Cytostatic and antiviral 6-arylpurine ribonucleosides IX. Synthesis and evaluation of 6-substituted 3-deazapurine ribonucleosides

Article abstract of DOI:10.1135/cccc20080665

A series of 3-deazapurine ribonucleosides 5a-51 bearing diverse C-substituents (alkyl, aryl and heteroaryl) in the position 6 were prepared by Pd-catalyzed cross-coupling reactions of either free 6-chloro-3-deazapurine ribonucleoside 4 or its acetyl protected congener 3 followed by deprotection. An improved synthesis of the starting 4-chloro-1-(2,3,5-tri-O-acetyl-β-D- ribofuranosyl)-1H-imidazo[4,5-c]pyridine (3) was developed by the application of Vorbruggen glycosylation of silylated nucleobase with 1,2,3,5-tetra-O-acetyl- β-D-ribofuranose (2). None of compounds 5a-51 showed any considerable cytostatic or antiviral activity.

Full text of DOI:10.1135/cccc20080665

Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
665
CYTOSTATIC AND ANTIVIRAL 6-ARYLPURINE RIBONUCLEOSIDES IX.+
SYNTHESIS AND EVALUATION OF 6-SUBSTITUTED 3-DEAZAPURINE
RIBONUCLEOSIDES
1,
Petr NAUŠ, Martin KUCHAŘ and Michal HOCEK *
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.,
Gilead Sciences & IOCB Research Center, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic;
1
e-mail: hocek@uochb.cas.cz
Received Jun e 5, 2008
Accepted Jun e 30, 2008
Publish ed on lin e July 25, 2008
Dedicated to the memory of Professor Otto Exner.
A series of 3-deazapurin e ribon ucleosides 5a–5l bearin g diverse C-substituen ts (alkyl, aryl
an d h eteroaryl) in th e position 6 were prepared by Pd-catalyzed cross-couplin g reaction s of
eith er free 6-ch loro-3-deazapurin e ribon ucleoside 4 or its acetyl protected con gen er 3 fol-
lowed by deprotection . An im proved syn th esis of th e startin g 4-ch loro-1-(2,3,5-tri-O-acetyl-
β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (3) was developed by th e application of
Vorbrüggen glycosylation of silylated n ucleobase with 1,2,3,5-tetra-O-acetyl-β-D-ribofuran ose
(2). Non e of com poun ds 5a–5l sh owed an y con siderable cytostatic or an tiviral activity.
Keyw ord s: Purin es; Im idazo[4,5-c]pyridin es; 3-Deazapurin es; Nucleosides; Glycosidation s;
Cross-couplin g reaction s; Cytostatic activity.
Purin e n ucleosides bearin g aryl or h etaryl substituen ts in position 6 are
cytostatic1. Moreover, som e 6-h etarylpurin e ribon ucleosides also exert
stron g an ti-HCV activities2. However, th e cytotoxic or cytostatic side effect
preven ts clin ical application s as an ti-HCV drugs. Th erefore, in order to
ach ieve selective in h ibition of HCV RNA polym erase, som e addition al
m odification s were pursued. From th e previous studies on sugar-m odified
derivatives it is kn own 2′- an d 5′-deoxyribon ucleosides3, 3′-deoxyribo-
n ucleosides4, as well as 2′-C-m eth ylribon ucleosides5 of th e 6-aryl- or 6-h et-
arylpurin e series are all in active, wh ile som e carbocyclic h om on ucleosides
+ For Part VIII, see ref.4
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© 2008 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20080665

666
Nauš, Kuchař, Hocek:
were reported6 to still exert som e cytostatic effects. Very recen tly, som e
L-ribon ucleosides were foun d7 to exert weak an ti-HCV effect in replicon
assay but th eir triph osph ates did n ot in h ibit HCV RNA polym erase. Also
m odification s of purin e rin g h ave been pursued to sh ow th at m ost
2-substituted8 an d 8-substituted9 6-arylpurin e ribon ucleosides were in ac-
tive, wh ile som e 6-aryl-1-deazapurin e n ucleosides10 still exerted som e activ-
ities. Th is sh ows th at th e N-1 n itrogen is n ot crucial for th e in teraction of
th ese com poun ds with th e target biological system (presum ably RNA poly-
m erase an d th e com plem en tary n ucleobase). Th erefore th e n ext logical step
was to look in to th e role of N-3 n itrogen wh ich does n ot m ake H-bon ds
with th e com plem en tary pyrim idin e n ucleobase durin g biosyn th esis of
RNA but is respon sible for crucial m in or groove in teraction s in th e active
site of th e polym erase. In th is paper we report on th e syn th esis an d evalua-
tion of cytostatic an d an ti-HCV activity of n ovel 6-aryl-3-deazapurin e
ribon ucleosides. Takin g in to accoun t also kn own cytostatic activities of
6-m eth ylpurin e11 an d recen tly reported 6-cyclopropylpurin e ribon ucleo-
sides12, th e series of 6-aryl an d h etaryl derivatives was also com plem en ted
by exam ples of 6-alkyl-3-deazapurin e n ucleosides.
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
667
3-Deazaaden osin e (c3A, 4-am in oim idazo[4,5-c]pyridin e) an d its an alogues
are substrates an d poten t in h ibitors of S-aden osyl-L-h om ocystein e h ydro-
lase13 an d subsequen t perturbation of tran sm eth ylation reaction s is at least
partly respon sible for th eir diverse biological effects. Th ese com poun ds
exert an tiviral14, cytotoxic15, tuberculostatic16 im m un osuppressive an d
an tiin flam m atory properties17. No 3-deazapurin e bearin g a C-substituen t in
position 6 was reported to th e best of our kn owledge.
RESULTS AND DISCUSSION
At first we h ad to prepare eith er protected or free 6-ch loro-3-deazapurin e
riboside in term ediates as startin g com poun ds for Pd-catalyzed cross-
couplin g reaction s with aryl(h etaryl)organ om etallics an d boron ic acids. To
our surprise all th e kn own syn th eses of th ese n ucleosides based on
glycosylation of 6-ch loro-3-deazapurin e 1 rely eith er on m ercury salt
m eth od18 or fusion m eth od19 both sufferin g from low overall yield, n eed
for excess of glycosyl com pon en t, com plicated separation from by-products
an d possible con tam in ation by m ercury salts. Th erefore we were attracted
by th e application of th e Hilbert–Joh n son reaction perform ed un der
Vorbrüggen con dition s20 as th is approach was recen tly successfully em -
ployed for 3,6-difluoro-3-deazapurin e21. Th us 4-ch loroim idazo[4,5-c]-
pyridin e22 (1) was silylated by treatm en t with BSA in aceton itrile an d th en
reacted with 1,2,3,5-tetra-O-acetyl-β-D-ribofuran ose (2) in presen ce of
TMSOTf at 80 °C for 1 h to afford th e desired crystallin e acetylated
n ucleoside 3 in 89% yield (Sch em e 1). Deprotection of 3 by treatm en t with
m eth an olic am m on ia at room tem perature for 24 h afforded desired free
n ucleoside 4 in 86% yield after crystallization .
