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S. Meneni et al. / Bioorg. Med. Chem. 15 (2007) 3082–3088
4-ethynyltoluene (3.65 mL, 28.8 mmol). The yellow mix-
ture was stirred at 40 ꢁC for 20 h. White powder (2.56 g,
7.48 mmol, 88%). Calcd for C18H18N2O5: C, 63.15; H,
5.30. Found: C, 62.73; H, 5.58. IR (m, cmꢀ1, KBr)
3433 br s, 3190 m br, 2220 vw, 1722 vs, 1669 vs, 1652
vs, 1618 m, 817 m. UV–vis (CH3OH, 5.5 · 10ꢀ5 M)
252 (9500), 266 (11000), 280 (9900), 311 (12000). MS
(FAB, gly, positive) 435 ((M+gly+1)+, 10%), 343
((M+1)+, 42%), 227 ((MꢀC„CC6H4CH3)+, 100%); no
other peaks above 200 of >6%; (negative) 433
((M+glyꢀ1)ꢀ, 13%), 341 ((Mꢀ1)ꢀ, 65%), 227
((MꢀC„CC6H4CH3ꢀ2)ꢀ, 100%); no other peaks
above 200 of >9%.
(t, J = 120.1, C-200), 21.8 (t, J = 124.3, C-400), 13.7 (q,
J = 123.2, C-500).
4.2.6.
5-[(4-tert-Butylphenyl)ethynyl]-20-deoxyuridine
(2f). From 5-iodo-20-deoxyuridine (1.00 g, 2.82 mmol),
Pd(PPh3)4 (0.326 g, 0.282 mmol), CuI (0.0539 g,
0.282 mmol), DMF (5 mL), Et3N (0.82 mL, 5.65 mmol),
and 4-(t-butyl)phenylacetylene (1.5 mL, 8.47 mmol).
The yellow mixture was stirred at 40 ꢁC for 25 h. Crys-
tallization from CHCl3 gave 2f as a white powder
(0.780 g, 2.03 mmol, 72%). A second crop, obtained
after concentration and silica gel column chromatogra-
phy (15 · 2.5 cm; CHCl3 ! CHCl3/MeOH 95:5), in-
creased the yield to a total of 1.02 g (2.65 mmol, 94%).
Calcd for C21H24N2O5Æ1.5H2O: C, 60.64; H, 5.82.
Found: C, 60.71; H, 5.90. IR (m, cmꢀ1, KBr) 3429 br
s, 2227 vw, 1701 vs br, 835 w. UV–vis (CH3OH,
4.9 · 10ꢀ5 M) 253 (13000), 266 (15000), 280 (13000),
309 (16000). MS (MeOH) 791 ((2M+Na)+, 78%), 407
((M+Na)+, 100%), 385 ((M+H )+, 12%); no other peaks
of >12%.
NMR (DMSO-d6):41 1H 11.68 (s, 1H, N-3), 8.33 (s, 1H,
H-6), 7.35 (d, J = 8.1, 2H, o-C6H4C„C), 7.21 (d,
J = 8.1, 2H, m-C6H4C„C), 6.13 (t, J = 6.5, 1H, H10),
5.27 (d, J = 3.8, 1H, OH-30), 5.17 (t, J = 4.3, 1H, OH-
50), 4.26 (q, J = 4.2, 1H, H-30), 3.81 (q, J = 3.6, 1H, H-
40), 3.71–3.52 (m, 2H, H-50), 2.33 (s, 3H, CH3), 2.16 (t,
J = 5.6, 2H, H-20); 13C 162.1 (d, J = 9.3, C-4), 149.9
(d, J = 7.5, C-2), 143.6 (dd, J = 181.2, 2.2, C-6), 138.3
(m, p-C6H4C„C), 131.1 (dd, J = 162.3, 6.2,
o-C6H4C„C), 129.4 (dq, J = 159.6, 5.4, m-C6H4C„C),
119.5 (t, J = 8.2, i-C6H4C„C), 98.3 (s, C-5), 91.8
(t, J = 5.4, dU-C„C), 87.6 (d, J = 147.9, C-40), 84.8
(d, J = 170.8, C-10), 82.1 (d, J = 5.5, dU-C„C), 69.9
(d, J = 148.0, C-30), 60.9 (t, J = 140.4, C-50), 40.2
(t, J = 133.5, C-20), 21.1 (qt, J = 126.2, 4.3, CH3).
NMR (DMSO-d6):41 1H 11.69 (s, 1H, N-3), 8.35 (s, 1H,
H-6), 7.41 (s, 4H, C6H4), 6.13 (t, J = 6.3, 1H, H-10), 5.26
(d, J = 3.7, 1H, OH-30), 5.16 (t, J = 4.4, 1H, OH-50),
4.33-4.17 (m, 1H, H-30), 3.86–3.74 (m, 1H, H-40),
3.72–3.51 (m, 2H, H-50), 2.17 (t, 2H, H-20), 1.28 (s,
9H, C(CH3)3); 13C 161.5 (d, J = 9.3, C-4), 151.4 (d,
J = 3.8, p-C6H4C„C), 149.4 (d, J = 8.1, C-2), 143.7
(dd, J = 184.6, 2.0, C-6), 130.9 (dd, J = 162.0, 4.0,
o-C6H4C„C), 125.6 (dd, J = 158.9, 3.9, m-C6H4C„C),
119.5 (t, J = 6.1, i-C6H4C„C), 98.3 (s, C-5), 91.9 (s,
dU-C„C), 87.6 (d, J = 147.2, C-40), 84.8 (d, J = 170.6,
C-10), 81.8 (d, J = 5.6, dU-C„C), 70.0 (d, J = 149.9,
C-30), 60.8 (t, J = 140.2, C-50), 40.2 (t, J = 133.0, C-20),
34.6 (s, C(CH3)3), 30.9 (qt, J = 125.8, 4.4, C(CH3)3).
