyribose derivative by the acid-catalyzed fusion method. The condensation reaction gave an anomeric mixture

Full text of DOI:10.1002/(SICI)1522-2675(19991215)82:12<2112::AID-HLCA2112>3.0.CO;2-2

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Helvetica Chimica Acta ± Vol. 82 (1999)
Synthesis and Adenosine Deaminase Inhibitory Activity of 3'-Deoxy-1-
deazaadenosines
by Rosaria Volpini, Stefano Costanzi, Sauro Vittori and Gloria Cristalli*
Dipartimento di Scienze Chimiche
and Giulio Lupidi
Á
Dipartimento di Biologia MCA, Universita di Camerino, I-62032 Camerino (MC)
Dedicated to Prof. Dr. Frank Seela on the occasion of his 60th birthday
New 1-deazapurine nucleosides were synthesized by coupling 2,6-dichloro-1-deaza-9H-purine (ˆ 5,7-
dichloro-3H-imidazo[4,5-b]pyridine) with a 3-deoxyribose derivative by the acid-catalyzed fusion method. The
condensation reaction gave an anomeric mixture of the N9-b-d- and N9-a-d-3'-deoxynucleosides, which were
treated with methanolic ammonia at room temperature to obtain the deprotected derivatives. Reaction of the b-
d-anomer with different amines gave 2-chloro-N6-substituted nucleosides, which were dechlorinated to give the
corresponding 3'-deoxy-1-deazaadenosines. Biological studies on adenosine deaminase from calf intestine
showed that the new compounds are inhibitors of the enzyme, the 3'-deoxy-1-deazaadenosine being the most
potent one with a Ki of 2.6 mm.
1. Introduction. ± 1-Deazaadenosine (c1A, I) is a nucleoside endowed with a
number of pharmacological properties: it has been shown to possess cytotoxic activity
[1], to inhibit platelet aggregation [2], and to act as an agonist of adenosine receptors
[3]. Furthermore, 1-deazaadenosine analogues exhibit good inhibitory activity against
adenosine deaminase (ADA) [4][5], an enzyme involved in the pathogenesis of the
severe combined immunodeficiency disease (SCID) [6 ± 8], and responsible for
deamination of potentially useful nucleoside-based drugs [9]. Elevated serum ADA
activity has been described in various autoimmune and inflammatory diseases,
including systemic lupus erythematosus [10].
Recently Seela et al. described the incorporation of 1-deazaadenosine into a
hammerhead ribozyme and the resulting catalytic activity [11].
In recent years, a number of 1-deazapurine nucleosides were synthesized by
coupling 5,7-dichloro-3H-imidazo[4,5-b]pyridine (1; Scheme 1) [12] with ribose, 2-
deoxyribose, and 2,3-dideoxyribose derivatives [13 ± 16]. Some of these molecules
exhibited in vitro activity against human immunodeficiency virus type-1 (HIV-1); in
particular compounds bearing an N6-cycloheptyl or a cyclooctyl ring were the most
active ones in every series, while the N6-unsubstituted derivatives proved to be good
inhibitors of adenosine deaminase (ADA).
In the present paper, we report for the first time the synthesis of a series of 1-
deazaadenosine derivatives obtained by modifying the 3'-position of the sugar moiety.
This goal was achieved by coupling 2,6-dichloro-1-deazapurine (1) with the 3-deoxy-b-
d-ribose derivative 2 to obtain the 3'-deoxy-1-deazapurine nucleosides of the general
formula II.

Helvetica Chimica Acta ± Vol. 82 (1999)
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Scheme 1
2. Results. ± 5,7-Dichloro-3H-imidazo[4,5-b]pyridine (1) [12] was treated with 1,2-
di-O-acetyl-5-O-benzoyl-3-deoxy-b-d-ribofuranose (2) [17] in the presence of a
catalytic amount of TsOH at 1608 in vacuo for 10 min. The coupling gave a mixture
of the N-3-b-d-3' and N-3-a-d-3'-deoxyribonucleosides 3 and 4 with a total yield of
81% (Scheme 1). These protected nucleosides were reacted with NH3/MeOH at room
temperature to give the compounds 5 and 8, respectively, from which the 1-
deazaadenosine derivatives 6 and 9, respectively, were obtained by treatment with
liquid NH3 at 1208 in a steel bomb (Scheme 2). Catalytic hydrogenolysis of the Cl-atom
in 6 or 9 with 10% Pd/C in absolute EtOH and in the presence of 1n NaOH afforded the
corresponding derivatives 7 and 10 (Scheme 2).