SCHEME 1
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Nauš, Kuchař, Hocek:
TABLE I
Suzuki–Miyaura reaction of ch loride 4 with boron ic acids un der Sh augh n essy con dition s
Reaction
tim e, h
Cross-Couplin g
Product (yield)
R′-B(OH)2
En try
1
R
3
3
5a (92%)
5b (88%)
2
3
4
3
2
5c (90%)
5d (72%)
5
6
2
5e (78%)
5f (50%)
24
7
15
5g (61%)
8a
24
20
5h (10%)a
5i (96%)
9
a
82% of startin g m aterial 4 recovered.
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
669
With startin g com poun ds in h an ds we h ave perform ed cross-couplin g re-
action s leadin g to our desired 6-substituted derivatives. At first, we at-
tem pted aqueous Suzuki–Miyaura reaction s of free ribon ucleoside 4 un der
th e Sh augh n essy con dition s23,24. Th e treatm en t of 6-ch loro-3-deazapurin e
riboside 4 with diverse aryl- or h etarylboron ic acids in th e presen ce of
Pd(OAc)2, TPPTS, an d Na2CO3 in H2O–CH3CN (2:1) at 100 °C provided de-
sired 6-aryl(h etaryl)-3-deazapurin e ribosides 5a–5i (Table I). Th e reaction s
proceeded sm ooth ly an d clean ly for ph en yl-, 3-pyridyl- an d for 2- an d 3-
furyl- an d th ien ylboron ic acids, providin g th e desired products in h igh
yields (en tries 1–5, 9). For 2-pyrrolyl an d 3-pyrrolyl th e isolated yields of
products 5f an d 5g were on ly m oderate (en tries 6, 7), but all startin g ch lo-
ride 4 was always fully con sum ed in dicatin g possible partial decom position
of products 5f an d 5g un der reaction con dition s. It sh ould be also n oted,
th at N-protectin g groups in both startin g pyrrolylboron ic acids were sim ul-
tan eously rem oved un der th e con dition s of couplin g (BOC for 2-pyrrolyl
an d triisopropylsilyl for 3-pyrrolyl). Th e reaction of 4 with 1H-pyrazole-
5-boron ic acid was very sluggish givin g product 5h (en try 8) in on ly 10%
yield after crystallization an d 82% of startin g ch loride 4 was recovered.
Wh ile th e attem pts to in troduce sim ilarly m eth yl an d eth yl substituen ts
by Suzuki reaction of 4 with correspon din g alkylboron ic acids un der above
m en tion ed con dition s failed (in th e case of m eth yl on ly trace of th e prod-
uct was obtain ed an d for eth yl n o reaction was observed) we turn ed to reac-
tion s with trialkylalum in um s kn own 25 to be suitable for in troduction of
alkyl substituetn ts to purin es. Th us acetylated 6-ch loro-3-deazapurin e
riboside 3 was reacted with trim eth yl- an d trieth ylalum in um s in th e pres-
en ce of Pd(PPh 3)4 in refluxin g THF affordin g 6-alkylpurin e n ucleosides 6a
an d 6b in 53 an d 60% yields, respectively (Sch em e 2). Th ese acetylated
products 6a an d 6b were deprotected with catalytic sodium m eth oxide in
m eth an ol givin g th e desired n ucleosides 5j an d 5k in 71 an d 70% yields, re-
SCHEME 2
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670
Nauš, Kuchař, Hocek:
spectively, after recrystallization . For th e preparation cyclopropyl derivative
Negish i reaction between ch loride 3 an d cyclopropylzin c ch loride in th e
presen ce of Pd(PPh 3)4 was con ducted to furn ish protected cyclopropyl de-
rivative 6c in m oderate 38% yield an d subsequen t deprotection gave free
n ucleoside 5l (70%).
It sh ould be n oted, th at som e of th e attem pted cross-couplin gs (success-
ful in 6-ch loropurin es) failed h ere with 6-ch loro-3-deazapurin es 3 or 4. Th e
Stille reaction of acetylated n ucleoside 3 with 2-(tributylstan n yl)th iazole or
2-(tributylstan n yl)pyridin e an d th e Negish i reaction with ben zoyloxy-
m eth ylzin c iodide26 can serve as exam ple. Markedly decreased reactivity of
3-deazapurin e derivatives com pared to correspon din g purin es in n ucleo-
ph ilic substitution s of 6-ch loro group is kn own 19
.
All th e title 6-substituted 3-deazapurin e ribon ucleosides 5a–5l were
subjected to biological activity screen in g. Th e cytostatic activity in vitro
(in h ibition of cell growth ) was studied on th e followin g cell cultures:
m ouse leukem ia L1210 cells (ATCC CCL 219), h um an prom yelocytic leu-
kem ia HL60 cells (ATCC CCL 240), h um an cervix carcin om a HeLaS3
cells (ATCC CCL 2.2) an d h um an T lym ph oblastoid CCRF-CEM cell lin e
(ATCC CCL 119). An tiviral activity of n ucleosides 5a–5l was evaluated in
a HCV subgen om ic replicon assay27. Non e of th e com poun ds sh owed an y
con siderable cytostatic or an tiviral activity in th ese assays up to 10 µM con -
cen tration . Apparen tly, rem oval of th e N-3 n itrogen leads to in active com -
poun ds in dicatin g th at som e specific in teraction s of th is n itrogen with th e
target biological system (m ost probably m in or groove H-bon d in teraction
in th e active site of th e RNA polym erase) are crucial for th e biological activ-
ity of th is class of com poun ds.
EXPERIMENTAL
NMR spectra were recorded on Bruker Avan ce 400 MHz (1H at 400 MHz, 13C at 100.6 MHz)
an d Bruker Avan ce 500 MHz (500 MHz for 1H an d 125.7 MHz for 13C) spectrom eters. Ch em -
ical sh ifts (in ppm , δ-scale) were referen ced to TMS as in tern al stan dard. Couplin g con stan ts
(J) are given in Hz. Th e assign m en t of carbon s was based on C,H-HSQC an d C,H-HMBC ex-
perim en ts. IR spectra (waven um bers in cm –1) were recorded on a Brucker IFS 88 spectro-
m eter. Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. Optical
rotation s were m easured at 25 °C on an Autopol IV (Rudolph Research An alytical) polari-
m eter, [α]D values are given in 10–1 deg cm 2 g–1. High resolution m ass spectra (HR MS) were
m easured on a LTQ Orbitrap XL (Th erm o Fish er Scien tific) spectrom eter usin g electrospray
ion ization . High perform an ce flash ch rom atograph y (HPFC) purification s were perform ed
usin g SP1 Flash Purification System (Biotage) on C-18 colum n s usin g water–m eth an ol
gradien t. THF was dried an d fresh ly distilled from sodium /ben zoph en on e.
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
671
4-Ch loro-1-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (3)
To a slurry of 4-ch loro-1H-im idazo[4,5-c]pyridin e22 (1; 1.69 g, 11 m m ol) in dry CH3CN (50 m l),
BSA (2.72 m l, 11 m m ol) was added an d th e m ixture was stirred at RT for 20 m in (clear solu-
tion ), followed by addition of tetracetyl ribose 2 (3.85 g, 12.1 m m ol). TMSOTf (1.99 m l,
11 m m ol) was th en added dropwise at 0 °C an d th e m ixture was h eated at 80 °C for 3 h . Af-
ter coolin g an d dilution with CHCl3 (100 m l) th e m ixture was wash ed with saturated aque-
ous NaHCO3 (50 m l). Aqueous ph ase was re-extracted with CHCl3 (2 × 10 m l), collected
organ ics were dried over MgSO4 an d fin al colum n ch rom atograph y on silica (h ex-
an es–AcOEt, 1:1) provided n ucleoside 3 (4.05 g, 89%) as a colorless crystallin e solid, m .p.
