Synthesis of fluorinated purine and 1-deazapurine glycosides as potential inhibitors of adenosine deaminase

Article abstract of DOI:10.1021/jo102579g

The synthesis of 2- and 6-trifluoromethylated purines and 1-deazapurines was performed by formal [3 + 3]-cyclization reactions of 5-aminoimidazoles with a set of trifluoromethyl-substituted 1,3-CCC- and 1,3-CNC-dielectrophiles. The corresponding fluorinated nucleosides were synthesized by glycosylation of 9-unsubstituted purines and 1-deazapurines with peracetylated β-ribose, β-glucose, and rhamnose and subsequent deprotection. These scaffolds can be considered as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate dehydrogenase (IMPDH) enzymes.

Full text of DOI:10.1021/jo102579g

NOTE
pubs.acs.org/joc
Synthesis of Fluorinated Purine and 1-Deazapurine Glycosides
as Potential Inhibitors of Adenosine Deaminase
Viktor O. Iaroshenko,*,†,‡ Dmytro Ostrovskyi,†,‡ Andranik Petrosyan,† Satenik Mkrtchyan,†
Alexander Villinger,† and Peter Langer*,†,§
†Institut f€ur Chemie der Universit€at Rostock, Albert-Einstein-Strasse 3a, D-18059 Rostock, Germany
‡National Taras Shevchenko University, Volodymyrska st 62., Kyiv-33, 01033, Ukraine
§Leibniz Institut f€ur Katalyse e.V. an der Universit€at Rostock, Albert-Einstein-Strasse 29a, D-18059 Rostock, Germany
S Supporting Information
b
ABSTRACT: The synthesis of 2- and 6-trifluoromethylated
purines and 1-deazapurines was performed by formal [3 þ 3]-
cyclization reactions of 5-aminoimidazoles with a set of triflu-
oromethyl-substituted 1,3-CCC- and 1,3-CNC-dielectrophiles.
The corresponding fluorinated nucleosides were synthesized by
glycosylation of 9-unsubstituted purines and 1-deazapurines with
peracetylated β-ribose, β-glucose, and rhamnose and subsequent
deprotection. These scaffolds can be considered as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate
dehydrogenase (IMPDH) enzymes.
he subject of the present paper is to report the synthesis of
novel CF3-containing purine and 1-deazapurine nucleosides
T
as a platform for the design of adenosine deaminase (ADA)
enzyme pitfalls. Deaminases are of particular interest since many
of these enzymes represent potential drug targets for the design
and synthesis of potent drugs for the treatment of various
diseases, such as HIV and cancers. Adenosine deaminase
(ADA) and RNA-specific adenosine deaminase (ADAR) play a
very important role in medicine chemistry and drug design.1 The
inhibition of these enzymes has been reported to have substantial
therapeutic potential and could be used for the treatment of
cancer and genetic disorders.1
Figure 1. Concept: 2- and 6-trifluoromethyl-containing purines and
1-deazapurines as inhibitors of adenosine deaminase (ADA).
The electron-withdrawing CF3 group in purine-like scaffolds 1
facilitates the addition of water to the 6-position of purine
(purine isosteres)6 and maintains the stability of the formed
6-hydrates 2 and 3 (Figure 1). Previously, a theoretical study has
been carried out to establish 6-CF3-substituted purine isosteres
as promising inhibitors of ADA.6 Since the CF3 group is also
isosterically close to the amino group,4,7 the modification of the
compounds, which mimic the putative transition state of ADA by
isosterical change of the amino function to a CF3 group, should
not cause a problem of substrate recognition and can be expected
to lead to enzyme inhibition (Figure 1).
In general, imidazo[4,5-b]pyridines (1-deazapurines) are an
important class of heterocyclic compounds that exhibit a wide
range of activities.2 1-Deazapurine is a common structural motif
found in numerous molecules which display antiviral, antifungal,
antibacterial, and antiproliferative activities. The potent biologi-
cal activity and the prevalence of 1-deazapurines in both natural
products and pharmaceuticals have inspired significant interest in
the synthesis of these heterocycles.3
In our opinion, purines and their isosteres bearing a perfluoro-
alkyl substituent at positions 2 and/or 6 should be also con-
sidered as potential inosine monophosphate dehydrogenase
(IMPDH) inhibitors,8a due to the possibility of covalent binding
of the Cys 331 moiety of the active side of the enzyme with the
sufficiently strong electrophilic carbon atoms C-6 and C-2 to
form stable Meisenheimer-type adducts. It was shown that, for
example, the 6-chloro-substituted purine base8 is dehalogenated
Efforts to design potent and specific inhibitors of deaminases
have been focused so far on molecules that mimic the transition
state (TS) structure. Since the TS structure most likely resembles
the hydrated intermediate, stable TS mimics containing a
hydroxyl group attached to a tetrahedral carbon, located in a
position analogous to the purine hydration site, were designed.4,5
Alternatively, substrate analogues that undergo reversible cova-
lent hydration may represent an even better strategy since the
hydrated product has higher structural similarity to the TS
structure and, therefore, would be expected to exhibit greater
potency and specificity (Figure 1).4,5
Received: December 28, 2010
Published: March 11, 2011
r
2011 American Chemical Society
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|

