Cytostatic 6-arylpurine nucleosides IV. Synthesis of 2-substituted 6-phenylpurine ribonucleosides

Article abstract of DOI:10.1135/cccc20020325

A series of 2-X-substituted-6-phenyl-9-(β-D-ribofuranosyl)purines (X = Cl, Br, I, CH₃, CF₃ and Ph) was prepared by halo-deaminations of protected 2-amino-6-phenylpurine ribonucleoside, by regioselective Suzuki-Miyaura reactions of 2,

Full text of DOI:10.1135/cccc20020325

Cytostatic 6-Arylpurine Nucleosides
325
CYTOSTATIC 6-ARYLPURINE NUCLEOSIDES IV+.
SYNTHESIS OF 2-SUBSTITUTED 6-PHENYLPURINE RIBONUCLEOSIDES
a2
b
Michal HOCEKa1,*, Antonín HOLÝ and Hana DVOŘÁKOVÁ
a
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
2
CZ-16610 Prague 6, Czech Republic; e-mail: hocek@uochb.cas.cz, holy@uochb.cas.cz
Laboratory of NMR Spectroscopy, Institute of Chemical Technology, Prague, CZ-166 28 Prague 6,
Czech Republic; e-mail: hana.dvorakova@vscht.cz
b
Received February 13, 2002
Accepted March 25, 2002
A series of 2-X-substituted-6-ph en yl-9-(β-D-ribofuran osyl)purin es (X = Cl, Br, I, CH3, CF3 an d
Ph ) was prepared by h alo-deam in ation s of protected 2-am in o-6-ph en ylpurin e ribon ucleo-
side, by regioselective Suzuki–Miyaura reaction s of 2,6-dih alopurin es with ph en ylboron ic
acid or by cross-couplin g reaction s of th e correspon din g 2-h alo-6-ph en ylpurin es followed by
deprotection . Non e of th e title n ucleosides exh ibited an y con siderable cytostatic activity.
Keyw ord s: Purin es; Nucleosides; Cross-couplin g reaction s; An tin eoplastic agen ts; Deam in -
ation s; Trifluorom eth ylation .
Recen tly, with in th e fram ework of our system atic studies of purin es bearin g
C-substituen ts in position s 2, 6 an d/or 8, a n ew efficien t syn th esis of aryl-
purin es usin g th e Suzuki–Miyaura cross-couplin g m eth odology h as been de-
veloped1. Th is m eth od h as been applied to th e syn th esis of purin e bases
an d n ucleosides2,3, as well as of acyclic n ucleotide an alogues4. A sign ifican t
cytostatic activity h as been foun d with several 6-(substituted ph en yl)purin e
ribon ucleosides2. Th e SAR studies revealed a crucial in fluen ce of th e pres-
en ce of th e β-D-ribofuran osyl m oiety in th e position N-9 an d th e effect of
substitution at th e purin e an d ben zen e rin gs on th eir biological activity.
Th e 6-(4-substituted ph en yl)purin e ribon ucleosides displayed2 sign ifican t in
vitro cytostatic activity (in h ibition of th e cell growth of L1210, HeLa S3 an d
CCRF-CEM cell cultures, IC50 = 0.25–10 µm ol l–1), wh ile th e 6-ph en ylpurin e
bases an d 2-am in o-6-ph en ylpurin e ribon ucleosides were en tirely in active
in th ese assays. Also several 6-h etaryl an d 6-ben zylpurin e ribon ucleosides
+ For Part III, see ref.5
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20020325

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Hocek, Holý, Dvořáková:
sh owed5 con siderable activity. In con trast, sugar-m odified 6-arylpurin e
n ucleosides6 (2′- or 5′-deoxyribosides an d acyclon ucleosides) as well as
6-(h et)arylpurin e acyclic n ucleotide an alogues4,7 were devoid of an y cyto-
static activity. As an exten sion of th e SAR study of th is class of com poun ds,
we report h ere on th e syn th esis of 6-ph en ylpurin e ribon ucleosides bearin g
diverse substituen ts (h alo, alkyl an d aryl) in position 2. In th e selection of
various types of 2-substituen ts, we took in to accoun t structural resem blan ce
to som e im portan t biologically active purin e derivatives (e.g. an tiviral
2-(trifluorom eth yl)aden in es8 or an titum or 2-ch loroaden in e n ucleosides9).
Th ere are two altern ative approach es for th e preparation of th e target
2-substituted-6-ph en ylpurin es: (i) selective Suzuki–Miyaura cross-couplin g
reaction s of 2,6-dih alopurin es1b with ph en ylboron ic acid or (ii) deam in -
ative tran sform ation s of easily available 2-am in o-6-ph en ylpurin e n ucleo-
sides. Both of th ese approach es h ave been advan tageously used in th is
study depen din g on th e n ature of th e 2-substituen t required an d on th e ef-
ficien cy of th e syn th esis.
Th us th e kn own
2-am in o-6-ph en yl-9-(2,3,5-tri-O-acetyl-β-D-ribo-
furan osyl)purin e2 (1) was subjected to a series of h alo-deam in ation re-
action s (Sch em e 1, an alogy to th e kn own h alo-deam in ation s10 of ch loro-
(i)
N
N
(ii)
N
N
N
N
N
N
N
H2N
AcO
I
N
O
CF3
RO
N
O
N
O
RO
OAc OAc
1
OR OR
OR OR
4
5
(iii)
(iv)
R
3-5
a
N
N
N
Ac
H
N
(v)
Br
N
N
O
RO
b
Cl
N
N
AcO
O
OR OR
3
OAc OAc
2
(i) I2, CuI, CH2I2, i-AmONO, THF; (ii) CF3SiMe3, CuI, KF, DMF, NMP; (iii) CHBr3, NiBr2, i-AmONO,
THF; (iv) SbCl3, ClCH2CH2Cl, i-AmONO; (v) MeONa, MeOH
SCHEME 1
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Cytostatic 6-Arylpurine Nucleosides
327
guan osin es). Th e attem pted ch loro-deam in ation usin g SbCl3 an d CCl4 in
presen ce of isoam yl n itrite (i-Am ONO) gave a com plex m ixture of products
out of wh ich th e desired 2-ch loro derivative 2 was isolated in m oderate
yield of 30% on ly. An an alogous brom o-deam in ation usin g brom oform an d
i-Am ONO un der literature con dition s10 gave a com plex m ixture wh ich did
n ot con tain th e required 2-brom o-6-ph en ylpurin e n ucleoside 3a (MS an aly-
sis of th e crude reaction m ixture). Wh en usin g a com bin ation of
brom oform , NiBr2 an d i-Am ONO, th e 2-brom o derivative 3a was isolated in
th e yield of 61%. Th e iodo-deam in ation usin g CH2I2, CuI an d i-Am ONO
proceeded well to give 2-iodopurin e 4a in 54% yield. Th ese h alo-
deam in ation reaction s were n ot very clean an d th e 2-h alopurin e products
2–4a h ad to be isolated by careful colum n ch rom atograph y. Th e 2-iodo-
6-ph en ylpurin e n ucleoside 4a was used as startin g com poun d for th e prepa-
ration of 6-ph en yl-2-(trifluorom eth yl)purin e n ucleoside 5a (48% yield)
usin g CF3Si(CH3)3, KF an d CuI (in an alogy to th e kn own 11 trifluorom eth yl-
ation of 6-iodopurin es).