160–161 °C (h exan e– AcOEt); ref.19 158.5–159 °C. 1H NMR (400 MHz, CDCl3): 2.10, 2.15,
2.16 (3 × s, 3 × 3 H, CH3CO); 4.39 (dd, 1 H, Jgem = 12.6, J5′b,4′ = 2.7, H-5′b); 4.46 (dd, 1 H,
Jgem = 12.6, J5′a,4′ = 2.9, H-5′a); 4.51 (ddd, 1 H, J4′,3′ = 5.1, J4′,5′ = 2.9, 2.7, H-4′); 5.38 (dd, 1 H,
J3′,2′ = 5.3, J3′,4′ = 5.1, H-3′); 5.51 (t, 1 H, J2′,1′ = 5.3, J2′,3′ = 5.3, H-2′); 6.07 (d, 1 H, J1′,2′ = 5.3,
H-1′); 7.53 (d, 1 H, J7,6 = 5.6, H-7); 8.23 (d, 1 H, J6,7 = 5.6, H-6); 8.27 (s, 1 H, H-2). 13C NMR
(100.6 MHz, CDCl3): 20.32, 20.45 an d 20.73 (3 × CH3CO); 62.46 (CH2-5′); 69.81 (CH-3′);
73.53 (CH-2′); 80.54 (CH-4′); 87.44 (CH-1′); 105.94 (CH-7); 138.25 (C-7a); 138.63 (C-3a);
141.78 (CH-2); 142.08 (CH-6); 143.34 (C-4); 169.27, 169.46 an d 170.00 (3 × CO). IR (CCl4):
2959, 2927, 2855, 1759, 1234, 1219, 1211, 967. HR MS (ESI): calculated for C17H18ClN3NaO7
[M + Na] 434.0731, foun d 434.0727. For C17H18ClN3O7 calculated: 49.58% C, 4.41% H,
10.20% N; foun d: 49.41% C, 4.38% H, 10.04% N.
4-Ch loro-1-(β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (4)
Acetylated n ucleoside 3 (3.29 g, 7.99 m m ol) was treated with m eth an olic am m on ia (24%,
70 m l) at RT for 24 h . After rem oval of volatiles un der reduced pressure, th e product was
crystallized from 96% eth an ol affordin g ch loro riboside 4 (1.96 g, 86%) as colorless prism s,
m .p. 192–193 °C; ref.19 192.5–193.5 °C. [α]D –39.1 (c 0.13, DMSO); ref.18 [α]D –39.1 (c 1.02,
MeOH); ref.19 [α]D –41.6 (c 1.25, MeOH). 1H NMR (400 MHz, DMSO-d6): 3.64 (ddd, 1 H,
Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.69 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′
=
3.5, H-5′a); 4.01 (td, 1 H, J4′,5′ = 3.5, J4′,3′ = 3.0, H-4′); 4.12 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.6,
J3′,4′ = 3.0, H-3′); 4.34 (ddd, 1 H, J2′,OH = 6.3, J2′,1′ = 6.3, J2′,3′ = 5.1, H-2′); 5.20 (dd, 1 H,
JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.27 (d, 1 H, JOH,3′ = 4.6, OH-3′); 5.54 (d, 1 H, JOH,2′ = 6.3,
OH-2′); 5.93 (d, 1 H, J1′,2′ = 6.3, H-1′); 7.91 (d, 1 H, J7,6 = 5.5, H-7); 8.17 (d, 1 H, J6,7 = 5.6,
H-6); 8.70 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 61.59 (CH2-5′); 70.63 (CH-3′);
74.69 (CH-2′); 86.62 (CH-4′); 89.73 (CH-1′); 108.25 (CH-7); 138.00 (C-3a); 139.71 (C-7a);
141.55 (C-4); 141.59 (CH-6); 145.07 (CH-2). IR (KBr): 1604, 1570, 1489, 1445, 1309, 1216,
1202, 1114, 1082, 1043. HR MS (ESI): calculated for C11H12ClN3NaO4 [M + Na] 308.0414,
foun d 308.0408. For C11H12ClN3O4 calculated: 46.25% C, 4.23% H, 14.71% N; foun d:
46.11% C, 4.26% H, 14.31% N.
Preparation of 6-Aryl(h etaryl)-3-deazapurin e Ribosides 5a–5i. Gen eral Procedure
To an argon purged flask con tain in g 6-ch loro-3-deazapurin e riboside 4 (214 m g, 0.75 m m ol),
boron ic acid (0.94 m m ol) an d Na2CO3 (236 m g, 2.25 m m ol), a pre-prepared solution of
Pd(OAc)2 (8 m g, 0.037 m m ol) an d TPPTS (53 m g, 0.093 m m ol) in water–CH3CN (2:1, 4 m l)
was added. Th e reaction m ixture was stirred at 100 °C for 2–24 h . After coolin g th e m ixture
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Nauš, Kuchař, Hocek:
was n eutralized by th e addition of aqueous HCl (3 M solution ) an d after con cen tration in
vacuo fin al purification by reverse ph ase ch rom atograph y afforded products 5a–5i.
4-Phenyl-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5a). Yield 92%. Reaction tim e 3 h .
Wh ite solid after lyoph ilization , m .p. 99–104 °C. [α]D –59.5 (c 1.6, DMSO). 1H NMR (400 MHz,
DMSO-d6): 3.66 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.71 (ddd, 1 H,
Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 4.03 (td, 1 H, J4′,5′ = 3.5, J4′,3′ = 3.1, H-4′); 4.16
(ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.1, H-3′); 4.42 (ddd, 1 H, J2′,OH = 6.4, J2′,1′ = 6.3,
J2′,3′ = 5.1, H-2′); 5.21 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.30 (d, 1 H, JOH,3′ = 4.7,
OH-3′); 5.57 (d, 1 H, JOH,2′ = 6.4, OH-2′); 5.97 (d, 1 H, J1′,2′ = 6.3, H-1′); 7.42–7.56 (m , 3 H,
H-m,p-Ph ); 7.82 (d, 1 H, J7,6 = 5.5, H-7); 8.46 (d, 1 H, J6,7 = 5.5, H-6); 8.68–8.72 (m , 3 H, H-2
an d H-o-Ph ). 13C NMR (100.6 MHz, DMSO-d6): 61.17 (CH2-5′); 70.15 (CH-3′); 73.97 (CH-2′);
85.89 (CH-4′); 88.87 (CH-1′); 106.50 (CH-7); 128.19 (CH-m-Ph ); 128.91 (CH-o-Ph ); 128.97
(CH-p-Ph ); 137.62 (C-i-Ph ); 138.26 (C-3a); 138.95 (C-7a); 141.43 (CH-6); 143.64 (CH-2);
147.72 (C-4). IR (KBr): 1602, 1585, 1574, 1301, 1221, 1100, 1060. HR MS (ESI): calculated
for C17H18N3O4 [M + H] 328.1297, foun d 328.1295. For C17H17N3O4·0.7H2O calculated:
60.06% C, 5.46% H, 12.36% N; foun d: 60.38% C, 5.23% H, 12.05% N.