Compound 5 was also reacted with cycloheptyl amine or cyclooctylamine, at 1058
for 16 h, to provide the 5-chloro-7-(cycloheptylamino)-1-(3-deoxy-b-d-ribofuranosyl)-
3H-imidazo[4,5-b]pyridine (11), and the 5-chloro-7-(cyclooctylamino)-1-(3-deoxy-b-
d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (13), which were dechlorinated under
the above-mentioned conditions to give 12 and 14 (Scheme 3), respectively.
It is worth noting that previously reported coupling of the same sugar, 2, with 2,6-
dichloro-3-deazapurine afforded, in addition to the b-d- and a-d-anomers of the 3'-
deoxyribonucleoside, the a-anomer of the 3'-deoxyarabino-nucleoside, derived from
epimerization at C(2) of the sugar [18].
Structural Assignment. The glycosylation site and the anomeric configuration were
assigned on the basis of UV data and 1H-NMR spectra, including 1D-1H-NOE
difference spectra, of the deprotected nucleosides 5 ± 9.

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Helvetica Chimica Acta ± Vol. 82 (1999)
Scheme 2
Scheme 3
The UV spectra of nucleosides 5 and 8 as 6 and 9 were essentially identical (see Exper. Part).
An NOE at the H C(2) upon saturation of H C(1') indicated N(1) or N(3) as glycosylation site in the case
of all compounds 5 ± 9 (see Table 1).

Helvetica Chimica Acta ± Vol. 82 (1999)
2115
However, since no NOE was observed on the 7-NH2 group in compounds 6 and 9, the presence of N(1)-
regioisomers can be excluded [19][20]. This assignment was also unequivocal for the chloro compounds 5 and 8,
as the amino compounds were obtained from the chloro derivatives. Furthermore, the lack of an NOE on
H
C(5) upon irradiation of H C(1') in compound 7 confirmed N(3) as glycosylation site, excluding the
presence of N(4)-regioisomers.
Table 1. NOE Data [%] of Imidazo[4,5-b]pyridine Nucleosides in (D6)DMSO at 238
Com- Irradiated Observed NOE [%]
pound proton
5
H
H
H
H
H
H
C(1')
C(4')
C(1')
C(1')
C(1')
C(1')
H
H
H
H
H
H
C(2) (2.3), H C(2') (1.7), H C(4') (1.0), Hb C(3') (0.4)
C(2) (0.3), H C(6) (1.4), H C(1') (1.3), Hb C(3') (3.1), H C(5') (1.7), H C(5') (1.7)
C(2) (1.4), H C(2') (and H C(4')) (2.1), Ha C(3') (0.7)
C(2) (2.6), H C(2') (1.2), H C(4') (1.1), Hb C(3') (0.4)
C(2) (1.5), H C(2') (and H C(4')) (2.2), Ha C(3') (0.7)
C(2) (4.0), H C(2') (2.0), H C(4') (1.0)
8
6
9
7
The NOEs on H C(4') upon irradiation of H C(1') in compounds 5, 6, and 7 established the b-d-
configuration in all three cases; NOEs on Hb C(3') were observed in compounds 5 and 6 and not in 7. On the
other hand, irradiation of H C(1') in compounds 8 and 9 gave NOEs on Ha C(3') and none on H C(4'),
establishing the a-d-configuration [21].