As th e preparation of 2-ch loro-6-ph en ylpurin e n ucleoside 2 by ch loro-
deam in ation of th e correspon din g 2-am in opurin e 1 was n ot efficien t, we
h ave used an altern ative approach . Perben zoylated 2,6-dich loropurin e
ribon ucleoside12 6 was prepared by Sn Cl4-m ediated glycosidation of 2,6-di-
ch loropurin e with 1-O-acetyl-2,3,5-tri-O-ben zoyl-D-ribofuran ose in 52%
yield. Th e Suzuki–Miyaura reaction of th e 2,6-dich loropurin e n ucleoside 6
with on e equivalen t of ph en ylboron ic acid afforded selectively 2-ch loro-
6-ph en ylpurin e 7a in th e yield of 80% (Sch em e 2). Th is selectivity is in ac-
cord with th e reported regioselective Suzuki1b an d Stille13 couplin gs of
Cl
Cl
N
(iii)
(ii)
N
N
(i)
N
N
N
N
N
N
N
N
N
Cl
N
H
N
CH3
RO
Cl
N
O
Cl
N
O
+
RO
BzO
O
BzO
O
OAc
OR OR
8
OR OR
OBz OBz
OBz OBz
7
R
7, 8
a
6
Bz
H
(iv)
b
(i) SnCl4, acetonitrile; (ii) PhB(OH)2, [Pd(PPh3)4], toluene; (iii) (CH3)3Al, [Pd(PPh3)4],THF;
(iv) MeONa, MeOH
SCHEME 2
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Hocek, Holý, Dvořáková:
2,6-dih alopurin es. Reaction of com poun d 7a with trim eth ylalum in ium (in
an alogy to th e kn own 14 m eth ylation of 6-ch loropurin es) un der [Pd(PPh 3)4]
catalysis afforded th e 2-m eth yl-6-ph en ylpurin e 8a in a good yield (86%).
In con trast to th e 2,6-dich loropurin e 6, an an alogous reaction of th e
kn own 10 6-ch loro-2-iodopurin e n ucleoside 9 with on e equivalen t of
ph en ylboron ic acid gave selectively (in accord with previous results1b,13
)
th e isom eric 6-ch loro-2-ph en ylpurin e 10a in 76% yield (Sch em e 3). Its reac-
tion with 2 equivalen ts of ph en ylboron ic acid led to th e expected 2,6-di-
ph en ylpurin e 11a. Com poun ds 10a an d 11a were previously prepared15
less efficien tly by a ph otoch em ical approach usin g irradiation of h igh ly
dilute solution of 9 in ben zen e.
Cl
Cl
N
N
N
N
N
N
(i)
(ii)
N
N
N
N
I
N
N
AcO
RO
O
O
RO
O
OAc OAc
OR OR
R
10, 11
9
OR OR
10
Ac
H
a
b
11
(iii)
(i) PhB(OH)2 (1 eq.), [Pd(PPh3)4], toluene; (ii) PhB(OH)2 (2.6 eq.), [Pd(PPh3)4], toluene;
(iii) MeONa, MeOH
SCHEME 3
Th e acyl-protected ribon ucleosides 3a–5a, 7a, 8a, 10a an d 11a were
deprotected by th e treatm en t with catalytic am oun t of sodium m eth oxide
in m eth an ol to give free n ucleosides 3b–5b, 7b, 8b, 10b an d 11b in good
yields (ca 90%).
All com poun ds were fully ch aracterized by 1H an d 13C NMR an d m ass
spectra an d by elem en tal an alysis or HR MS. Th e structure of com poun d 6
was in depen den tly verified by m ean s of COSY, HMBC, HMQC an d NOE
experim en ts. Assign m en t of th e sign als of th e oth er products was based on
an alogy with our previous results1,2,5
.
In con clusion , th e 2-substituted-6-ph en ylpurin e ribon ucleosides were
prepared by h alo-deam in ation s of 2-am in o-6-ph en ylpurin es, by th e selec-
tive Suzuki–Miyaura cross-couplin g reaction s of 2,6-dih alopurin es an d by
subsequen t alkylation of th e 2-h alopurin es followed by MeONa-m ediated
deprotection . Th e title n ucleoside an alogues 3b–5b, 7b, 8b, 10b an d 11b
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Cytostatic 6-Arylpurine Nucleosides
329
were tested for th eir cytostatic activity (in h ibition of cell growth of th e fol-
lowin g cell cultures: m ouse leukem ia L1210 cells (ATCC CCL 219), m urin e
L929 cells (ATCC CCL 1), h um an cervix carcin om a HeLa S3 cells (ATCC
CCL 2.2) an d h um an T lym ph oblastoid CCRF-CEM cell lin e (ATCC CCL
119)). In con trast to th e sign ifican t in vitro activity of th e correspon din g
2-un substituted 6-ph en ylpurin e ribon ucleosides in th ese cell lin es, n eith er
th e 2-substituted-6-ph en ylpurin e n ucleosides 3b–5b, 7b, 8b an d 11b n or
th e 6-ch loro-2-ph en ylpurin e riboside 10b exerted an y con siderable activity
in an y of th ese assays16. Th ese results, togeth er with th e previous kn owl-
edge2 of th e in activity of 2-am in o-6-ph en ylpurin es, sh ow th at th e replace-
m en t of th e h ydrogen in position 2 of cytostatic 6-ph en ylpurin e ribo-
n ucleosides by diverse types of substituen ts leads to th e loss of activity17
.