4-(Furan-2-yl)-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5b). Yield 88%. Reaction tim e
3 h. Colorless crystals from water, m.p. 119–122 °C. [α]D –57.2 (c 3.5, DMSO). 1H NMR (400 MHz,
DMSO-d6): 3.65 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.71 (ddd, 1 H,
Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 4.02 (td, 1 H, J4′,5′ = 3.5, J4′3′ = 3.1, H-4′); 4.15
(ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.1, H-3′); 4.40 (ddd, 1 H, J2′,OH = 6.4, J2′,1′ = 6.3,
J2′3′ = 5.1, H-2′); 5.21 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.29 (d, 1 H, JOH,3′ = 4.7,
OH-3′); 5.57 (d, 1 H, JOH,2′ = 6.4, OH-2′); 5.95 (d, 1 H, J1′,2′ = 6.3, H-1′); 6.72 (dd, 1 H, J4,3
3.4, J4,5 = 1.8, H-4-furyl); 7.72 (dd, 1 H, J3,4 = 3.4, J3,5 = 0.9, H-3-furyl); 7.76 (d, 1 H, J7,6
=
=
5.6, H-7); 7.90 (dd, 1 H, J5,4 = 1.8, J5,3 = 0.9, H-5-furyl); 8.36 (d, 1 H, J6,7 = 5.6, H-6); 8.68
(s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 61.19 (CH2-5′); 70.18 (CH-3′); 74.05 (CH-2′);
85.94 (CH-4′); 88.92 (CH-1′); 106.24 (CH-7); 112.15 (CH-4-furyl); 113.44 (CH-3-furyl);
136.25 (C-3a); 138.35 (C-7a); 140.24 (C-4); 141.39 (CH-6); 143.93 an d 144.14 (CH-2 an d
CH-5-furyl); 150.81 (C-2-furyl). IR (KBr): 1596, 1499, 1480, 1407, 1311, 1216, 1121, 1107,
1084, 1013. HR MS (ESI): calculated for C15H15N3NaO5 [M + Na] 340.0909, foun d 340.0905.
For C15H15N3O5·1.5H2O calculated: 52.32% C, 5.27% H, 12.20% N; foun d: 52.71% C, 5.00% H,
12.03% N.
1-(β-D-Ribofuranosyl)-4-(thiophen-2-yl)-1H-imidazo[4,5-c]pyridine (5c). Yield 90%. Reaction
tim e 3 h . Cotton -like colorless crystals from 99% EtOH, m .p. 192–193 °C. [α]D –41.3 (c 0.1,
DMSO). 1H NMR (400 MHz, DMSO-d6): 3.65 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5,
H-5′b); 3.71 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 4.03 (td, 1 H, J4′,5′ = 3.5,
J4′3′ = 3.1, H-4′); 4.15 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.1, H-3′); 4.40 (ddd, 1 H,
J2′,OH = 6.4, J2′,1′ = 6.3, J2′3′ = 5.1, H-2′); 5.20 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.29
(d, 1 H, JOH,3′ = 4.7, OH-3′); 5.57 (d, 1 H, JOH,2′ = 6.4, OH-2′); 5.95 (d, 1 H, J1′,2′ = 6.3, H-1′);
7.25 (dd, 1 H, J4,5 = 5.1, J4,3 = 3.7, H-4-th ien yl); 7.69 (dd, 1 H, J5,4 = 5.1, J5,3 = 1.2,
H-5-th ien yl); 7.75 (d, 1 H, J7,6 = 5.6, H-7); 8.31 (d, 1 H, J6,7 = 5.6, H-6); 8.58 (dd, 1 H, J3,4
=
3.7, J3,5 = 1.2, H-3-th ien yl); 8.71 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 61.16
(CH2-5′); 70.15 (CH-3′); 74.04 (CH-2′); 85.93 (CH-4′); 88.93 (CH-1′); 106.19 (CH-7); 128.37
(CH-4-th ien yl); 128.46 (CH-5-th ien yl); 129.06 (CH-3-th ien yl); 136.32 (C-3a); 138.53 (C-7a);
141.34 (CH-6); 142.53 (C-2-th ien yl); 143.66 (C-4); 144.00 (CH-2). IR (KBr): 1592, 1578,
1465, 1278, 1213, 1131, 1085, 1075, 1065, 1046, 992. HR MS (ESI): calculated for
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
673
C15H16N3O4S [M + H] 334.0862, foun d 334.0859. For C15H15N3O4S calculated: 54.04% C,
4.54% H, 12.60% N, 9.62% S; foun d: 53.74% C, 4.48% H, 12.45% N, 9.46% S.
4-(Furan-3-yl)-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5d ). Yield 72%. Reaction tim e
2 h . Cotton -like wh ite crystals from water, m .p. 181–186 °C. [α]D –59.3 (c 1.8, DMSO).
1H NMR (400 MHz, DMSO-d6): 3.65 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b);
3.70 (ddd, 1 H, Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 4.04 (td, 1 H, J4′,5′ = 3.5, J4′,3′
3.1, H-4′); 4.15 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.1, H-3′); 4.39 (ddd, 1 H, J2′,OH
=
=
6.4, J2′,1′ = 6.3, J2′,3′ = 5.1, H-2′); 5.19 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.28 (d,
1 H, JOH,3′ = 4.7, OH-3′); 5.55 (d, 1 H, JOH,2′ = 6.4, OH-2′); 5.94 (d, 1 H, J1′,2′ = 6.3, H-1′); 7.33
(dd, 1 H, J4,5 = 1.8, J4,2 = 0.8, H-4-furyl); 7.73 (d, 1 H, J7,6 = 5.5, H-7); 7.82 (dd, 1 H, J5,4
1.8, J5,2 = 1.6, H-5-furyl); 8.35 (d, 1 H, J6,7 = 5.6, H-6); 8.66 (s, 1 H, H-2); 8.75 (dd, 1 H, J2,5
=
=
1.6, J2,4 = 0.8, H-2-furyl). 13C NMR (100.6 MHz, DMSO-d6): 61.17 (CH2-5′); 70.16 (CH-3′);
74.00 (CH-2′); 85.89 (CH-4′); 88.89 (CH-1′); 105.85 (CH-7); 109.40 (CH-4-furyl); 124.62
(C-3-furyl); 137.43 (C-3a); 138.01 (C-7a); 141.47 (CH-6); 143.08 (C-4); 143.60 (2 C, CH-2 an d
CH-5-furyl); 143.82 (CH-2-furyl). IR (KBr): 1592, 1304, 1222, 1111, 1096, 1066, 873. HR MS
(ESI): calculated for C15H16N3O5 [M + H] 318.1090, foun d 318.1088. For C15H15N3O5·H2O
calculated: 53.73% C, 5.11% H, 12.53% N; foun d: 53.74% C, 4.96% H, 12.50% N.