Discussion. ± The new compounds 6, 7, and 11 ± 14 were evaluated as inhibitors of
adenosine deaminase from calf intestine [22], and the results are listed in Table 2. The
2'-deoxy-1-deazaadenosine (16) and the corresponding 2-Cl derivative 15 were
reported as reference compounds [14 ± 16]. The results show that none of the tested
compounds were substrates of the enzyme, and the 3'-deoxy-1-deazaadenosine (7),
although less potent than the corresponding 2'-deoxy derivative 16 (Ki ˆ 0.19 mm), was
still a good ADA inhibitor with a Ki of 2.6 mm. The presence of a Cl-atom at C(2) of 1-
deazapurine produced a decrease of activity (7, Ki ˆ 2.6 mm vs. 6, Ki ˆ 35 mm) compared
to 2'-deoxy-1-deazaadenosines 16 and 15 (Table 2) and the corresponding ribose- and
2',3'-dideoxyribose derivatives [16]. As expected, substitution at N(6) with bulky and
hydrophobic cycloalkyl rings brought about a relevant decrease of ADA inhibitory
activity (11 ± 14, Ki from 38 to 115 mm). In these cases, the Cl-atom at C(2) does not
significantly affect the activity. All these findings are in agreement with our previous
hypothesis of a direct interaction of the 1-deazaadenosine derivatives with the catalytic
site of the enzyme, involving 6-NH2 group as a H-bond donor [16]. Studies on human
immunodeficiency virus type-1 (HIV-1) are in progress and will be reported elsewhere.
Experimental Part
General. TLC: precoated TLC plates with silica gel 60 F-254 (Merck). FC: silica gel 60 (Merck). M.p.:
Büchi apparatus; uncorrected. UV Spectra: Perkin-Elmer Coleman 575 spectrophotometer. 1H-NMR Spectra:
Varian VXR 300-MHz spectrometer; d in ppm, J in Hz. Elemental analyses were determined on a Carlo Erba
model 1106 analyser, exper. values within Æ0.4% of calc. values.
Glycosylation of 5,7-Dichloro-3H-imidazo[4,5-b]pyridine (1) with 1,2-O-Diacetyl-5-O-benzoyl-3-deoxy-b-
d-ribofuranose (2). An intimate mixture of 1 [12] (100 mg, 0.53 mmol), 2 [17] (342 mg, 1.06 mmol), and TsOH
(cat. amount) was heated at 1608; when the fusion started, vacuum from a water aspirator (25 nm) was applied
until bubbling ceased (5 ± 10 min). The resulting solid was submitted to FC (silica gel; cyclohexane AcOEt

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Helvetica Chimica Acta ± Vol. 82 (1999)
Table 2. ADA Inhibitory Activity of 1-Deazapurine Nucleosides
Compound
R
R1
Ki [mm]
6
7
1
12
13
14
15
16
H
H
cC7H13
cC7H13
cC8H15
cC8H15
Cl
H
Cl
H
Cl
H
Cl
H
35
2.6
115
93
38
89
23
0.19
70 :30) to obtain a mixture of the two nucleosides 3 and 4 (195 mg; 81%). Anal. samples of 3 and 4 were
obtained as amorphous solids by separating the mixture on prep. TLC (CHCl3/MeOH 98 :2).
3-(2-O-Acetyl-5-O-benzoyl-3-deoxy-b-d-ribofuranosyl)-5,7-dichloro-3H-imidazo[4,5-b]pyridine (3): Yield
1
52%. H-NMR ((D6)DMSO): 2.13 (s, MeCO); 2.28 ± 2.42 (m, 1 H C(3')); 2.72 ± 2.89 (m, 1 H C(3')); 4.40 ±
4.78 (m, 2 H C(5'), H C(4')); 5.79 (d, J ˆ 6.7, H C(2')); 6.27 (s, H C(1')); 7.53 ± 7.43 (m, 2 arom. H); 7.69 ±
7.60 (m, 1 arom. H); 7.70 (s, H C(6)); 7.80 ± 7.88 (m, 2 arom H); 8.77 (s, H C(2)). Anal calc. for
C20H17Cl2N3O5 (450.27): C 53.35, H 3.81, N 9.33; found: C 53.50, H 3.92, N 9.12.