EXPERIMENTAL
Un less oth erwise stated, solven ts were evaporated at 40 °C/2 kPa an d com poun ds were dried
at 60 °C/2 kPa over P2O5. Meltin g poin ts were determ in ed on a Kofler block an d are un cor-
rected. Optical rotation s were m easured at 25 °C on a Autopol IV (Rudolph Research An alyt-
ical) polarim eter, [α]D values are given in 10–1 deg cm 2 g–1. NMR spectra were m easured on a
Bruker AMX-3 400 (400 MHz for 1H, 100.6 MHz for 13C an d 376.5 MHz for 19F), an d on a
Bruker DRX 500 (500 MHz for 1H, 125.8 MHz for 13C an d 470.59 MHz for 19F). Ch em ical
sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. TMS was used as in tern al
stan dard for 1H an d 13C NMR spectra; CFCl3 was an in tern al stan dard for 19F spectra. Mass
spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter usin g FAB (ion ization by
Xe, acceleratin g voltage 8 kV, glycerol m atrix). Toluen e was degassed in vacuo an d stored
over m olecular sieves un der argon . DMF was distilled from P2O5, degassed in vacuo an d
stored over m olecular sieves un der argon . THF was refluxed with Na an d ben zoph en on e
un der argon an d fresh ly distilled prior to use. Cytostatic activity tests were perform ed as
described in ref.2. 6-Ch loro-2-iodo-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)purin e10 (9) an d
2-am in o-6-ph en yl-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)purin e2 (1) were prepared accordin g
to literature procedures.
2-Ch loro-6-ph en yl-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)purin e (2)
A solution of of 2-am in o-6-ph en ylpurin e n ucleoside 1 (470 m g, 1 m m ol) in 1,2-dich loro-
eth an e (10 m l) was stirred at –10 °C wh ile a solution of SbCl3 (350 m g, 1.5 m m ol) in
1,2-dich loroeth an e (10 m l) was added dropwise followed by i-Am ONO (1 m l, 7.5 m m ol).
Stirrin g at –10 °C was con tin ued for 3 h , th en th e solven t was evaporated an d th e residue
was ch rom atograph ed on a silica gel colum n (50 g, eth yl acetate–ligh t petroleum 1 : 2) to
give com poun d 2 as colourless oil; yield 145 m g (30%). EI MS, m/z (rel.%): 488 (7) [M], 259
(42), 138 (43), 43 (100). 1H NMR (500 MHz, CDCl3): 2.10, 2.17 an d 2.18 (3 × s, 3 × 3 H, 3 ×
CH3CO); 4.43–4.50 (m , 3 H, H-4′ an d 2 × H-5′); 5.62–5.64 (m , 1 H, H-3′); 5.85 (t, 1 H, J =
5.7, H-2′); 6.30 (d, 1 H, J = 5.7, H-1′); 7.55–7.57 (m , 3 H, H-arom .); 8.28 (s, 1 H, H-8);
8.76–8.78 (m , 2 H, H-arom .). 13C NMR (100.6 MHz, CDCl3): 20.36, 20.54 an d 20.78 (3 ×
CH3); 63.02 (CH2-5′); 70.69 (CH-3′); 73.18 (CH-2′); 80.66 (CH-4′); 85.91 (CH-1′); 128.73,
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

330
Hocek, Holý, Dvořáková:
130.09 an d 131.93 (CH-arom .); 130.53 an d 134.21 (C-5 an d C-i-arom .); 142.63 (CH-8);
153.71, 154.54 an d 157.21 (C-4, C-2 an d C-6); 169.38, 169.57 an d 170.24 (3 × CO). HR MS
(EI), calculated for C22H21ClN4O7 [M]: 488.1099; foun d: 488.1082.
2-Brom o-6-ph en yl-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)purin e (3a)
Isoam yl n itrite (2 m l, 15 m m ol) was added to a stirred m ixture of 2-am in o-6-ph en ylpurin e
n ucleoside 1 (490 m g, 1.04 m m ol), CHBr3 (6 m l, 69 m m ol) an d NiBr2 (250 m g, 1.9 m m ol)
in THF (20 m l) at room tem perature. Th en th e m ixture was refluxed for 8 h an d th e solven t
was evaporated. Th e residue was dissolved in ch loroform (100 m l) an d wash ed with water (2 ×
100 m l). Th e organ ic layer was dried with MgSO4 an d evaporated. Th e residue was
ch rom atograph ed on a silica gel colum n (100 g, eth yl acetate–ligh t petroleum 1 : 2 to 1 : 1)
to give com poun d 3a as yellowish foam ; yield 340 m g (61%). FAB MS, m/z (rel.%): 535/533
(30) [M + H], 277/275 (100). 1H NMR (400 MHz, CDCl3): 2.11, 2.17 an d 2.19 (3 × s, 3 × 3 H,
3 × CH3CO); 4.42–4.51 (m , 3 H, H-4′ an d 2 × H-5′); 5.62–5.66 (m , 1 H, H-3′); 5.85 (dd, 1 H, J =
5.6 an d 5.7, H-2′); 6.30 (d, 1 H, J = 5.7, H-1′); 7.55–7.57 (m , 3 H, H-arom .); 8.26 (s, 1 H,
H-8); 8.75–8.78 (m , 2 H, H-arom .). 13C NMR (100.6 MHz, CDCl3): 20.36, 20.54 an d 20.79 (3 ×
CH3); 63.07 (CH2-5′); 70.76 (CH-3′); 73.28 (CH-2′); 80.73 (CH-4′); 86.02 (CH-1′); 128.73,
130.15 an d 131.93 (CH-arom .); 130.93 an d 134.22 (C-5 an d C-arom .); 142.45 (CH-8);
145.26, 153.58 an d 157.20 (C-2, C-4 an d C-6); 169.40, 169.57 an d 170.25 (3 × CO). HR MS
(FAB), calculated for C22H2281BrN4O7 [M + H]: 535.0651; foun d: 535.0625.