1-(β-D-Ribofuranosyl)-4-(thiophen-3-yl)-1H-imidazo[4,5-c]pyridine (5e). Yield 78%. Reaction
tim e 2 h . Yellowish crystals from water, m .p. 105–109 °C. [α]D –66.5 (c 2.6, DMSO). 1H NMR
(400 MHz, DMSO-d6): 3.65 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.71 (ddd,
1 H, Jgem = 12.0, J5′a,OH = 5.4, J5′a,4′ = 3.5, H-5′a); 4.03 (td, 1 H, J4′,5′ = 3.5, J4′3′ = 3.1, H-4′);
4.16 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.1, H-3′); 4.41 (ddd, 1 H, J2′,OH = 6.4, J2′,1′
6.3, J2′3′ = 5.1, H-2′); 5.20 (dd, 1 H, JOH,5′a = 5.4, JOH,5′b = 5.1, OH-5′); 5.29 (d, 1 H, JOH,3′
=
=
4.7, OH-3′); 5.56 (d, 1 H, JOH,2′ = 6.4, OH-2′); 5.95 (d, 1 H, J1′,2′ = 6.3, H-1′); 7.65 (dd, 1 H,
J5,4 = 5.1, J5,2 = 3.0, H-5-th ien yl); 7.76 (d, 1 H, J7,6 = 5.6, H-7); 8.21 (dd, 1 H, J4,5 = 5.1, J4,2
=
1.1, H-4-th ien yl); 8.38 (d, 1 H, J6,7 = 5.6, H-6); 8.70 (s, 1 H, H-2); 8.83 (dd, 1 H, J2,5 = 3.0,
J2,4 = 1.1, H-2-th ien yl). 13C NMR (100.6 MHz, DMSO-d6): 61.18 (CH2-5′); 70.16 (CH-3′);
74.00 (CH-2′); 85.89 (CH-4′); 88.89 (CH-1′); 106.07 (CH-7); 125.80 (CH-5-th ien yl); 126.89
(CH-2-th ien yl); 127.63 (CH-4-th ien yl); 137.44 (C-3a); 138.58 (C-7a); 140.01 (C-3-th ien yl);
141.39 (CH-6); 143.71 (CH-2); 144.50 (C-4). IR (KBr): 1596, 1580, 1463, 1221, 1106, 1061,
1037. HR MS (ESI): calculated for C15H16N3O4S [M + H] 334.0862, foun d 334.0857. For
C
15H15N3O4S·H2O calculated: 51.27% C, 4.88% H, 11.96% N; foun d: 51.13% C, 4.81% H,
11.75% N.
4-(Pyrrol-2-yl)-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5f). Yield 50%. Reaction tim e
24 h . Wh ite crystals from MeOH, m .p. 205–206 °C. [α]D –53.4 (c 1.9, DMSO). 1H NMR
(400 MHz, DMSO-d6): 3.64 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.70 (ddd,
1 H, Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 4.01 (td, 1 H, J4′,5′ = 3.5, J4′,3′ = 3.0, H-4′);
4.14 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.6, J3′,4′ = 3.0, H-3′); 4.39 (ddd, 1 H, J2′,OH = 6.1, J2′,1′
6.3, J2′,3′ = 5.1, H-2′); 5.18 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.28 (d, 1 H, JOH,3′
=
=
4.6, OH-3′); 5.56 (d, 1 H, JOH,2′ = 6.1, OH-2′); 5.91 (d, 1 H, J1′,2′ = 6.3, H-1′); 6.21 (dt, 1 H,
J4,3 = 3.7, J4,5 = J4,NH = 2.4, H-4-pyrr); 6.95 (ddd, 1 H, J5,NH = 2.7, J5,4 = 2.4, J5,3 = 1.6,
H-5-pyrr); 7.38 (ddd, 1 H, J3,4 = 3.7, J3,NH = 2.3, J3,5 = 1.6, H-3-pyrr); 7.58 (d, 1 H, J7,6 = 5.6,
H-7); 8.26 (d, 1 H, J6,7 = 5.6, H-6); 8.63 (s, 1 H, H-2); 11.54 (br s, 1 H, NH-pyrr). 13C NMR
(100.6 MHz, DMSO-d6): 61.18 (CH2-5′); 70.14 (CH-3′); 73.97 (CH-2′); 85.81 (CH-4′); 88.80
(CH-1′); 104.27 (CH-7); 109.28 (CH-4-pyrr); 111.56 (CH-3-pyrr); 120.89 (CH-5-pyrr); 129.58
(C-2-pyrr); 135.53 (C-3a); 138.17 (C-7a); 141.17 (CH-6); 142.71 (C-4); 143.08 (CH-2). IR (KBr):
3352, 1601, 1588, 1470, 1220, 1135, 1084, 1063, 1045. HR MS (ESI): calculated for
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 665–678

674
Nauš, Kuchař, Hocek:
C15H17N4O4 [M + H] 317.1250, foun d 317.1248. For C15H16N4O4·0.5H2O calculated: 55.38% C,
5.27% H, 17.22% N; foun d: 55.49% C, 4.92% H, 16.95% N.
4-(Pyrrol-3-yl)-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5g). Yield 61%. Reaction tim e
15 h. Greenish solid from water, m .p. 119–126 °C. [α]D –48.8 (c 1.7, DMSO). 1H NMR (400 MHz,
DMSO-d6): 3.64 (ddd, 1 H, Jgem = 11.9, J5′b,OH = 5.1, J5′b,4′ = 3.65, H-5′b); 3.70 (ddd, 1 H, Jgem
=
11.9, J5′a,OH = 5.3, J5′a,4′ = 3.6, H-5′a); 4.00 (td, 1 H, J4′,5′ = 3.6, J4′3′ = 3.2, H-4′); 4.14 (ddd, 1 H,
J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.2, H-3′) 4.39 (ddd, 1 H, J2′,OH = 6.5, J2′,1′ = 6.3, J2′3′ = 5.1,
H-2′); 5.17 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.26 (d, 1 H, JOH,3′ = 4.7, OH-3′); 5.54
(d, 1 H, JOH,2′ = 6.5, OH-2′); 5.89 (d, 1 H, J1′,2′ = 6.3, H-1′); 6.84 (td, 1 H, J5,4 = J5,NH = 2.6,
J5,2 = 2.0, H-5-pyrr); 7.03 (td, 1 H, J4,5 = J4,NH = 2.6, J4,2 = 1.5, H-4-pyrr); 7.51 (d, 1 H, J7,6
=
5.6, H-7); 8.03 (ddd, 1 H, J2,NH = 2.8, J2,5 = 2.0, J2,4 = 1.5, H-2-pyrr); 8.23 (d, 1 H, J6,7 = 5.6,
H-6); 8.55 (s, 1 H, H-2); 11.10 (br s, 1 H, NH-pyrr). 13C NMR (100.6 MHz, DMSO-d6): 61.23
(CH2-5′); 70.16 (CH-3′); 73.90 (CH-2′); 85.72 (CH-4′); 88.72 (CH-1′); 103.68 (CH-7); 107.69
(CH-4-pyrr); 118.23 (CH-5-pyrr); 120.58 (CH-2-pyrr); 122.08 (C-3-pyrr); 136.47 (C-3a);
137.94 (C-7a); 141.26 (CH-6); 142.47 (CH-2); 146.96 (C-4). IR (KBr): 3388, 1588, 1552, 1480,
1460, 1217, 1111, 1063, 1041. HR MS (ESI): calculated for C15H17N4O4 [M + H] 317.1250,
foun d 317.1245. For C15H16N4O4·1.5H2O calculated: 52.47% C, 5.58% H, 16.32% N; foun d:
52.76% C, 5.45% H, 16.04% N.