4.2.5. 5-[(p-Pentylphenyl)ethynyl]-20-deoxyuridine (2e).
From 5-iodo-20-deoxyuridine (5.01 g, 14.1 mmol),
Pd(PPh3)4
(1.63 g,
1.41 mmol),
CuI
(0.269 g,
1.41 mmol), DMF (30 mL), Et3N (4.00 mL, 28.0 mmol),
and 1-ethynyl-4-pentylbenzene (6.32 mL, 32.5 mmol).
The yellow mixture was stirred at 40 ꢁC for 35 h. White
powder (4.29 g, 10.8 mmol, 76%). Calcd for
C22H26N2O5: C, 66.32; H, 6.58. Found: C, 66.20; H,
6.57. IR (m, cmꢀ1, KBr) 3418 br s, 2224 vw, 1699 vs,
1678 vs. UV–vis (CH3OH, 2.8 · 10ꢀ5 M) 253 (18000),
266 (21000), 281 (18000), 311 (24000). MS (ES+,
MeOH) 835 ((2M+K)+, 15%), 819 ((2M+Na)+, 100%),
797 ((2M+H)+, 11%), 453 (unassigned, 51%), 437
((M+K)+, 32%), 421 ((M+Na)+, 80%), 399 ((M+H)+,
8%); no other peaks above 300 of >7%.
4.2.7. 5-[(Trimethylsilyl)ethynyl]-20-deoxyuridine (2g).15
From 5-iodo-20-deoxyuridine (3.96 g, 11.2 mmol),
Pd(PPh3)4
(1.29 g,
1.12 mmol),
CuI
(0.213 g,
1.12 mmol), DMF (25 mL), Et3N (3.20 mL, 22.4 mmol),
and (trimethylsilyl)acetylene (7.90 mL, 55.9 mmol). The
yellow mixture was stirred at 55 ꢁC for 24 h. Crystalliza-
tion from CHCl3 gave 2g as a white powder (1.02 g,
3.16 mmol, 28%). A second crop, obtained after concen-
tration and silica gel column chromatography
(15 · 2.5 cm; CHCl3 ! CHCl3/MeOH 95:5), increased
the yield to a total of 3.34 g (10.3 mmol, 92%).
NMR (DMSO-d6):41 1H 11.65 (s, 1H, N-3), 8.36 (s, 1H,
H-6), 7.32 (d, J = 8.1, 2H, o-C6H4C„C), 7.14 (d,
J = 8.1, 2H, m-C6H4C„C), 6.13 (t, J = 6.3, 1H, H-10),
5.24 (d, J = 4.2, 1H, OH-30), 5.14 (t, J = 4.5, 1H, OH-
50), 4.26 (p, J = 3.5, 1H, H-30), 3.86–3.75 (m, 1H,
H-4000), 3.71–3.51 (m, 2H, H-50), 2.50 (t, J = 7.2, 2H,
H-1 ), 2.14 (t, J = 5.1, 2H, H-20), 1.48 (p, J = 6.7, 2H,
H-200), 1.30–1.10 (m, 4H, H-300, H-400), 0.77 (t, J = 6.3,
3H, H-500); 13C 161.4 (d, J = 9.3, C-4), 149.3 (d,
J = 8.0, C-2), 143.4 (d, J = 184.3, C-6), 143.1 (s,
p-C6H4C„C), 131.0 (dd, J = 162.3, 6.1, o-C6H4C„C),
128.4 (dd, J = 159.2, 5.4, m-C6H4C„C), 119.5 (t,
J = 8.2, i-C6H4C„C), 98.4 (s, C-5), 91.9 (t, J = 4.7,
dU-C„C), 87.5 (d, J = 147.6, C-40), 84.7 (d, J = 169.5,
C-10), 81.6 (d, J = 5.5, dU-C„C), 70.0 (d, J = 148.5,
C-30), 60.8 (t, J = 140.3, C-50), 40.2 (t, J = 133.7, C-20),
34.9 (t, J = 113.2, C-100), 30.7 (t, J = 120.3, C-300), 30.3
NMR (DMSO-d6): 1H data matched those reported ear-
lier.15 13C 161.5 (d, J = 9.3, C-4), 149.5 (d, J = 8.0, C-2),
144.7 (d, J = 184.2, C-6), 98.3 (s, C-5), 98.0 (d, J = 5.4,
dU-C„C), 97.0 (s, dU-C„C), 87.6 (d, J = 147.6,
C-40), 84.8 (d, J = 169.4, C-10), 69.9 (d, J = 140.7,
C-30), 60.8 (t, J = 140.3, C-50), 40.2 (t, J = 133.8, C-20),
ꢀ0.03 (q, J = 99.2, Si(CH3)3).
4.3. Cytotoxicity experiments (IC50)
Nucleoside samples were additionally passed through a
silica gel column, to exclude contamination with metals.
The experiments were performed according to estab-
lished procedures with some modifications.39a
A