2-Iodo-6-ph en yl-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)purin e (4a)
Isoam yl n itrite (2 m l, 15 m m ol) was added to a stirred m ixture of 2-am in o-6-ph en ylpurin e
n ucleoside 1 (1.4 g, 3 m m ol), I2 (750 m g, 3 m m ol), CuI (600 m g, 3.2 m m ol), CH2I2 (2.5 m l,
31 m m ol) in THF (20 m l) at room tem perature. Th en th e m ixture was refluxed for 5 h an d
th e solven t was evaporated. Th e residue was dissolved in ch loroform (100 m l) an d wash ed
with saturated aqueous Na2S2O3 (2 × 100 m l) an d water (100 m l). Th e organ ic layer was
dried with MgSO4 an d evaporated. Th e residue was ch rom atograph ed on a silica gel colum n
(100 g, eth yl acetate–ligh t petroleum 1 : 2 to 1 : 1) to give com poun d 4a as yellowish foam ;
yield 940 m g (54%). FAB MS, m/z (rel.%): 581 (7) [M + H], 97 (100). 1H NMR (400 MHz,
CDCl3): 2.11, 2.15 an d 2.18 (3 × s, 3 × 3 H, 3 × CH3CO); 4.40–4.50 (m , 3 H, H-4′ an d 2 ×
H-5′); 5.65 (m , 1 H, H-3′); 5.84 (dd, 1 H, J = 5.5 an d 5.7, H-2′); 6.26 (d, 1 H, J = 5.5, H-1′);
7.53–7.55 (m , 3 H, H-arom .); 8.18 (s, 1 H, H-8); 8.72–8.75 (m , 2 H, H-arom .). 13C NMR
(100.6 MHz, CDCl3): 20.39, 20.54 an d 20.83 (3 × CH3); 63.07 (CH2-5′); 70.74 (CH-3′); 73.33
(CH-2′); 80.70 (CH-4′); 86.19 (CH-1′); 119.74, 131.49 an d 134.30 (C-2, C-5 an d C-arom .);
128.70, 130.10 an d 131.79 (CH-arom .); 142.06 (CH-8); 152.90 an d 156.66 (C-4 an d C-6);
169.37, 169.53 an d 170.23 (3 × CO). HR MS (FAB), calculated for C22H22IN4O7 [M + H]:
581.0533; foun d: 581.0546.
6-Ph en yl-9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-2-(trifluorom eth yl)purin e (5a)
A m ixture of 2-iodo-6-ph en ylpurin e n ucleoside 4a (580 m g, 1 m m ol), CF3SiMe3 (206 µl,
1.4 m m ol), KF (82 m g, 1.4 m m ol), CuI (304 m g, 1.6 m m ol) in DMF (1 m l) an d 1-m eth yl-
2-pyrrolidin on e (1 m l) was stirred in a sealed 5-m l glass vial at 60 °C for 24 h . After coolin g
to room tem perature, th e solven ts were evaporated an d th e residue was ch rom atograph ed
on a silica gel colum n (50 g, eth yl acetate–ligh t petroleum 1 : 2) to give com poun d 5a as
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Cytostatic 6-Arylpurine Nucleosides
331
colourless oil; yield 250 m g (48%). FAB MS, m/z (rel.%): 523 (33) [M + H], 139 (100).
1H NMR (400 MHz, CDCl3): 2.09, 2.12 an d 2.18 (3 × s, 3 × 3 H, 3 × CH3CO); 4.40–4.52 (m ,
3 H, H-4′ an d 2 × H-5′); 5.70 (m , 1 H, H-3′); 5.89 (dd, 1 H, J = 5.5 an d 5.2, H-2′); 6.32 (d,
1 H, J = 5.2, H-1′); 7.56–7.58 (m , 3 H, H-arom .); 8.41 (s, 1 H, H-8); 8.85–8.88 (m , 2 H,
H-arom .). 13C NMR (100.6 MHz, CDCl3): 20.27, 20.49 an d 20.65 (3 × CH3); 63.04 (CH2-5′);
70.72 (CH-3′); 73.52 (CH-2′); 80.79 (CH-4′); 86.86 (CH-1′); ca 120 (very weak q, CF3); 128.79,
130.22 an d 131.98 (CH-arom .); 132.33 an d 134.38 (C-5 an d C-arom .); 144.35 (CH-8); ca 150
(very weak q, C-2); 152.10 an d 155.94 (C-4 an d C-6); 169.39, 169.50 an d 170.23 (3 × CO).
19F NMR (470.6 MHz, CDCl3): –69.33. HR MS (FAB), calculated for C23H22F3N4O7 [M + H]:
523.1441; foun d: 523.1442.
2,6-Dich loro-9-(2,3,5-tri-O-ben zoyl-β-D-ribofuran osyl)purin e12 (6)
Sn Cl4 (2.4 m l, 20 m m ol) was added to a stirred solu tion of 2,6-dich loropu rin e (1.89 g,
10 m m ol) an d 1-O-acetyl-2,3,5-tri-O-ben zoyl-D-ribofuran ose (5.04 g, 10 m m ol) in aceton itrile
(50 m l), an d th e m ixture was stirred at room tem perature for 6 h . Th en th e solven t was
evaporated an d th e residue was dissolved in ch loroform (250 m l) an d wash ed with saturated
aqueous NaHCO3 (2 × 200 m l) an d water (200 m l). Th e organ ic layer was dried with MgSO4
an d evaporated. Th e residue was ch rom atograph ed on a silica gel colum n (250 g, eth yl ace-
tate–ligh t petroleum 1 : 2 to 1 : 1). Th e 9-substituted β-D-ribofuran osylpurin e 9 was isolated
in pure form as th e m ajor product alon g with a m ixture of m in or isom ers; yield 3.32 g
(52%), yellowish foam . FAB MS, m/z (rel.%): 633 (5) [M + H], 105 (100). 1H NMR (500 MHz,
CDCl3): 4.73 (dd, 1 H, J = 4.1 an d 12.3, H-5′b); 4.88 (ddd, 1 H, J = 3.2, 4.1 an d 5.5, H-4′);
4.93 (dd, 1 H, J = 3.2 an d 12.3, H-5′a); 6.14 (dd, 1 H, J1 = J2 = 5.5, H-3′); 6.18 (dd, 1 H, J1
=
J2 = 5.5, H-2′); 6.49 (d, 1 H, J = 5.5, H-1′); 7.36–7.39, 7.42–7.48, 7.54–7.62 an d 7.92–8.07 (m ,
15 H, H-arom .); 8.29 (s, 1 H, H-8). 13C NMR (100.6 MHz, CDCl3): 63.46 (CH2-5′); 71.53
(CH-3′); 74.28 (CH-2′); 81.50 (CH-4′); 86.97 (CH-1′); 128.58, 128.61, 128.72, 129.60, 129.85,
129.89, 133.63, 133.87 an d 133.98 (CH-arom .); 128.07, 129.02 an d 131.32 (C-5 an d
C-arom .); 143.80 (CH-8); 152.32 an d 153.46 (C-2 an d C-6); 152.60 (C-4); 165.12, 165.28 an d
166.03 (C=O). HR MS (FAB), calculated for C31H23Cl2N4O7 [M + H]: 633.0944; foun d:
633.0910.