4-(1H-Pyrazol-5-yl)-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5h ). Yield 10% after
crystalization , 82% of startin g com poun d 4 recovered. Reaction tim e 24 h . Colorless crystals
from water, m .p. 139–143 °C. [α]D –59.0 (c 1.7, DMSO). 1H NMR (500 MHz, DMSO-d6 + DCl):
3.66, 3.71 (2 × dd, 2 × 1 H, Jgem = 12.2, J5′,4′ = 3.2, H-5′b); 4.08 (dt, 1 H, J4′,3′ = 3.6, J4′,5′
=
3.2, H-4′); 4.17 (dd, 1 H, J3′,2′ = 5.1, J3′,4′ = 3.6, H-3′); 4.37 (dd, 1 H, J2′,1′ = 5.7, J2′,3′ = 5.1,
H-2′); 6.14 (d, 1 H, J1′,2′ = 5.7, H-1′); 7.64 (d, 1 H, J4,5 = 2.4, H-4-pyrazolyl); 8.13 (d, 1 H,
J5,4 = 2.4, H-5-pyrazolyl); 8.38 (d, 1 H, J7,6 = 6.7, H-7); 8.48 (d, 1 H, J6,7 = 6.7, H-6); 9.17 (s,
1 H, H-2). 13C NMR (125.7 MHz, DMSO-d6 + DCl): 60.97 (CH2-5′); 70.25 (CH-3′); 75.19
(CH-2′); 86.85 (CH-4′); 90.20 (CH-1′); 108.95 (CH-7); 109.25 (CH-4-pyrazolyl); 132.09
(CH-5-pyrazolyl); 134.12 (CH-6); 137.18 (C-3a); 138.05 (C-4); 140.54 (C-3-pyrazolyl); 143.30
(C-7a); 148.84 (CH-2). IR (KBr): 3429, 1633, 1605, 1592, 1482, 1402, 1304, 1221, 1137,
1112, 1084. HR MS (ESI): calculated for C14H15N5NaO4 [M + Na] 340.1022, foun d 340.1018.
For C14H15N5O4·1.35H2O calculated: 49.22% C, 5.22% H, 20.50% N; foun d: 49.47% C,
5.09% H, 20.22% N.
4-(Pyridin-3-yl)-1-(β-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (5i). Yield 96%. Reaction tim e
20 h . Wh ite crystallin e solid from water, m .p. 111–115 °C. [α]D –55.3 (c 1.7, DMSO). 1H NMR
(400 MHz, DMSO-d6): 3.66 (ddd, 1 H, Jgem = 12.0, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.72 (ddd,
1 H, Jgem = 12.0, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 4.04 (td, 1 H, J4′,5′ = 3.5, J4′,3′ = 3.1, H-4′);
4.16 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.7, J3′,4′ = 3.1, H-3′); 4.42 (ddd, 1 H, J2′,OH = 6.3, J2′,1′
6.3, J2′,3′ = 5.1, H-2′); 5.22 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.1, OH-5′); 5.31 (d, 1 H, JOH,3′
=
=
4.7, OH-3′); 5.59 (d, 1 H, JOH,2′ = 6.3, OH-2′); 5.99 (d, 1 H, J1′,2′ = 6.3, H-1′); 7.57 (ddd, 1 H,
J5,4 = 8.0, J5,6 = 4.8, J5,2 = 1.0, H-5-py); 7.90 (d, 1 H, J7,6 = 5.5, H-7); 8.50 (d, 1 H, J6,7 = 5.5,
H-6); 8.65 (dd, 1 H, J6,5 = 4.7, J6,4 = 1.7, H-6-py); 8.75 (s, 1 H, H-2); 8.97 (ddd, 1 H, J4,5 = 8.0,
J4,2 = 2.2, J4,6 = 1.7, H-4-py); 9.81 (dd, 1 H, J2,4 = 2.2, J2,5 = 1.0, H-2-py). 13C NMR (100.6 MHz,
DMSO-d6): 61.17 (CH2-5′); 70.18 (CH-3′); 74.06 (CH-2′); 85.99 (CH-4′); 88.97 (CH-1′); 107.20
(CH-7); 123.53 (CH-5-py); 133.14 (C-3-py); 135.89 (CH-4-py); 138.51 (C-3a); 138.97 (C-7a);
141.74 (CH-6); 144.21 (CH-2); 145.37 (C-4); 149.69 an d 149.78 (CH-2,6-py). IR (KBr): 1606,
1592, 1583, 1502, 1460, 1101, 1050, 984, 940. HR MS (ESI): calculated for C16H17N4O4
Collect. Czech. Chem. Commun. 2008, Vol. 73, No. 5, pp. 665–678

Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
675
[M + H] 329.1250, foun d 329.1247. For C16H16N4O4)·1.8H2O calculated: 53.27% C, 5.48% H,
15.53% N; foun d: 53.42% C, 5.37% H, 15.34% N.
4-Meth yl-1-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (6a)
An argon purged flask con tain in g a m ixture of acetylated 6-ch loro-3-deazapurin e riboside 3
(300 m g, 0.73 m m ol), trim eth ylalum in um (2 M solution in toluen e; 0.73 m l, 1.46 m m ol)
an d Pd(PPh 3)4 (42 m g, 0.036 m m ol) in THF (4 m l) was stirred at 100 °C for 3 h . Th e m ixture
was diluted with CHCl3 (20 m l) an d treated with saturated aqueous NH4Cl (20 m l). Th e
slurry was filtered th rough cellite an d after ph ase separation , aqueous ph ase was re-extracted
with CHCl3 (2 × 10 m l). Collected organ ic extracts were dried over MgSO4, volatiles were re-
m oved in vacuo an d th e residue was ch rom atograph ed on silica gel (AcOEt) affordin g prod-
uct 6a as colorless oil (151 m g, 53%). 1H NMR (400 MHz, CDCl3): 2.09, 2.17 an d 2.19 (3 × s,
3 × 3 H, 3 × CH3CO); 2.90 (s, 3 H, CH3); 4.41 (dd, 1 H, Jgem = 12.6, J5′b,4′ = 2.8, H-5′b); 4.46
(dd, 1 H, Jgem = 12.6, J5′a,4′ = 3.0, H-5′a); 4.50 (ddd, 1 H, J4′,3′ = 4.4, J4′,5′ = 3.0, 2.8, H-4′); 5.43
(dd, 1 H, J3′2′ = 5.6, J3′4′ = 4.4, H-3′); 5.56 (t, 1 H, J2′,1′ = J2′,3′ = 5.6, H-2′); 6.08 (d, 1 H, J1′,2′
=
5.6, H-1′); 7.39 (d, 1 H, J7,6 = 5.7, H-7); 8.17 (s, 1 H, H-2); 8.35 (d, 1 H, J6,7 = 5.7, H-6).