3-(2-O-Acetyl-5-O-benzoyl-3-deoxy-a-d-ribofuranosyl)-5,7-dichloro-3H-imidazo[4,5-b]pyridine (4): Yield
1
29%. H-NMR ((D6)DMSO): 1.78 (s, MeCO); 2.42 ± 2.58 (m, 2 H C(3')); 4.38 ± 4.54 (m, 2 H C(5')); 4.97 ±
5.09 (m, H C(4')); 5.59 ± 5.70 (m, H C(2')); 6.69 (d, J ˆ 4.8, H C(1')); 7.42 ± 7.60 (m, 3 arom. H); 7.71 (s,
H
C(6); 7.99 ± 8.10 (m, 2 arom. H); 8.76 (s, H C(2)). Anal calc. for C20H17Cl2N3O5 (450.27): C 53.35, H 3.81,
N 9.33; found: C 53.55, H 4.03, N 9.17.
5,7-Dichloro-3-(3-deoxy-b-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (5) and 5,7-Dichloro-3-(3-deoxy-
a-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (8). To the mixture 3/4 (526 mg, 1.17 mmol) was added MeOH
sat. at 08 with NH3 (30 ml), and the mixture was allowed to stand at r.t. for 16 h. After evaporation, the residue
was separated by FC (CHCl3/MeOH 98 :2) to obtain 5 (198 mg, 56%) and 8 (102 mg, 29%) as white solids.
Data of 5: M.p. 164 ± 1658. UV (EtOH): 260 (9800), 287 (15500). 1H-NMR ((D6)DMSO): 1.75 ± 2.00 (m,
1 H C(3')); 2.17 ± 2.36 (m, 1 H C(3')); 3.49 ± 3.66 (m, 1 H C(5')); 3.68 ± 3.83 (m, 1 H C(5')); 4.35 ± 4.50 (m,
H
C(4')); 4.53 ± 4.64 (m, H C(2')); 6.00 (s, H C(1')); 7.70 (s, H C(6)); 8.89 (s, H C(2)). Anal. calc. for
C11H11Cl2N3O3 (304.13): C 43.44, H 3.65, N 13.82; found: C 43.55, H 3.70, N 13.71.
1
Data of 8: M.p. 182 ± 1838. UV (EtOH): 260 (6600), 287 (9800). H-NMR ((D6)DMSO): 2.04 ± 2.29 (m,
2 H C(3')); 3.38 ± 3.63 (m, 2 H C(5')); 4.49 ± 4.64 (m, H C(4'), H C(2')); 6.33 (d, J ˆ 4.4, H C(1')); 7.68 (s,
H
C(6)); 8.61 (s, H C(2)). Anal. calc. for C11H11Cl2N3O3 (304.13): C 43.44, H 3.65, N 13.82; found: C 43.48,
H 3.72, N 13.70.
7-Amino-5-chloro-3-(3-deoxy-b-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (6) and 7-Amino-5-chloro-3-
(3-deoxy-a-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (9). To compound 5 or 8 (100 mg, 0.33 mmol) liq. NH3
(10 ml) was added, and the mixture was heated in a steel bomb at 1208 for 12 h. After evaporation of the NH3,
the residue was chromatographed (silica gel; CHCl3/MeOH 92 :8) to obtain 6 (48 mg, 52%) or 9 (46 mg, 49%),
as chromatographically pure solids.
Data of 6: M.p. 204 ± 2058. UV (EtOH): 266 (19600). 1H-NMR ((D6)DMSO): 1.85 ± 1.98 (m, 1 H C(3'));
2.17 ± 2.33 (m, 1 H C(3')); 3.47 ± 3.59 (m, 1 H C(5')); 3.62 ± 3.78 (m, 1 H C(5')); 4.29 ± 4.40 (m, H C(4'));
4.50 ± 4.60 (m, H C(2')); 5.85 (d, J ˆ 1.5, H C(1')); 6.39 (s, H C(6)); 6.79 (br. s, NH2); 8.34 (s, H C(2)).
Anal. calc. for C11H13ClN4O3 (284.70): C 46.41, H 4.60, N 19.68; found: C 46.50, H 4.71, N 19.61.