Th e Suzuki–Miyaura Cross-Couplin g of Ph en ylboron ic Acid with Halopurin es.
Gen eral Procedure
Toluen e (10 m l) was added to an argon -purged flask con tain in g th e protected h alopurin e
n ucleoside 6 or 9 (1 m m ol), K2CO3 (200 m g, 1.5 m m ol), ph en ylboron ic acid (1.0-2.6 m m ol)
an d [Pd(PPh 3)4] (59 m g, 0.05 m m ol) an d th e m ixture was stirred un der argon at 100 °C for
8 h . After coolin g to am bien t tem perature, th e m ixture was evaporated in vacuo an d th e resi-
due was ch rom atograph ed on a silica gel colum n (50 g, eth yl acetate–ligh t petroleum 1 : 2
to 9 : 1). Evaporation an d dryin g of th e product con tain in g fraction s afforded th e arylpurin e
n ucleosides 7a, 10a or 11a as foam s or am orph ous solids.
2-Chloro-6-phenyl-9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine (7a). Th is com poun d was
prepared from 2,6-dich loropurin e n ucleoside 6 (1.267 g, 2 m m ol) an d Ph B(OH)2 (244 m g,
2 m m ol); yield 1.08 g (80%); yellowish am orph ous solid. FAB MS, m/z (rel.%): 675 (40) [M + H],
445 (100). 1H NMR (500 MHz, CDCl3): 4.76 (dd, 1 H, J = 12.1 an d 4.2, H-5′b); 4.86–4.89 (m ,
1 H, H-4′); 4.93 (dd, 1 H, J = 12.1 and 3.1, H-5′a); 6.19 (t, 1 H, J = 5.6, H-3′); 6.24 (t, 1 H, J = 5.6,
H-2′); 6.57 (d, 1 H, J = 5.5, H-1′); 7.35–7.62 (m , 12 H, H-arom .); 7.96 (d, 2 H, J = 7.5,
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Hocek, Holý, Dvořáková:
H-arom .); 8.04 (d, 2 H, J = 7.4, H-arom .); 8.09 (d, 2 H, J = 7.5, H-arom .); 8.29 (s, 1 H, H-8);
8.73–8.76 (m , 2 H, H-arom .). 13C NMR (100.6 MHz, CDCl3): 63.70 (CH2-5′); 71.58 (CH-3′);
74.28 (CH-2′); 81.24 (CH-4′); 86.48 (CH-1′); 128.57, 128.59, 128.70, 129.67, 129.88, 129.93,
130.11, 131.88, 133.53, 133.81 an d 133.89 (CH-arom .); 128.24, 129.17, 130.57 an d 134.25
(C-5 an d C-arom .); 142.75 (CH-8); 153.76, 154.61 an d 157.21 (C-2, C-4 an d C-6); 165.17,
165.33 an d 166.11 (C=O). HR MS (FAB), calculated for C37H28ClN4O7 [M + H]: 675.1647;
foun d: 675.1667.
6-Chloro-2-phenyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine15 (10a). Th is com poun d was
prepared from 6-ch loro-2-iodopurin e n ucleoside 9 (538 m g, 1 m m ol) an d Ph B(OH)2 (130 m g,
1.07 m m ol); yield 370 m g (76%), yellowish am orph ous solid. FAB MS, m/z (rel.%): 489 (29)
[M + H], 97 (100). 1H NMR (500 MHz, CDCl3): 1.96, 2.11 an d 2.18 (3 × s, 3 × 3 H, 3 ×
CH3CO); 4.31–4.35 an d 4.43–4.49 (2 × m , 3 H, H-4′ an d 2 × H-5′); 5.85 (dd, 1 H, J = 5.6 an d
5.4, H-3′); 6.12 (dd, 1 H, J = 5.6 an d 4.3, H-2′); 6.30 (d, 1 H, J = 4.3, H-1′); 7.49–7.52 (m , 3 H,
H-arom .); 8.22 (s, 1 H, H-8); 8.50–8.53 (m , 2 H, H-arom .). 13C NMR (100.6 MHz, CDCl3):
20.38, 20.50 an d 20.54 (3 × CH3); 62.54 (CH2-5′); 70.03 (CH-3′); 73.13 (CH-2′); 80.07
(CH-4′); 87.22 (CH-1′); 128.65, 128.69 an d 131.04 (CH-arom .); 130.74 (C-5); 136.26
(C-i-arom .); 143.66 (CH-8); 151.51, 151.94 an d 159.93 (C-4, C-2 an d C-6); 169.31, 169.44
an d 170.26 (3 × CO). HR MS (FAB), calculated for C22H22ClN4O7 [M + H]: 489.1177; foun d:
489.1192.
2,6-Diphenyl-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine15 (11a ). Th is com poun d was
prepared from 6-ch loro-2-iodopurin e n ucleoside 9 (538 m g, 1 m m ol) an d Ph B(OH)2 (320 m g,
3 m m ol); yield 440 m g (83%), yellowish am orph ous solid. FAB MS, m/z (rel.%): 531 (30)
[M + H], 273 (100). 1H NMR (500 MHz, CDCl3): 1.98, 2.12 an d 2.20 (3 × s, 3 × 3 H, 3 ×
CH3CO); 4.33–4.37 (m , 1 H) an d 4.47–4.52 (m , 2 H, H-4′ an d 2 × H-5′); 5.95 (t, 1 H, J = 5.4,
H-3′); 6.21 (dd, 1 H, J = 4.4 an d 5.4, H-2′); 6.29 (d, 1 H, J = 4.4, H-1′); 7.48–7.62 (m , 6 H,
H-arom .); 8.23 (s, 1 H, H-8); 8.68 (d, 2 H, J = 7.3, H-arom .); 8.91 (d, 2 H, J = 7.3, H-arom .).
13C NMR (125.8 MHz, CDCl3): 20.48, 20.61 an d 20.64 (3 × CH3); 62.76 (CH2-5′); 70.26
(CH-3′); 73.23 (CH-2′); 79.98 (CH-4′); 87.03 (CH-1′); 128.57, 128.61, 128.66, 129.91, 130.36
an d 131.12 (CH-arom .); 130.43 (C-5); 135.89 an d 138.04 (C-i-arom .); 142.97 (CH-8); 152.97
(C-4); 154.99 an d 159.24 (C-2 an d C-6); 169.44, 169.54 an d 170.45 (3 × CO). HR MS (FAB),
calculated for C28H27N4O7 [M + H]: 531.1880; foun d: 531.1873.