13C NMR (100.6 MHz, CDCl3): 19.85 (CH3); 20.31, 20.50 an d 20.75 (3 × CH3CO); 62.73
(CH2-5′); 70.10 (CH-3′); 73.29 (CH-2′); 80.40 (CH-4′); 87.05 (CH-1′); 104.05 (CH-7); 136.92
(C-7a); 139.82 (C-3a); 140.39 (CH-2); 142.20 (CH-6); 152.68 (C-4); 169.20, 169.49 an d
170.09 (3 × CO). IR (CCl4): 1758, 1602, 1590, 1371, 1219, 1100, 1063, 1048. HR MS (ESI):
calculated for C18H22N3O7 [M + H] 392.1458, foun d 392.1453.
4-Eth yl-1-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (6b)
An argon purged flask con tain in g a m ixture of acetylated 6-ch loro-3-deazapurin e riboside 3
(288 m g, 0.70 m m ol), trieth ylalum in um (1 M solution in h exan e; 1.4 m l, 1.4 m m ol) an d
Pd(PPh 3)4 (40 m g, 0.035 m m ol) in THF (4 m l) was stirred at 100 °C for 3 h . Th e m ixture was
diluted with CHCl3 (20 m l) an d treated with saturated aqueous NH4Cl (20 m l). Th e slurry
was filtered th rough cellite an d after ph ase separation , aqueous ph ase was re-extracted with
CHCl3 (2 × 10 m l). Collected organ ic extracts were dried over MgSO4, volatiles were re-
m oved in vacuo an d th e residue was ch rom atograph ed on silica gel (AcOEt) affordin g prod-
uct 6b as colorless oil (169 m g, 60%). 1H NMR (400 MHz, CDCl3): 1.44 (t, 3 H, Jvic = 7.6,
CH3CH2); 2.10, 2.17, 2.18 (3 × s, 3 × 3 H, 3 × CH3CO); 3.28 (q, 2 H, Jvic = 7.6, CH2CH3);
4.41 (dd, 1 H, Jgem = 12.5, J5′b,4′ = 2.8, H-5′b); 4.46 (dd, 1 H, Jgem = 12.5, J5′a,4′ = 3.0, H-5′a);
4.50 (ddd, 1 H, J4′,3′ = 4.3, J4′,5′ = 3.0, 2.8, H-4′); 5.43 (dd, 1 H, J3′2′ = 5.6, J3′4′ = 4.3, H-3′);
5.56 (t, 1 H, J2′,1′ = J2′,3′ = 5.6, H-2′); 6.09 (d, 1 H, J1′,2′ = 5.6, H-1′); 7.39 (d, 1 H, J7,6 = 5.7,
H-7); 8.16 (s, 1 H, H-2); 8.39 (d, 1 H, J6,7 = 5.7, H-6). 13C NMR (100.6 MHz, CDCl3): 13.22
(CH3CH2); 20.33, 20.50 an d 20.76 (3 × CH3CO); 26.85 (CH2CH3); 62.73 (CH2-5′); 70.11
(CH-3′); 73.30 (CH-2′); 80.37 (CH-4′); 87.04 (CH-1′); 104.01 (CH-7); 137.09 (C-7a); 139.20
(C-3a); 140.33 (CH-2); 142.32 (CH-6); 157.55 (C-4); 169.22, 169.50 an d 170.10 (3 × CO).
IR (CCl4): 1757, 1600, 1588, 1371, 1220, 1103, 1063, 1048. HR MS (ESI): calculated for
C
19H24N3O7 [M + H] 406.1614, foun d 406.1609.
4-Cyclopropyl-1-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (6c)
Tetrah ydrofuran (4 m l) was added to flam e-vacuum dried zin c ch loride (340 m g, 2.5 m m ol)
un der argon . Th e m ixture was stirred at –10 °C an d a solution of cyclopropylm agn esium
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brom ide (1 M solution in THF; 2.5 m l) was added dropwise. Th e m ixture was stirred for
40 m in an d th en a solution of a 6-ch loro-3-deazapurin e riboside 3 (205 m g, 0.5 m m ol) an d
Pd(PPh 3)4 (40 m g, 0.035 m m ol) in THF (5 m l) was added. Th e resultin g m ixture was stirred
at 70 °C for 8 h . Th en th e reaction m ixture was diluted with water (50 m l) an d wash ed with
eth yl acetate (3 × 50 m l). Th e collected organ ic layers were wash ed with brin e, dried over
MgSO4 an d th e residue was purified by colum n ch rom atograph y on silica gel (AcOEt–h exan e
0–30%) providin g com poun d 6c as a wh ite foam (80 m g, 38%). 1H NMR (500 MHz, CDCl3):
1.13 an d 1.31 (2 × m , 2 × 2 H, H-2,3-cycloprop); 2.09, 2.17 an d 2.18 (3 × s, 3 × 3 H,
CH3CO); 2.87 (tt, 1 H, Jvic = 8.3, 4.7, H-1-cycloprop); 4.41 (dd, 1 H, Jgem = 12.5, J5′b,4′ = 2.9,
H-5′b); 4.45 (dd, 1 H, Jgem = 12.5, J5′a,4′ = 3.0, H-5′a); 4.49 (ddd, 1 H, J4′,3′ = 4.3, J4′,5′ = 3.0,
2.9, H-4′); 5.43 (dd, 1 H, J3′,2′ = 5.6, J3′,4′ = 4.3, H-3′); 5.55 (dd, 1 H, J2′,1′ = 5.9, J2′,3′ = 5.6,
H-2′); 6.07 (d, 1 H, J1′,2′ = 5.9, H-1′); 6.07 (d, 1 H, J7,6 = 5.9, H-7); 8.16 (s, 1 H, H-2); 8.28 (d,
1 H, J6,7 = 5.9, H-6). 13C NMR (125.7 MHz, CDCl3): 10.01 an d 10.04 (CH2-2,3-cycloprop);
12.67 (CH-1-cycloprop); 20.30, 20.50 an d 20.75 (CH3CO); 62.77 (CH2-5′); 70.13 (CH-3′);
73.26 (CH-2′); 80.38 (CH-4′); 86.97 (CH-1′); 102.90 (CH-7); 136.63 (C-7a); 139.52 (C-3a);
140.31 (CH-2); 142.42 (CH-6); 157.06 (C-4); 169.21, 169.52 an d 170.14 (CO). IR (CHCl3):
1591, 1372, 1232, 1199, 1096, 1067. HR MS (ESI): calculated for C20H24N3O7 [M + H]
418.1609, foun d 418.1602.