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NOTE
Table 1. Synthesis of 1-Deazapurine Nucleosides 14 and 15
RF
R1
14a,b
14a,d
15a,c
15a,e
a
b
c
CF3
Me
Ph
10
11
13
10
4
6
5
7
3
5
CF3
CF3
CF3
10
11
10
d
CF2Cl
Me
7
10
8
a Yields of isolated products. b Reaction was performed using 5a.
c Reaction was performed using 5b. d 5a was generated in situ from
12a. e 5b was generated in situ from 12b.
Scheme 2a
Figure 2. Retrosynthetic analysis.
Scheme 1a
a Reagents and conditions: (i) CH2Cl2, under argon, reflux, 2 h;
(ii) TFA, 20 °C, 24ꢀ72 h.
well as its acylated derivative 5b, is unstable and very difficult to
prepare.11 We have synthesized the corresponding nucleosides 5
and studied their reactions with the fluorinated 1,3-diketones 13.
Starting this investigation, we have focused on the development
of optimal reaction conditions for the pyridine ring annulation.
Unfortunately, extremely low yields were obtained using various
solvents (AcOH, CH3OH, CH3CN, H2O). The employment of
acidic catalysts, such as p-toluenesulfonic acid (PTSA), or ion-
exchange resins did not allow improved yields. The best yields of
1-deazapurine nucleosides 14 and 15 were obtained using dry
DMF and conducting the reaction under inert atmosphere.
Unfortunately, the products were isolated only in the range of
13% yield.
The main reason for the low yields lies in the fact that, in the
case of compounds 5, a Dimroth rearrangement takes place with
formation of product 16.11 We have also used a decarboxylation
reaction of 1211c,14 to generate 5 in situ in the presence of 1,3-
diketones. The reactions were carried out in absolute DMF
under argon atmosphere at 60ꢀ80 °C11b and delivered the
corresponding protected and unprotected 1-deazapurine nucleo-
sides 14 and 15 with yields in the range of 3ꢀ10% (Table 1).
With these unsatisfactory results in hand, we next focused our
attention on path B. As a source for the in situ generation of
5-aminoimidazole 8, we have used the reaction of imidate 10 with
p-methoxybenzyl amine 11. The subsequent reaction of 8 with a
number of 1,3-CCC-dielectrophiles afforded 1-deazapurines 17
in good yields (Scheme 2; Table 2). Under the mild reaction
conditions, we have succeeded in isolating the corresponding
intermediate 19 and have proved its structure by 2D NMR
methods. Hydrate 19 is relatively stable and was dehydrated
a Reagents and conditions: (i) HOAc, absolute DMSO under argon, 60
to 80 °C; (ii) absolute DMF, under argon, 60 to 80 °C.
by IMPDH and a covalent bond is formed at position C-6 with
Cys 331.
Retrosynthetically, the synthesis of our target molecules can
be achieved by two different strategies. Following the (natural)
biosynthetic pathways for the synthesis of purine nucleotides, we
have called these strategies de novo9 and salvage10 (Figure 2). The
first one is built on the regioselective electrophilic annulation of
the pyridine and pyrimidine ring on the enamine moiety of the
AIR-riboside11 using diverse fluorine-containing 1,3-CCC- and
1,3-CNC-dielectrophiles. The second strategy relies on the initial
assembly of the CF3-containing purine/1-deazapurine frame-
work starting with 5-aminoimidazole 8 which bears a p-methoxy-
benzyl (PMB) protecting group at position 9. Subsequent
deprotection and glycosylation will furnish the desired scaffolds
9 (Figure 2).
Previously, we and others have developed several new strate-
gies toward CF3- and CF2H-containing purines and purine
isosteres (Scheme 1).12,13
At the beginning of this project, we considered path A to be
more efficient and easy to perform. AIR-riboside 5a is a key
substance in the de novo purine biosynthesis. Compound 5a, as
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NOTE
Table 2. Synthesis 1-Deazapurines 17 and 18
Scheme 4a
R1
R2
17a
18a
a
b
c
CF3
Me
Ph
77
71
55
80
66
65
60
74
75
81
CF3
CF3
CF3
Me
Me
d
CF2Cl
CO2Me
e
a Yields of isolated products.
Scheme 3a
a Reagents and conditions: (i) MeOH, NH3, rt, 24 h.
a Reagents and conditions: (i) BSA (O,N-bis(trimethylsilyl)acetamide),
TMSOTf; (ii) MeOH, NH3, 20 °C, 24 h.
1-deazapurine core structures by glycosylation of 18 and 21 with
peracetylated rhamnose and β-D-glucose which deliver the
correspondent peracetylated R-L-rhamnosides 23 and 27a and
β-D-glucosides 25 and 27b. The latter compounds were treated
with a 7 M solution of ammonia in methanol to remove the acetyl
protective groups and to give the desired R-L-rhamnosides and
β-D-glucosides 24, 26, and 33 (Scheme 4; Table 4).
To better understand the structure of the products obtained,
we attempted to grow crystals of all 1-deazapurine nucleosides
suitable for X-ray diffraction analysis. The X-ray crystal structure
