3'-deoxyribofuranose derivatives of 1-deaza and 3-deaza-adenosine and their activity as adenosine deaminase inhibitors.

Article abstract of DOI:10.1081/NCN-100002486

2,6-Dichloro-1-deazapurine and 2,6-dichloro-3-deazapurine were coupled with 1,2-O-diacetyl-5-O-benzoyl-3-deoxy-beta-D-ribofuranose. Deprotection of the obtained compounds and reaction with liquid ammonia gave the desired 2-chloroadenine nucleosides, which were dechlorinated to afford the corresponding 1-deaza and 3-deazaadenosine derivatives. Biological studies performed on ADA from calf intestine showed that these new nucleosides are inhibitors of the enzyme.

Full text of DOI:10.1081/NCN-100002486

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3′-DEOXYRIBOFURANOSE DERIVATIVES OF 1-DEAZA
AND 3-DEAZA-ADENOSINE AND THEIR ACTIVITY AS
ADENOSINE DEAMINASE INHIBITORS
S. Costanzi , C. Lambertucci , R. Volpini , S. Vittori , G. Lupidi a & G. Cristalli
a Dipartimento di Biologia M.C.A. , University of Camerino , Camerino, I-62032, Italy
Published online: 07 Feb 2007.
To cite this article: S. Costanzi , C. Lambertucci , R. Volpini , S. Vittori , G. Lupidi & G. Cristalli (2001) 3′-
DEOXYRIBOFURANOSE DERIVATIVES OF 1-DEAZA AND 3-DEAZA-ADENOSINE AND THEIR ACTIVITY AS ADENOSINE DEAMINASE
INHIBITORS, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1037-1041, DOI: 10.1081/NCN-100002486
To link to this article: http://dx.doi.org/10.1081/NCN-100002486
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1037–1041 (2001)
3ꢀ-DEOXYRIBOFURANOSE DERIVATIVES OF
1-DEAZA AND 3-DEAZA-ADENOSINE AND
THEIR ACTIVITY AS ADENOSINE
DEAMINASE INHIBITORS
S. Costanzi,1 C. Lambertucci,1 R. Volpini,1 S. Vittori,1
G. Lupidi,2 and G. Cristalli1,∗
1Dipartimento di Scienze Chimiche, via S. Agostino 1, Italy
2Dipartimento di Biologia M.C.A., University of Camerino,
I-62032, Camerino, Italy
ABSTRACT
2,6-Dichloro-1-deazapurine and 2,6-dichloro-3-deazapurine were coupled
with 1,2-O-diacetyl-5-O-benzoyl-3-deoxy-β-D-ribofuranose. Deprotection of
the obtained compounds and reaction with liquid ammonia gave the desired
2-chloroadenine nucleosides, which were dechlorinated to afford the corre-
sponding 1-deaza and 3-deazaadenosine derivatives. Biological studies per-
formed on ADA from calf intestine showed that these new nucleosides are
inhibitors of the enzyme.
INTRODUCTION
Adenosine deaminase (ADA) is an important catabolic enzyme, which con-
verts adenosine and deoxyadenosine to inosine and deoxyinosine, respectively.
Moreover ADA is involved in the pathogenesis of the Severe Combined Immuno-
deficiency Disease (SCID) and is responsible for deamination of potentially useful
drugs with a nucleosidic structure. Elevated serum ADA activity has been de-
scribed in various autoimmune and inflammatory diseases, including Systemic
Lupus Erythematosus (SLE) (1).
∗Corresponding author.
1037
ꢀ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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COSTANZI ET AL.
Modifications of the purine moiety or/and substitution of the sugar moiety of
adenosine with aliphatic chains led to derivatives with good ADA inhibitory activity
(2). We reported in previous papers that 1-deazaadenosine analogues exhibit good
inhibitory activity on ADA from several sources. In this research, we compared
coupling of 2,6-dichloro-1-deazapurine or 3-deazapurine with 1,2-O-diacetyl-5-
O-benzoyl-3-deoxy-β-D-ribofuranose and evaluated the obtained compounds as
ADA inhibitors.
CHEMISTRY
Couplingof2,6-dichloro-1-deazapurine(1)with1,2-O-diacetyl-5-O-benzoyl-
3-deoxy-β-D-ribofuranose (2), using tin tetrachloride as the acidic-catalyst, yielded
only the β-anomer 3 (Scheme 1).
Deprotection with methanolic ammonia gave the the dichloro-1-deazanucleo-
side 5. On the other hand, coupling of compounds 1 and 2 using the fusion method
yielded a mixture of β- and α-anomers as shown in Scheme 1.
Room temperature standing of the protected compounds with methanolic
ammonia gave the corresponding dichloro-1-deazanucleosides 5 and 6 (3,4).
In the case of 2,6-dichloro-3-deazapurine (7), coupling with sugar 2 in the
presence of tin tetrachloride gave the β-anomer 8 in low yield. Deprotection with
methanolic ammonia afforded the dichloro-1-deazanucleoside 12. 2,6-Dichloro-3-
deazapurine (7) was also coupled with 2 under fusion reaction conditions as shown
in Scheme 2 (5).
The glycosylation site and the anomeric configuration were assigned on the
1
1
basis of UV data and H NMR spectra, including 1D H NOE difference spec-
tra, of the deprotected nucleosides 12–15, obtained by treating compounds 8–11
with methanolic ammonia at room temperature. In a previous work we isolated,
Scheme 1.