4-Meth yl-1-(β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (5j)
Com poun d 6a (129 m g, 0.33 m m ol) was treated with 1 M NaOMe/MeOH (100 µl, 0.1 m m ol)
in MeOH (2 m l) at RT for 1 h an d, after rem oval of volatiles, th e crude product was desalted
by reverse ph ase ch rom atograph y an d crystallized from water affordin g n ucleoside 5j as col-
orless crystals (62 m g, 71%), m .p. 245–249 °C. [α]D –68.3 (c 2.2, DMSO). 1H NMR (400 MHz,
DMSO-d6): 2.70 (s, 3 H, CH3); 3.62 (ddd, 1 H, Jgem = 11.9, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b);
3.67 (ddd, 1 H, Jgem = 11.9, J5′a,OH = 5.3, J5′a,4′ = 3.5, H-5′a); 3.99 (td, 1 H, J4′,5′ = 3.5, J4′,3′
3.0, H-4′); 4.12 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.6, J3′,4′ = 3.0, H-3′); 4.36 (ddd, 1 H, J2′,OH
=
=
6.4, J2′,1′ = 6.4, J2′,3′ = 5.1, H-2′); 5.16 (dd, 1 H, JOH,5′a = 5.3, JOH,5′b = 5.0, OH-5′); 5.26 (d, 1 H,
JOH,3′ = 4.6, OH-3′); 5.51 (d, 1 H, JOH,2′ = 6.5, OH-2′); 5.88 (d, 1 H, J1′,2′ = 6.4, H-1′); 7.64 (d,
1 H, J7,6 = 5.7, H-7); 8.19 (d, 1 H, J6,7 = 5.7, H-6); 8.53 (s, 1 H, H-2). 13C NMR (100.6 MHz,
DMSO-d6): 19.53 (CH3); 61.20 (CH2-5′); 70.15 (CH-3′); 73.86 (CH-2′); 85.78 (CH-4′); 88.77
(CH-1′); 105.29 (CH-7); 137.02 (C-7a); 139.35 (C-3a); 140.96 (CH-6); 142.80 (CH-2); 150.65
(C-4). IR (KBr): 3366, 3254, 1603, 1592, 1493, 1466, 1419, 1314, 1305, 1121, 1092, 1081,
1081, 1045. HR MS (ESI): calculated for C12H16N3O4 [M + H] 266.1141, foun d 266.1133. For
C
12H15N3O4 calculated: 54.33% C, 5.70% H, 15.84% N; foun d: 53.98% C, 5.79% H, 15.51% N.
4-Eth yl-1-(β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (5k)
Com poun d 6b (149 m g, 0.37 m m ol) was treated with 1 M NaOMe/MeOH (110 µl, 0.11 m m ol)
in MeOH (2 m l) at RT for 1 h an d, after rem oval of volatiles, th e crude product was desalted
by reverse ph ase ch rom atograph y an d crystallized from water affordin g n ucleoside 5k as col-
orless crystals (72 m g, 70%), m .p. 94 °C. [α]D –41.0 (c 1.4, DMSO). 1H NMR (400 MHz,
DMSO-d6): 1.31 (t, 3 H, Jvic = 7.6, CH3CH2); 3.10 (q, 2 H, Jvic = 7.6, CH2CH3); 3.62 (ddd, 1 H,
Jgem = 11.9, J5′b,OH = 5.1, J5′b,4′ = 3.5, H-5′b); 3.67 (ddd, 1 H, Jgem = 11.9, J5′a,OH = 5.3, J5′a,4′
=
3.5, H-5′a); 3.99 (td, 1 H, J4′,5′ = 3.5, J4′,3′ = 3.0, H-4′); 4.12 (ddd, 1 H, J3′,2′ = 5.1, J3′,OH = 4.6,
J3′,4′ = 3.0, H-3′); 4.37 (ddd, 1 H, J2′,OH = 6.4, J2′,1′ = 6.3, J2′,3′ = 5.1, H-2′); 5.16 (dd, 1 H,
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Cytostatic and Antiviral 6-Arylpurine Ribonucleosides
677
JOH,5′a = 5.3, JOH,5′b = 5.0, OH-5′); 5.26 (d, 1 H, JOH,3′ = 4.6, OH-3′); 5.51 (d, 1 H, JOH,2′ = 6.5,
OH-2′); 5.88 (d, 1 H, J1′,2′ = 6.3, H-1′); 7.64 (d, 1 H, J7,6 = 5.7, H-7); 8.22 (d, 1 H, J6,7 = 5.7,
H-6); 8.52 (s, 1 H, H-2). 13C NMR (100.6 MHz, DMSO-d6): 13.13 (CH3CH2); 26.11 (CH2CH3);
61.23 (CH2-5′); 70.19 (CH-3′); 73.84 (CH-2′); 85.81 (CH-4′); 88.75 (CH-1′); 105.32 (CH-7);
137.21 (C-7a); 138.73 (C-3a); 141.03 (CH-6); 142.81 (CH-2); 155.40 (C-4). IR (KBr): 3280,
1605, 1593, 1493, 1477, 1415, 1312, 1217, 1119, 1087, 998. HR MS (ESI): calculated for
C
13H18N3O4 [M + H] 280.1297, foun d 280.1291. For C13H17N3O4·H2O calculated: 52.52% C,
6.44% H, 14.13% N; foun d: 52.57% C, 6.46% H, 14.09% N.
4-Cyclopropyl-1-(β-D-ribofuran osyl)-1H-im idazo[4,5-c]pyridin e (5l)
Com poun d 6c (72 m g, 0.17 m m ol) was treated with 1 M NaOMe/MeOH (52 µl, 0.52 m m ol)
in MeOH (2 m l) at RT for 1 h an d, after rem oval of volatiles, th e crude product was desalted
by reverse ph ase ch rom atograph y an d crystallized from water–MeOH affordin g n ucleoside 5l
as colorless crystals (35 mg, 70%), m.p. 107–113 °C. [α]D –43.0 (c 0.23, MeOH). 1H NMR (500 MHz,
DMSO-d6): 1.13 an d 1.22 (2 × m , 2 × 2 H, H-2,3-cycloprop); 2.86 (tt, 1 H, Jvic = 8.1, 4.8,
H-1-cycloprop); 3.72 an d 3.77 (2 × dd, 2 H, Jgem = 12.0, J5′,4′ = 3.6, H-5′); 4.08 (td, 1 H, J4′,5′
=
3.6, J4′,3′ = 3.1, H-4′); 4.21 (dd, 1 H, J3′,2′ = 5.2, J3′,4′ = 3.1, H-3′); 4.44 (dd, 1 H, J2′,1′ = 6.4,
J2′,3′ = 5.2, H-2′); 5.96 (d, 1 H, J1′,2′ = 6.4, H-1′); 7.63 (d, 1 H, J7,6 = 5.6, H-7); 8.24 (d, 1 H,
J6,7 = 5.6, H-6); 8.62 (s, 1 H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 9.84 an d 9.86
(CH2-2,3-cycloprop); 12.68 (CH-1-cycloprop); 61.44 (CH2-5′); 70.37 (CH-3′); 74.14 (CH-2′);
86.01 (CH-4′); 89.02 (CH-1′); 104.51 (CH-7); 137.07 (C-7a); 139.23 (C-3a); 141.47 (CH-6);
143.08 (CH-2); 155.14 (C-4). IR (KBr): 3480, 3403, 1601, 1593, 1473, 1455, 1388, 1366,
1221, 1102, 1063, 989, 976. HR MS (ESI) calculated for C14H18N3O4 [M + H] 292.1292,
foun d 292.1291. For C14H17N3O4·1.15H2O calculated: 53.89% C, 6.23% H, 13.47% N; foun d:
53.83% C, 6.22% H, 13.43% N.
This work is a part of the research project Z4 055 0506. It was supported by the “Centre for
New Antivirals and Antineoplastics” (1M0508), by the Programme of Targeted Projects of
Academy of Sciences of the Czech Republic (1QS400550501) and by Gilead Sciences, Inc. (Foster
City, CA, U.S.A.). Cytostatic activity was studied by Dr I. Votruba (IOCB) and anti-HCV activity
by E. Mabery and Dr I. Shih and Dr R. Mackman (Gilead). The contribution of these scientists
is gratefully acknowledged.
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