3146
L. Vandromme et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3144–3146
para-substituted phenyl derivatives at C-2 display the
same order of activity against Cdk 1 and 5.
8. Hockemeyer, J.; Burbiel, J. C.; M u¨ ller, C. E. J. Org. Chem.
004, 69, 3308.
. (a) Hocek, M.; Hockov a´ , D.; Dvofi a´ kov a´ , H. Synthesis
004, 889; (b) Hocek, M. Eur. J. Org. Chem. 2003, 245; (c)
Hocek, M.; Dvorakova, H. J. Org. Chem. 2003, 68, 5773;
d) Havelkova, M.; Dvorak, D.; Hocek, M. Synthesis
001, 1704; (e) Hocek, M.; Holy, A.; Votruba, I.;
Dvorakova, H. J. Med. Chem. 2000, 43, 1817.
0. Hoechst Marion Roussel, Inc. WO 99/43675, 1999.
2
9
2
These results are encouraging, suggesting that the Suzu-
ki cross-coupling reaction can be used to construct new
more active Cdk inhibitors. In particular, it will be inter-
esting to screen the anti-Cdk activity of other C-2 meta-
or ortho-substituted (hetero)aryl purine derivatives.
Taking into consideration the potent activities revealed
for the purines 4 and 5, 2-(hetero)aryl-substituted pur-
ines may also display activity against other protein
targets.
(
2
1
11. All compounds gave satisfactory spectral data as well as
elemental analyses. As a typical procedure, 8 was obtained
2
c
in 77% yield from 2-iodo derivative 7 (0.5 g, 1.38 mmol),
-formylphenyl boronic acid (311 mg, 2.07 mmol), K CO
955 mg, 6.92 mmol), and Pd(PPh ) (80 mg, 0.07 mmol),
4
2
3
(
3
4
2
in degassed H O (3 ml) and degassed dioxane (12 ml) (Ar
2
or N bubbling). The reaction mixture was stirred at
Acknowledgments
1
00 °C for 2–5 h, with phenylboronic acid, (for 12–18 h
with thiophene-2-boronic acids), and monitored by TLC,
before evaporation of the solvent and extraction in
The authors thank ARC (Association pour la Recherche
sur le Cancer, France) (Contract No. 4660 to M.L.), the
French Ministry of Research (MENRT fellowship for
L.V.) and EEC (FP6-2002-Life Sciences and Health,
Pro-kinase research project) (L.M.) and the ‘Cancero-
pole Grand-Ouest’ (L.M.).
2 2 4
CH Cl . After drying (MgSO ) and evaporation, 8 was
purified on silica gel column to give a white solid. Mp
1
1
2
47 °C. H NMR (CDCl ) d: 10.09 (s, 1H, HCO), 8.65 (d,
3
0
0
H ar bb , J = 8.3 Hz); 7.95 (d, 2H ar aa , J = 8.3 Hz); 7.85
s, 1H, H8); 6.21 (br s, 1H, NH); 4.94 (sept, 1H, CH iPrN,
(
J = 6.8 Hz); 4.00 (br s, 2H, CH N); 3.69 (t, 2H, CH O,
J = 5.2 Hz); 3.42 (s, 3H, CH O); 1.66 (d, 6H, 2CH iPr,
2
2
3
3
1
3
J = 6.8 Hz). C NMR (CDCl
3
) d: 192.3 (CO); 157.1 (C2);
54.5 (C4); 150.0 (C–C2); 138.2 (C8); 136.8 (C–CHO);
29.6 (2CH Ar); 128.6 (2CH Ar); 119.6 (C5); 71.3 (CH O);
References and notes
1
1
2
i
1
. (a) Gray, N. S.; Wodicka, L.; Thunnissen, A. M. W. H.;
Norman, T. C.; Kwon, S. J.; Espinoza, F. H.; Morgan, D.
O.; Barnes, G.; LeClerc, S.; Meijer, L.; Kim, S. H.;
Lockhart, D. J.; Schultz, P. G. Science 1998, 281, 533; (b)
Knockaert, M.; Greengard, P.; Meijer, L. Trends Phar-
macol. Sci. 2002, 23, 417; (c) Krystof, V.; Lenobel, R.;
Havlicek, L.; Kuzma, M.; Strnad, M. Bioorg. Med. Chem.