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DERIVATIVES OF 1-DEAZA AND 3-DEAZA-ADENOSINE
1039
Scheme 2.
besides the N(9)-β- and the N(9)-α-3ꢁ-deoxyribonucleosides 12 and 13, also the
N(9)-α-3ꢁ-deoxyarabinonucleoside 15 (5). Now with further studies we also iden-
tified the N(9)-β-3ꢁ-deoxyarabino derivative 14.
The UV spectra of the four nucleosides were practically identical. Satura-
tion of H-C(1ꢁ) resulted in a NOE at the H-C(8) and H-C(3) signals in all four
cases. The latter excludes without any doubt N(7) as glycosylation site. NOE at
the H-C(4ꢁ) upon saturation of H-C(1ꢁ) of 12 established the β configuration. In
the case of 14, saturation of H-C(1ꢁ) gave a strong NOE at the H-C(2ꢁ) signal
but not at the H-C(4ꢁ) one. This is probably due to the distortion induced in the
sugar moiety by the different position of the OH-C(2ꢁ). NOE at the Ha-C(3ꢁ) upon
saturation of H-C(1ꢁ) of 13 and 15 established the α configuration. The epimer-
ization at C(2ꢁ) of nucleosides 14 and 15 has been demonstrated by the NOE
observed at the Hb-C(3ꢁ) signal upon saturation of either H-C(2ꢁ) or H-C(4ꢁ). This
result confirmed that the three protons are located on the same side of the sugar
ring.
Reaction of compounds 5 and 12 with liquid ammonia at 130◦C gave the nu-
cleosides 16 and 18, which were dechlorinated by catalytic hydrogenolysis to obtain
the corresponding 3ꢁ-deoxy-1-deazaadenosine (17) and 3ꢁ-deoxy-3-deazaadenosine
(19) as shown in Scheme 3. The same procedure could be utilized in order to intro-
duce different amines in 6 position of these molecules.

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COSTANZI ET AL.
Scheme 3.
Table 1. ADA Inhibitory Activity of 1-deaza and 3-deaza Adenosines
Cpd.
X
Y
Z
R
R1
Ki (µM)
Ia
Ib
Ic
Id
16
17
CH
CH
CH
CH
CH
CH
N
Cl
H
Cl
H
Cl
H
OH
OH
H
H
OH
OH
OH
OH
OH
OH
H
30
0.38
23
0.19
>100
2.5
N
N
N
N
N
H
IIa
IIb
IIc
18
N
N
N
N
N
CH
CH
CH
CH
CH
Cl
H
Cl
Cl
H
OH
OH
H
OH
OH
OH
OH
OH
H
37
400
61
152
411
19
H
RESULTS
The3ꢁ-deoxy-1-deazaadenosines(16and17)and3ꢁ-deoxy-3-deazaadenosines
(18 and 19) were tested for their ability to inhibit calf intestine ADA (6). In Table 1
the activity of these compounds is compared to that of the corresponding ribose
and 2ꢁ-deoxyribose derivatives.
2ꢁ-Deoxy-1-deazaadenosine (Id, Ki = 0.19 µM) proved to be the most potent
compound of the series, and it resulted more active than 1-deazaadenosine itself (Ib,
Ki = 0.38 µM). The 3-deaza derivatives are still inhibitors of the enzyme although
always less potent than the corresponding 1-deaza analogues.
It is interesting to note that in the case of the 1-deaza nucleosides the presence
of a chlorine atom on C(2) produces a decrease in the ADA inhibitory activity (Ib,
Ki = 0.38 µM vs Ia, Ki = 30 µM), while in the case of the 3-deaza analogues
the same substitution leads to more potent compounds (IIb, Ki = 400 µM vs IIa,
Ki = 37 µM).

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1041
ACKNOWLEDGMENTS
Work supported by the Italian Ministry of Research (Grant n. 9905155535,
1999) and University of Camerino (Fondo di Ricerca d’Ateneo).
REFERENCES
1. Cristalli, G.; Costanzi, S.; Lambertucci, C.; Lupidi, G.; Vittori, S.; Volpini, R.;
Camaioni, E. Med. Res. Rev., in press.
2. Cristalli, G.; Eleuteri, A.; Vittori, S.; Volpini, R.; Camaioni, E.; Lupidi, G. Drug. Dev.
Res., 1993, 28, 253–258.
3. Vittori, S.; Camaioni, E.; Costanzi, S.; Volpini, R.; Cristalli, G. Nucleosides &
Nucleotides, 1999, 18, 587–590.
4. Volpini, R.; Costanzi, S.; Vittori, S.; Cristalli, G.; Lupidi, G. Helv. Chim. Acta, 1999,
82, 2112–2118.
5. Volpini, R.; Camaioni, E.; Costanzi, S.; Vittori, S.; Cristalli, G. Helv. Chim. Acta, 1998,
81, 2326–2331.
6. Lupidi, G.; Cristalli, G.; Marmocchi, F.; Riva, F.; Grifantini, M. J. Enzyme Inhib.,
1985, 31, 1179–1183.

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