Helvetica Chimica Acta ± Vol. 82 (1999)
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Data of 9: M.p. 189 ± 1918. UV (EtOH): 265 (14300). 1H-NMR ((D6)DMSO): 2.02 ± 2.26 (m, 2 H C(3'));
3.38 ± 3.60 (m, 2 H C(5')); 4.40 ± 4.55 (m, H C(4'), H C(2')); 6.18 (d, J ˆ 4.3, H C(1')); 6.38 (s, H C(6));
6.76 (br. s, NH2); 8.12 (s, H C(2)). Anal. calc. for C11H13ClN4O3 (284.70): C 46.41, H 4.60, N 19.68; found:
C 46.53, H 4.69, N 19.62.
7-Amino-3-(3-deoxy-b-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (7) and 7-Amino-3-(3-deoxy-a-d-ri-
bofuranosyl)-3H-imidazo[4,5-b]pyridine (10). To compound 6 or 9 (30 mg, 0.11 mmol) in abs. EtOH (10 ml), 1n
NaOH (1 ml) and a cat. amount of 10% Pd/C were added. The mixture was hydrogenated at 40 psi for 6 h. The
catalyst was removed by filtration and the filtrate evaporated. Purification by FC (CHCl3/MeOH 94 :6) gave 7
(20 mg, 73%) or 10 (16 mg, 55%) as colorless solids.
1
Data of 7: M.p. 183 ± 1858. UV (H2O): 262 (17000). H-NMR ((D6)DMSO): 1.87 ± 2.03 (m, 1 H C(3'));
2.18 ± 2.36 (m, 1 H C(3')); 3.42 ± 3.58 (m, 1 H C(5')); 3.62 ± 3.77 (m, 1 H C(5')); 4.27 ± 4.42 (m, H C(4'));
4.57 ± 4.70 (m, H C(2')); 5.87 (d, J ˆ 2.9, H C(1')); 6.32 ± 6.48 (m, H C(6), NH2); 7.80 (d, J ˆ 5.5, H C(5));
8.27 (s, H C(2)). Anal. calc. for C11H14N4O3 (250.25): C 52.79, H 5.64, N 22.39; found: C 52.91, H 5.70, N 22.22.
Data of 10: M.p. 177 ± 1798. UV (H2O): 261 (13400). 1H-NMR ((D6)DMSO): 2.02 ± 2.25 (m, 2 H C(3'));
3.32 ± 3.62 (m, 2 H C(5')); 4.38 ± 4.56 (m, H C(4'), H C(2')); 6.23 ± 6.40 (m, H C(1'), H C(6), NH2); 7.80
(d, J ˆ 5.3, H C(5)); 8.10 (s, H C(2)). Anal. calc. for C11H14N4O3 (250.25): C 52.79, H 5.64, N 22.39; found:
C 52.88, H 5.68, N 22.18.
5-Chloro-(cycloheptylamino)-3-(3-deoxy-b-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (11) and 5-
Chloro-7-(cyclooctylamino)-3-(3-deoxy-b-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (13). To
5 (125 mg,
0.41 mmol), cycloheptylamine or cyclooctylamine (10 ml) was added, and the mixture was heated at 1058 for
16 h. The excess amine was evaporated and the residue purified by FC (CHCl3/MeOH 99 :1) to give colorless
solids which were crystallized from Et2O to yield 11 (115 mg, 73%) and 13 (122 mg, 76%).
Data of 11: M.p. 140 ± 1428. UV (EtOH): 271 (16000), 286 (15200). 1H-NMR ((D6)DMSO): 1.40 ± 1.75 (m,
10 cycloheptyl H); 1.82 ± 2.01 (m, 2 cycloheptyl H) 1 H C(3')); 2.16 ± 2.32 (m, 1 H C(3')); 3.46 ± 3.59 (m,
1 H C(5')); 3.62 ± 3.77 (m, 1 H C(5')); 3.98 ± 4.22 (m, 1 cycloheptyl H); 4.28 ± 4.42 (m, H C(4')); 4.47 ± 4.59
(m, H C(2')); 5.85 (s, H C(1')); 6.35 (s, H C(6)); 6.93 (d, J ˆ 8.4, NH2); 8.35 (s, H C(2)). Anal. calc. for
C18H25ClN4O3 (380.87): C 56.76, H 6.62, N 14.71; found: C 56.88, H 6.79, N 14.60.