2-Meth yl-6-ph en yl-9-(2,3,5-tri-O-ben zoyl-β-D-ribofuran osyl)purin e (8a)
Trim eth ylalum in ium (2 M solution in toluen e, 1.5 m l, 3 m m ol) was added dropwise to a
stirred solution of 2-ch loro-6-ph en ylpurin e n ucleoside 10a (675 m g, 1 m m ol) an d [Pd(PPh 3)4]
(58 m g, 0.05 m m ol) in THF (15 m l) un der argon atm osph ere at room tem perature. Th e m ix-
ture was th en stirred at 80 °C for 7 h an d allowed to stan d at room tem perature overn igh t.
Th en th e m ixture was poured in to a m ixture of crush ed ice (200 m l) an d NaHCO3 (1 g), an d
extracted with ch loroform (2 × 100 m l). Th e organ ic layers were dried with MgSO4 an d
evaporated. Th e residue was ch rom atograph ed on a silica gel colum n (100 g, eth yl acetate–
ligh t petroleum 1 : 2 to 1 : 1) to give com poun d 11a as yellowish oil; yield 560 m g (86%).
FAB MS, m/z (rel.%): 655 (7) [M + H], 105 (100). 1H NMR (400 MHz, CDCl3): 2.85 (s, 3 H,
CH3); 4.73–4.78 (m , 1 H) an d 4.85–4.95 (m , 2 H, H-4′ an d H-5′); 6.40 (t, 1 H, J = 5.4, H-3′);
6.45 (dd, 1 H, J = 5.4 an d 4.7, H-2′); 6.49 (d, 1 H, J = 4.7, H-1′); 7.35–7.60 (m , 12 H,
H-arom .); 7.94–8.04 (m , 6 H, H-arom .); 8.20 (s, 1 H, H-8); 8.69–8.71 (m , 2 H, H-arom .).
13C NMR (100.6 MHz, CDCl3): 26.13 (CH3); 63.68 (CH2-5′); 71.58 (CH-4′); 74.13 (CH-3′);
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Cytostatic 6-Arylpurine Nucleosides
333
80.68 (CH-2′); 87.16 (CH-1′); 128.53, 128.57, 129.65, 129.78, 129.84, 129.87, 130.84, 133.36,
133.65 an d 133.76 (CH-arom .); 128.85, 129.33 an d 135.70 (C-5 an d C-arom .); 142.20
(CH-8); 152.55, 155.16 an d 162.67 (C-2, C-4 an d C-6); 165.15, 165.28 an d 166.13 (C=O).
HR MS (FAB), calculated for C38H31N4O7 [M + H]: 655.2193; foun d: 655.2189.
Deacylation of Nucleosides 3a–5a, 7a, 8a, 10a an d 11a.
Gen eral Procedure
A 1 M m eth an olic MeONa (100 µl, 0.1 m m ol) was added to a solution of a protected
n ucleoside 3a–5a, 7a, 8a, 10a or 11a (0.5–0.8 m m ol) in MeOH (20 m l) an d th e m ixture was
stirred at am bien t tem perature overn igh t. Th e solven t was evaporated an d th e residue was
ch rom atograph ed on a silica gel colum n (50 g, eth yl acetate–MeOH 9 : 1). Th e crude prod-
ucts were recrystallized from EtOH/toluen e/h eptan e to give free n ucleosides 3b–5b, 7b, 8b,
10b or 11b.
2-Bromo-6-phenyl-9-(β-D-ribofuranosyl)purine (3b). Wh ite crystals, yield 86%, m .p. 115–118 °C,
[α]D –22.4 (c 0.6, DMF). FAB MS, m/z (rel.%): 409/407 (25) [M + H], 277/275 (100). 1H NMR
(500 MHz, DMSO-d6): 3.60–3.63 (m , 1 H, H-5′b); 3.70–3.74 (m , 1 H, H-5′a); 4.00–4.03 (m ,
1 H, H-4′); 4.20–4.22 (m , 1 H, H-3′); 4.59–4.61 (m , 1 H, H-2′); 5.12, 5.28 an d 5.61 (3 × vbrs,
3 × OH); 6.03 (d, 1 H, J = 5.3, H-1′); 7.62–7.65 (m , 3 H, H-arom .); 8.74–8.77 (m , 2 H,
H-arom .); 8.96 (s, 1 H, H-8). 13C NMR (125.8 MHz, DMSO-d6): 60.97 (CH2-5′); 70.08 (CH-3′);
73.84 (CH-2′); 85.71 (CH-4′); 87.61 (CH-1′); 128.87, 129.53 an d 131.94 (CH-arom .); 130.51
an d 133.96 (C-5 an d C-i-arom .); 143.77 (C-2); 145.43 (C-8); 153.95 an d 154.88 (C-4 an d
C-6). HR MS (FAB), calculated for C16H1679BrN4O4 [M + H]: 407.0355; foun d: 407.0337. For
C
16H15BrN4O4 (407.2) calculated: 47.19% C, 3.71% H, 13.76% N; foun d: 47.38% C, 3.85% H,
13.42% N.
2-Iodo-6-phenyl-9-(β-D-ribofuranosyl)purine (4b). Wh ite crystals, yield 96%, m .p. 131–133 °C,
[α]D –8.8 (c 0.5, DMF). FAB MS, m/z (rel.%): 455 (52) [M + H], 323 (100). 1H NMR (400 MHz,
DMSO-d6): 3.57–3.63 (m , 1 H, H-5′b); 3.69–3.74 (m , 1 H, H-5′a); 3.98-4.02 (m , 1 H, H-4′);
4.18–4.22 (m , 1 H, H-3′); 4.58–4.63 (m , 1 H, H-2′); 5.05 (t, 1 H, J = 5.4, 5′-OH); 5.26 (d, 1 H,
J = 5.1, 3′-OH); 5.56 (d, 1 H, J = 5.8, 2′-OH); 6.02 (d, 1 H, J = 5.5, H-1′); 7.60–7.63 (m , 3 H,
H-arom .); 8.70–8.75 (m , 2 H, H-arom .); 8.86 (s, 1 H, H-8). 13C NMR (100.6 MHz, DMSO-d6):
61.06 (CH2-5′); 70.19 (CH-3′); 73.75 (CH-2′); 85.77 (CH-4′); 87.43 (CH-1′); 120.17 (C-2);
128.77, 129.43 an d 131.69 (CH-arom .); 130.81 an d 134.05 (C-5 an d C-i-arom .); 144.85 (C-8);
153.30 an d 154.34 (C-4 an d C-6). HR MS (FAB), calculated for C16H16IN4O4 [M + H]:
455.0216; foun d: 455.0247. For C16H15IN4O4 (454.2) calculated: 42.31% C, 3.33% H, 12.33% N;
foun d: 42.54% C, 3.48% H, 12.05% N.
