A. Bra˚the et al. / Bioorg. Med. Chem. Lett. 13 (2003) 877–880
879
1
3. For synthesis of 2d and 4f see: Bakkestuen, A. K.; Gun-
dersen, L.-L.; Langli, G.; Liu, F.; Nolsøe, J. M. J. Bioorg.
Med. Chem. Lett. 2000, 10, 1207.
1
4. For synthesis of 2e, 4e and 4g see: Langli, G.; Gundersen,
L.-L.; Rise, F. Tetrahedron 1996, 52, 5625.
5. For synthesis of 2c, see: Nolsøe, J. M. J.; Gundersen, L.-
L.; Rise, F. Acta Chem. Scand. 1999, 53, 366.
6. For synthesis of 3a, 3b, 4d see Gundersen, L.-L.; Bakkes-
tuen, A. K.; Aasen, A. J.; Øveras, H.; Rise, F. Tetrahedron
1
1
˚
1
1
1
1
994, 50, 9743.
7. For synthesis of 4b see Gundersen, L.-L. Tetrahedron Lett.
994, 35, 3155.
8. Compound 2g was prepared essentially as described
before: Koyama, S.; Kumazawa, Z.; Kashimura, N. Nucl.
Acids Res., Symp. Ser. 1982, 11, 41.
Figure 2. Difference in cytotoxicity (a) for the 6-vinylpurines 3a (*)
and 3b (*); (b) 6-phenylalkynylpurines 2d (*) and 2e (*).
1
0
9. Synthesis of compound 4h: Vinyltributyltin (175 mL,
0 0 0
.60 mmol) was added to a solution of 6-chloro-2 ,3 ,5 -tris-
2
7
O-(tert-butyldimethylsilyl)-9-b-d-ribofuranosyl-9H-purine
(
in dry DCE (10 mL) and the resultingmixture was stirred at
3 2 2
315 mg, 0.50 mmol) and (Ph P) PdCl (17.5 mg, 0.025 mmol)
6
potential anticancer compounds,
-position have attracted considerable interest as
0,11,26
reflux under Ar for 4.5 h, cooled to ambient temperature and
evaporated under reduced pressure. The residue was dissolved
in satd. KF in MeOH (20 mL), stirred for 1 h and evaporated.
The crude product was purified by flash chromatography on
silica gel eluting with 0–6% acetone in hexane to give the
1
the highly cyto-
toxic 6-phenylalkynyl- and 6-trans-styrylpurinenucleo-
sides, 2g and 4h have never before been examined in this
context. In the assay employed, these compounds dis-
played toxicity comparable to well known anticancer
drugs.
6
-vinylpurine, pale yellow oil, which was dissolved in dry
DMF (3 mL). Iodobenzene (67 mL, 0.6 mmol), palladium ace-
tate (5.6 mg, 0.025 mg) and ethyldiisopropylamine (260 mL,
1
6
.5 mmol) were added and the resultingmixture was stirred at
ꢃ
0 C under Ar for 15 h. The reaction mixture was evaporated
Acknowledgements
under reduced pressure, and crude product was purified by
flash chromatography on silica gel eluting with 0–6% acetone
in hexane. Yield 225 mg(65%) of the O-silylated styrylpurine,
The Norwegian Research Council is greatly acknowl-
edged for partial financing of Bruker Avance NMR
instruments used in this study. We thank Anne Kristin
Bakkestuen, Geir Langli and Jens Nolsøe for the
preparation of compounds 3b, 4g and 2c, respectively.
1
coloress oil. H NMR (200 MHz, CDCl
8.46 (s, 1H, H-8), 8.42 (d, 1H, J=17.0 Hz), 7.77 (m, 3H), 7.33
3
) d 8.93 (s, 1H, H-2),
(
(
m, 3H), 6.17 (d. 1H, J=5.2 Hz), 4.75 (t, 1H, J=4.6 Hz), 4.38
t, 1H, J 4.0 Hz), 4.19 (m, 1H), 4.07 (dd, 1H, J=11.3 and
4
(
.0 Hz), 3.83 (dd, 1H, J=11.3 and 2.7 Hz), 0.99 (s, 9H), 0.97
s, 9H), 0.82 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H), 0.14 (s, 6H),