analysis of 26b proved that the glycosylation reaction occurred at
position 9 of the 1-deazapurine framework. The anomeric carbon
atom possesses a R-configuration (Figure 1 in Supporting
Information).16
Table 3. Synthesis of 1-Deazapurine Nucleosides 14 and 15
R1
R2
14a
15a
a
b
c
CF3
Me
Ph
61
45
67
75
77
98
99
98
99
b
CF3
CF3
CF3
Me
Me
d
e
CF2Cl
CO2Me
a Yields of isolated products. b See Scheme 5.
under acidic conditions or by prolonged reflux in CH2Cl2. The
stability of 19 supports our concept (Figure 1). Purine 21 was
prepared by inverse electron demand DielsꢀAlder reaction of 8
with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine which proceeded
smoothly to give 20. Subsequently, the PMB group was cleaved
to give 21 (Scheme 2).
As an extension of our current study, we have decided to intro-
duce a carboxylic acid group at position 6 of the 1-deazapurines
and synthesize the correspondent 9-sugar-modified derivatives.
Compound 18e was prepared from 17e and easily converted to
the desired riboside 14e, glycoside 30, and rhamnoside 32 by
direct N-glycosylation. Subsequent deprotection was carried out
with ammonia. At the same time, we observed the transformation
of the ester function into an amide, and the resulting products
proved to be 9-glycosylated 5-methyl-3H-imidazo[4,5-b]pyridine-
7-carboxamides 29, 31, and 33 (Scheme 5).
In conclusion, we have developed a new and general strategy
for the assembly of 6-CF3-1-deazapurines bearing a ribose,
rhamnose, and glucose moiety at position 9. The synthesized
scaffolds constitute a platform for the mechanism-based design
and synthesis of adenosine deaminase (ADA) and inosine
monophosphate dehydrogenase (IMPDH) enzyme inhibitors.
To obtain various 9-sugar-modified 6-CF3 purines and their
1-deaza analogues, we chose tetraacetyl-ribose 22 as a model
compound and have studied the direct glycosylation of 1-deaza-
purines 18. During the optimization, several conditions were
tried for the glycosylation. They include a diverse set of Lewis
acid catalysts (SnCl4, TiCl4, TiBr4, Me2O-BF3), base catalysts
(NaH, NaNH2, TMEDA, DBU), and solvents (CH3CN, DCM,
C6H6, toluene, 1,2-dichloroethane, DMF). The best results were
found to be the so-called silyl-HilbertꢀJohnson reaction
conditions.13ꢀ15 The glycosylations were performed in acetoni-
trile under reflux in inert atmosphere, using O,N-bis-
(trimethylsilyl)acetamide for the initial silylation of the
heterocyclic moiety. As a catalyst for the next glycosylation step,
TMSOTf was used. The deprotection of the sugar group was
carried out in a concentrated solution of ammonia in methanol to
give the correspondent unprotected ribosides 15 in quantitative
yields (Scheme 3; Table 3).
’ EXPERIMENTAL SECTION
General Procedure for the Synthesis of Compounds
14aꢀe. To a suspension of 1.33 mmol of deprotected imidazo-[4,5-b]-
pyridine (1 equiv) in 6 mL of dry acetonitrile was added 1.2 equiv of BSA
under argon atmosphere. The obtained clear solution was refluxed for 20
min and then was left to cool to room temperature. Afterward, the
solution of corresponding acetylated sugar (1.2 equiv) in dry acetonitrile
Using a previously elaborated strategy, the R-L-rhamnose and
β-D-glucose moieties can be swiftly introduced into purine and
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NOTE
Scheme 5a
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: viktor.iaroshenko@uni-rostock.de; peter.langer@
uni-rostock.de.
’ ACKNOWLEDGMENT
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for D. O.) and by the BMBF (Grant No.
03IS2081A, scholarship for habilitation of Dr. V. O. I.) is grate-
fully acknowledged.
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Table 4. Synthesis of 1-Deazapurine Nucleosides 22, 23, 24,
and 25
R1
R2
22a
23a
24a
25a
a
b
c
CF3
CF3
CF3
Me
Ph
61
45
67
96
97
97
75
79
66
95
94
93
CF3
a Yields of isolated products.
and TMSOTf (0.25 equiv) was added, and the reaction mixture was
refluxed for 2 h (until the color of the solution became yellow-orange).
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ribofuranosyl)-7-(trifluoromethyl)-5-phenyl-3H-imidazo-
[4,5-b]pyridine (14b): White oil, yield 45%, Rf (EtOAc/heptane,
1:1) = 0.55; 1H NMR (300.13 MHz, CDCl3) δ = 1.93 (s, 3H, Ac), 2.12
(s, 3H, Ac), 2.18 (s, 3H, Ac), 4.34 (dd, 1H, ꢀCH2ꢀ, J1 = 6.0 Hz, J2 = 3.0
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’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic procedures, com-
b
pound characterization, copies of NMR spectra, X-ray structure.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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