6-Phenyl-9-(β-D-ribofuranosyl)-2-(trifluoromethyl)purine (5b). Wh ite crystals, yield 91%, m .p.
91–94 °C, [α]D –35.9 (c 0.7, DMF). FAB MS, m/z (rel.%): 397 (100) [M + H]. 1H NMR (400 MHz,
DMSO-d6): 3.60–3.65 (m , 1 H, H-5′b); 3.70–3.75 (m , 1 H, H-5′a); 4.02–4.04 (brm , 1 H, H-4′);
4.24–4.26 (m , 1 H, H-3′); 4.66–4.71 (m , 1 H, H-2′); 5.04 (t, 1 H, J = 5.2, 5′-OH); 5.28 (d, 1 H,
J = 5.1, 3′-OH); 5.57 (d, 1 H, J = 5.7, 2′-OH); 6.14 (d, 1 H, J = 5.2, H-1′); 7.60–7.70 (m , 3 H,
H-arom .); 8.80–8.85 (m , 2 H, H-arom .); 9.16 (s, 1 H, H-8). 13C NMR (100.6 MHz, DMSO-d6):
1
61.03 (CH2-5′); 70.20 (CH-3′); 73.83 (CH-2′); 85.88 (CH-4′); 87.79 (CH-1′); 120.01 (q, JCF
=
274.9, CF3); 128.89, 129.58 an d 131.94 (CH-arom .); 128.56 an d 134.01 (C-5 an d C-i-arom .);
2
147.40 (C-8); 148.23 (q, JCF = 35.6, C-2); 152.45 an d 153.54 (C-4 an d C-6). 19F NMR
(470.6 MHz, DMSO-d6): –66.91. For C17H15F3N4O4 (396.3) calculated: 51.52% C, 3.81% H,
14.14% N; foun d: 51.24% C, 4.07% H, 13.89% N.
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Hocek, Holý, Dvořáková:
2-Chloro-6-phenyl-9-(β-D-ribofuranosyl)purine (7b). Wh ite crystals, yield 93%, m .p. 184–187 °C,
[α]D –38.0 (c 0.9, DMF). FAB MS, m/z (rel.%): 363 (40) [M + H], 231 (100). 1H NMR (400 MHz,
DMSO-d6): 3.58–3.65 (m , 1 H, H-5′b); 3.70–3.76 (m , 1 H, H-5′a); 3.99–4.03 (m , 1 H, H-4′);
4.19–4.22 (m , 1 H, H-3′); 4.57–4.62 (m , 1 H, H-2′); 5.08 (t, 1 H, J = 5.4, 5′-OH); 5.25 (d, 1 H,
J = 5.2, 3′-OH); 5.58 (d, 1 H, J = 5.8, 2′-OH); 6.03 (d, 1 H, J = 5.2, H-1′); 7.60–7.64 (m , 3 H,
H-arom .); 8.75–8.78 (m , 2 H, H-arom .); 8.97 (s, 1 H, H-8). 13C NMR (100.6 MHz, DMSO-d6):
60.95 (CH2-5′); 70.04 (CH-3′); 73.86 (CH-2′); 85.67 (CH-4′); 87.69 (CH-1′); 128.82, 129.50
an d 131.89 (CH-arom .); 130.16 an d 133.98 (C-5 an d C-i-arom .); 145.59 (C-8); 152.69, 154.05
an d 154.87 (C-2, C-4 an d C-6). HR MS (FAB), calculated for C16H16ClN4O4 [M + H]:
363.0860; foun d: 363.0824. For C16H15ClN4O4 (362.7) calculated: 52.97% C, 4.17% H,
9.77% Cl, 15.44% N; foun d: 53.33% C, 4.33% H, 9.40% Cl, 15.09% N.
2-Methyl-6-phenyl-9-(β-D-ribofuranosyl)purine (8b). Wh ite crystals, yield 92%, m .p. 166–169 °C,
[α]D –50.1 (c 0.7, DMF). FAB MS, m/z (rel.%): 343 (80) [M + H], 211 (100). 1H NMR (400 MHz,
DMSO-d6): 2.77 (s, 3 H, CH3); 3.58–3.64 (m , 1 H, H-5′b); 3.70–3.75 (m , 1 H, H-5′a);
3.99–4.03 (m , 1 H, H-4′); 4.19–4.23 (m , 1 H, H-3′); 4.64–4.69 (m , 1 H, H-2′); 5.20 (dd, 1 H, J =
6.2 an d 5.1, 5′-OH); 5.23 (d, 1 H, J = 4.9, 3′-OH); 5.50 (d, 1 H, J = 6.0, 2′-OH); 6.07 (d, 1 H, J =
5.9, H-1′); 7.56–7.61 (m , 3 H, H-arom .); 8.79–8.81 (m , 2 H, H-arom .); 8.81 (s, 1 H, H-8). 13C NMR
(100.6 MHz, DMSO-d6): 25.68 (CH3); 61.36 (CH2-5′); 70.43 (CH-3′); 73.56 (CH-2′); 85.81
(CH-4′); 87.39 (CH-1′); 128.53, 129.30 an d 130.93 (CH-arom .); 128.91 an d 135.30 (C-5 an d
C-i-arom .); 144.27 (C-8); 152.69, 152.81 an d 160.85 (C-2, C-4 an d C-6). HR MS (FAB), calcu-
lated for C17H19N4O4 [M + H]: 343.1406; foun d: 343.1377. For C17H18N4O4 (342.3) calcu-
lated: 59.64% C, 5.30% H, 16.37% N; foun d: 59.82% C, 5.43% H, 16.03% N.
6-Chloro-2-phenyl-9-(β-D-ribofuranosyl)purine (10b ). Yellowish crystals, yield 90%, slow
decom p. >156 °C, [α]D +32.5 (c 0.7, DMF). FAB MS, m/z (rel.%): 363 (12) [M + H], 93 (100).