1
3
ꢀ
0.02 (s, 3H), ꢀ0.16 (s, 3H); C NMR (50 MHz, CDCl
3
) d
References and Notes
1
1
53.6, 152.3, 151.6, 143.0, 139.4, 136.0, 131.5, 130.2, 129.3,
28.7, 127.8, 126.0, 122.1, 88.1, 85.5, 71.9, 62.4, 26.0, 25.8,
1
. Bra
K. E.; Rise, F. Bioorg. Med. Chem. 2002, 10, 1581.
. Sendobry, S. M.; Cornicelli, J. A.; Welch, K.; Bocan, T.;
˚
the, A.; Andresen, G.; Gundersen, L.-L.; Malterud,
25.6, 18.4, 18.0, 17.7, ꢀ4.5, ꢀ4.7, ꢀ4.5, ꢀ5.2, ꢀ5.4; MS (CI):
+ +
698 (53, M +1), 697 (100, M ), 682 (13), 681 (31), 641 (20),
640 (44), 639 (91), 379 (25), 343 (17), 261 (7), 223 (12), 89 (11),
73 (29). A solution of TBAF (621 mg, 1.97 mmol) in dry THF
(4 mL) was added to the O-silylated styrylpurineriboside
(162 mg, 0.395 mmol) and the resulting mixture was stirred at
2
Tait, B.; Trivedi, B. K.; Colbry, N.; Dyer, R. D.; Feinmark,
S. J.; Daughterty, A. Br. J. Pharmacol. 1997, 120, 1199.
3. Bocan, T. M. A.; Rosebury, W. S.; Mueller, S. B.; Kuchera,
S.; Welch, K.; Daugtherty, A.; Cornicelli, J. A. Atherosclerosis
4
ambient temperature under Ar for 16 h. Saturated NH Cl
1
998, 136, 203.
. Cyrus, T.; Witztum, J. L.; Rader, D. J.; Tanirala, R.; Fazio,
(1 mL) was added, and the mixture was evaporated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel eluting with 1:1 acetone/hexane,
followed by 5% EtOH in EtOAc and 10% EtOH in EtOAc.
Yield 66 mg(47%) of trans-6-styryl-9-b-d-ribofuranosyl-9H-
4
S.; Linton, M. F.; Funk, C. D. J. Clin. Invest. 1999, 103, 1597.
5
6
7
1
8
. Halliwell, B. Drugs 1991, 42, 569.
. Halliwell, B. Drugs Aging 2001, 18, 685.
. Rice-Evans, C. A.; Diplock, A. T. Free Radical Biol. Med.
993, 15, 77.
ꢃ
1
purine 4h, colorless powdery crystals, mp 157–160 C.
H
NMR (200 MHz, CD OD) d 8.74 (s, 1H, H-2), 8.66 (s, 1H, H-
3
. Bra
˚
the, A.; Gundersen, L.-L.; Rise, F.; Eriksen, A. B.;
8), 8.30 (d, 1H, J 16.1 Hz, CH¼), 7.67–7.57 (m, 3H, Ph and
CH¼), 7.35 (m, 3H, Ph), 6.06 (d, 1H, J 5.8 Hz), 4.70 (t, 1H, J
5.5 Hz), 4.30 (dd, 1H, J 5.0 and 3.5 Hz), 4.11 (q, 1H, J 3.0 Hz),
Vollsnes, A. V.; Wang, L. Tetrahedron 1999, 55, 211.
. Andresen, G.; Gundersen, L.-L.; Nissen-Meyer, J.; Rise,
F.; Spilsberg, B. Bioorg. Med. Chem. Lett. 2002, 12, 567.
0. Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med.
9
1
3
3
3.78 (dd, 2H, J 12.5 and 3.0 Hz); C NMR (50 MHz, CD OD)
1
d 155.2, 153.1, 152.7, 146.1, 142.0, 137.4, 132.7, 130.8, 130.0,
128.9, 122.7, 90.8, 87.7, 75.7, 72.3, 63.1; MS (ESI): 355 (100,
Chem. 2000, 43, 1817. (b) Hocek, M.; Holy, A.; Votruba, I.;
Dvorakova, H. Collect. Czech. Chem. Commun. 2001, 67, 483.
+
M +1), 339 (5), 283 (5), 225 (5), 224 (30); HRMS found
(
Chem. 2002, 45, 1383.
c) Gundersen, L.-L.; Nissen-Meyer, J.; Spilsberg, B. J. Med.
18 4
355.1383, calcd for C18H N O4 355.1400.
20. Lozzio, C. B.; Lozzio, B. B. Blood 1975, 45, 321.
21. K-562 cells were maintained in RPMI 1640 medium with
10% (vol/vol) fetal calf serum, 2 mM l-glutamine and 0.1 mg/
mL kanamycin in a humidified atmosphere containing5% CO .
2
22. K-562 cells in logarithmic growth at 4 ꢄ 10 cells/mL and
1
1
1
1
1. Hocek, M.; Votruba, I. Bioorg. Med. Chem. Lett. 2002,
2, 1055.
2. Compounds 2a, 2b and 2j were prepared accordingto ref
, and 2h, 2i, 4a, 4c, 4i–4s were prepared as described in ref 8.
4