Data of 13: M.p. 131 ± 1328. UV (EtOH): 271 (20100), 286 (19200). 1H-NMR ((D6)DMSO): 1.43 ± 1.99 (m,
14 cyclooctyl H, 1 H C(3')); 2.16 ± 2.32 (m, 1 H C(3')); 3.45 ± 3.60 (m, 1 H C(5')); 3.64 ± 3.79 (m,
1 H C(5')); 4.01 ± 4.26 (m, 1 cyclooctyl H); 4.29 ± 4.42 (m, H C(4')); 4.48 ± 4.61 (m, H C(2')); 5.86 (s,
H
C(1')); 6.36 (s, H C(6)); 6.95 (d, J ˆ 8.4, NH2); 8.36 (s, H C(2)). Anal. calc. for C19H27ClN4O3 (394.90):
C 57.79, H 6.89, N 14.19; found: C 57.91, H 6.97, N 14.28.
7-(Cycloheptylamino)-3-(3-deoxy-b-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (12) and 7-(Cyclooctyla-
mino)-3-(3-deoxy-a-d-ribofuranosyl)-3H-imidazo[4,5-b]pyridine (14). As described for 6 or 9, with 11 or 13
(0.17 mmol), abs. EtOH (15 ml), 1n NaOH (2 ml) and a cat. amount of 10% Pd/C. Purification by FC (CHCl3/
MeOH 99 :1) gave 12 (36 mg, 59%) or 14 (38 mg, 65%), both as colorless solids.
Data of 12: M.p. 140 ± 1428. UV (EtOH): 267 (12100), 288 (14500). 1H-NMR ((D6)DMSO): 1.40 ± 1.79 (m,
10 cycloheptyl H); 1.81 ± 2.10 (m, 2 cycloheptyl H, 1 H C(3')); 2.19 ± 2.39 (m, 1 H C(3')); 3.43 ± 3.60 (m,
1 H C(5')); 3.62 ± 3.80 (m, 1 H C(5')); 3.92 ± 4.15 (m, 1 cycloheptyl H); 4.27 ± 4.46 (m, H C(4')); 4.56 ± 4.71
(m, H C(2')); 5.89 (s, H C(1')); 6.34 (d, J ˆ 4.6, H C(6)); 6.49 (d, J ˆ 8.5, NH2); 7.87 (d, J ˆ 4.6, H C(5));
8.30 (s, H C(2)). Anal. calc. for C18H26N4O3 (346.42): C 62.41, H 7.56, N 16.17; found: C 62.58, H 7.77, N 16.01.
Data of 14: M.p. 136 ± 1378. UV (EtOH): 267 (15000), 288 (18000). 1H-NMR ((D6)DMSO): 1.48 ± 2.06 (m,
14 cyclooctyl H, 1 H C(3')); 2.16 ± 2.36 (m, 1 H C(3')); 3.42 ± 3.59 (m, 1 H C(5')); 3.62 ± 3.79 (m,
1 H C(5')); 3.98 ± 4.22 (m, 1 cyclooctyl H); 4.28 ± 4.34 (m, H C(4')); 4.55 ± 4.71 (m, H C(2')); 5.88 (s,
H
C(1')); 6.34 (d, J ˆ 4.5, H C(6)); 6.48 (d, J ˆ 8.5, NH2); 7.86 (d, J ˆ 4.5, H C(5)); 8.29 (s, H C(2)). Anal.
calc. for C19H28N4O3 (360.45): C 63.31, H 7.83, N 15.54; found: C 63.42, H 7.94, N 15.25.
Enzyme Assay. The method used for determination of the activity against ADA has been described in a
preceding paper [22].
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Received August 11, 1999