1H NMR (400 MHz, DMSO-d6): 3.60 (dd, 1 H, J = 11.8 an d 3.9, H-5′b); 3.72 (dd, 1 H, J = 11.8
an d 3.9, H-5′a); 4.00 (m , 1 H, H-4′); 4.25 (dd, 1 H, J = 4.7 an d 3.6, H-3′); 4.70 (dd, 1 H, J =
5.2 an d 4.7, H-2′); OH sign als were exch an ged; 6.12 (d, 1 H, J = 5.2, H-1′); 7.53–7.56 (m ,
3 H, H-arom .); 8.39–8.42 (m , 2 H, H-arom .); 8.91 (s, 1 H, H-8). 13C NMR (125.8 MHz,
DMSO-d6): 61.12 (CH2-5′); 70.19 (CH-3′); 73.83 (CH-2′); 85.70 (CH-4′); 88.03 (CH-1′);
128.00, 128.83 an d 131.00 (CH-arom .); 130.12 (C-5); 136.06 (C-i-arom .); 146.14 (C-8);
149.44 (C-4); 152.55 an d 157.87 (C-2 an d C-6). HR MS (FAB), calculated for C16H16ClN4O4
[M + H]: 363.0860; foun d: 363.0802. For C16H15ClN4O4 (362.7) calculated: 52.97% C, 4.17% H,
9.77% Cl, 15.44% N; foun d: 53.24% C, 4.38% H, 9.45% Cl, 15.14% N.
2,6-Diphenyl-9-(β-D-ribofuranosyl)purine (11b). Yellowish crystals, yield 84%, m .p. 196–199 °C,
[α]D +12.5 (c 0.9, DMF). FAB MS, m/z (rel.%): 405 (34) [M + H], 273 (100). 1H NMR (500 MHz,
DMSO-d6): 3.60–3.65 an d 3.72–3.77 (2 × m , 2 H, 2 × H-5′); 4.02 (m , 1 H, H-4′); 4.29 (m , 1 H,
H-3′); 4.78 (m , 1 H, H-2′); 5.07 (t, 1 H, J = 5.1, 5′-OH); 5.30 (d, 1 H, J = 4.7, 3′-OH); 5.60 (d,
1 H, J = 5.7, 2′-OH); 6.20 (d, 1 H, J = 5.5, H-1′); 7.52–7.65 (m , 6 H, H-arom .); 8.59 (d, 1 H, J =
7.2, H-arom .); 8.91 (s, 1 H, H-8); 8.95 (d, 1 H, J = 7.1, H-arom .). 13C NMR (125.8 MHz,
DMSO-d6): 61.31 (CH2-5′); 70.37 (CH-3′); 73.68 (CH-2′); 85.61 (CH-4′); 87.47 (CH-1′);
127.93, 128.69, 128.74 an d 129.45 (CH-arom .); 129.78 (C-5); 130.36 an d 131.20 (CH-arom .);
135.51 an d 137.63 (C-i-arom .); 145.34 (C-8); 152.76 (C-4); 153.38 an d 157.36 (C-2 an d C-6).
HR MS (FAB), calculated for
22H20N4O4 (404.4) calculated: 65.34% C, 4.98% H, 13.85% N; foun d: 65.62% C, 4.88% H,
13.52% N.
C22H21N4O4 [M + H]: 405.1563; foun d: 405.1493. For
C
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Cytostatic 6-Arylpurine Nucleosides
335
This work is a part of a research project Z4 055 905, supported by the Grant Agency of the Acad-
emy of Sciences of the Czech Republic (grant No. B4055201 to M. H.), by the COST programme
D.13.20 of the Ministry of Education, Youth and Sports of the Czech Republic (A. H.) and by Sumika
Fine Chemicals Co Ltd. (Osaka, Japan). The cytostatic activity was studied by Dr I. Votruba from
the Institute of Organic Chemistry and Biochemistry whose contribution is gratefully acknowledged.
The authors’ thanks are also due to Ms K. Havlíčková for excellent technical assistance and to the
staff of the mass spectrometry and analytical departments of the Institute.
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3. Lakshman M. K., Hilmer J. H., Martin J. Q., Keeler J. C., Dinh Y. Q. V., Ngassa F. N.,
Russon L. M.: J. Am. Chem. Soc. 2001, 123, 7779.
4. Česnek M., Hocek M., Holý A.: Collect. Czech. Chem. Commun. 2000, 65, 1357.
5. Hocek M., Holý A., Votruba I., Dvořáková H.: Collect. Czech. Chem. Commun. 2001, 66,
483.
6. Hocek M., Holý A., Votruba I., Dvořáková H.: Collect. Czech. Chem. Commun. 2000, 65,
1683.
7. Hocek M., Masojídková M., Holý A.: Collect. Czech. Chem. Commun. 1997, 62, 136.
8. a) Kelley J. L., Linn J. A., Selway J. W. T.: J. Med. Chem. 1989, 32, 1757; b) Kelley J. L.,
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J. W. T.: Eur. J. Med. Chem. 1990, 25, 131.
9. a) Williams B. A., Blay J., Hoskin D. W.: Exp. Cell Res. 1997, 233, 187; b) Carson D. A.,
Wasson D. B., Beutler E.: Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 2232; c) Saven A., Carrera
C. J., Carson D. A., Beutler E., Piro L. D.: Blood 1992, 80, 587.
10. Nair V., Richardson S. G.: Synthesis 1982, 670.
11. Hocek M., Holý A.: Collect. Czech. Chem. Commun. 1999, 64, 229.
12. Compound 6 was previously prepared by the mercuric chloride method: a) Gupta P. K.,
Bhakuni D. S.: Ind. J. Chem., Sect. B 1981, 20, 534; and by fusion of 2,6-dichloropurine
with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose: b) Keeling S. E., Albison F. D., Ayres
B. E., Butchers P. R., Chambers C. L., Cherry P. C., Ellis F., Ewan G. B., Gregson M.,
Knight J., Mills K., Ravenscroft P., Reynolds L. H., Sanjar S., Sheehan M. J.: Bioorg. Med.
Chem. Lett. 2000, 10, 403.
13. Langli G., Gundersen L.-L., Rise F.: Tetrahedron 1996, 52, 5625.
14. Hirota K., Kitade Y., Kanbe Y., Maki Y.: J. Org. Chem.1992, 57, 5268.
15. Nair V., Young D. A.: J. Org. Chem. 1984, 49, 4340.
16. Votruba I.: Unpublished results.
17. After acceptance of this manuscript, a paper reporting cytostatic activity of the
structurally related 2-chloro-6-furylpurine ribonucleoside appeared: Gundersen L.-L.,
Nissen-Meyer J., Spilsberg B.: J. Med. Chem. 2002, 45, 1383.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)