Lett. 2002, 12, 3283; (d) Legraverend, M.; Tunnah, P.;
Noble, M.; Ducrot, P.; Ludwig, O.; Grierson, D. S.; Leost,
M.; Meijer, L.; Endicott, J. J. Med. Chem. 2000, 43, 1282;
5
3 2 3
8.9 (CH O); 47.1 (CH PrN); 40.5 (CH N); 22.8 (2CH
i
Pr). HRMS Calcd m/z: 340.1768 [M+H]. Found m/z:
40.1773. Anal. Calcd for C H N O : C, 63.70; H, 6.24;
N, 20.64. Found: C, 63.99; H, 6.33; N, 20.58.
3
1
8
21
5
2
1
Compound 10: physical data: mp: 172 °C. H NMR
0
(
H8); 7.30 (d, 2H Ar mm , J = 8.7 Hz); 6.23 (br s, 1H, NH);
CDCl
3
) d: 8.47 (d, 2H Ar oo , J = 8.6 Hz); 7.82 (s, 1H,
0
i
.91 (sept, 1H, CH PrN, J = 6.8 Hz); 3.96 (br s, 2H,
4
CH
CH
2
N); 3.68 (t, 2H, CH
2
O, J = 5.3 Hz); 3.40 (s, 3H,
); 1.64 (d, 6H, 2CH iPr,
O); 3.04 (s, 3H, CH SO
3 3
2
3
1
3
(
f) Meijer, L.; Raymond, E. Acc. Chem. Res. 2003, 36, 417.
J = 6.7 Hz). C NMR (CDCl ) d: 157.8 (C2); 154.4 (C4);
3
2
. (a) Chang, Y. T.; Gray, N. S.; Rosiana, G. R.; Sutherlin,
D. P.; Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.;
Meijer, L.; Schultz, P. G. Chem. Biol. 1999, 6, 361; (b) Liu,
J.; Dang, Q.; Wei, Z.; Zhang, H.; Bai, X. J. Comb. Chem.
1
NHSO Me); 129.6 (2CH Ar); 119.8 (2CH Ar); 118.9
50.0 (C6); 138.0 (C–C2); 137.6 (CH, C8);136.1 (C–
2
i
(
C5); 71.3 (CH
2 3
O); 58.8 (CH O); 46.9 (CH– Pr); 40.7
(
CH NH); 39.3 (CH SO ); 22.7 (2CH iPr). HRMS Calcd
2
3
2
3
2
005, 7, 627; (c) Brun, V.; Legraverend, M.; Grierson, D.
m/z: 405.1703 [M+H]. Found: m/z 405.1712. Anal. Calcd
for C18 S: C, 53.45; H, 5.98; N, 20.78; S, 7.93.
Found: C, 53.57; H, 5.95; N, 20.57; S, 7.71.
S. Tetrahedron 2002, 58, 7911; (d) Brun, V.; Legraverend,
M.; Grierson, D. S. Tetrahedron Lett. 2001, 42, 8169; (e)
Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J.
Am. Chem. Soc. 2002, 124, 1594; (f) Ding, S.; Gray, N. S.;
Ding, Q.; Schultz, P. G. Tetrahedron Lett. 2001, 42, 8751.
. Wignall, S. M.; Gray, N. S.; Chang, Y.-T.; Juarez, L.;
Jacob, R.; Al Burlingame; Schultz, P. G.; Heald, R. Chem.
Biol. 2004, 11, 135.
24 6 3
H N O
1
Compound 14: mp: 159 °C. H NMR (CDCl ) d: 7.90 (d,
3
1
H Ar, J = 2.6 Hz); 7.81 (s, 1H, H8); 7.68 (d, 1H Ar,
i
J = 2.6 Hz); 6.06 (br s, 1H, NH); 4.86 (sept, 1H, CH PrN,
J = 6.6 Hz); 3.93 (br s, 2H, CH N); 3.66 (t, 2H, CH O,
J = 4.8 Hz); 3.41 (s, 3H, CH O); 2.59 (s, 3H, CH CO);
3
4
2
2
3
3
1
3
1
.63 (d, 6H, 2CH
3 3
iPr, J = 6.7 Hz). C NMR (CDCl ) d :
. Corbin, A. S.; Demehri, S.; Griswold, I. J.; Wang, Y.;
Metcalf, C. A., III; Sundaramoorthi, R.; Shakespeare, W.
C.; Snodgrass, J.; Wardwell, S.; Dalgarno, D.; Iuliucci, J.;
Sawyer, T. K.; Heinrich, M. C.; Druker, B. J.; Deininger,
M. W. N. Blood 2005, 106, 227.
1
91.2 (CO); 154.3 (C2); 153.0 (C4); 150.0 (C6); 145.1 (C–
CO); 138.1 (CH, C8); 132.9 (CH Ar); 128.6 (CH Ar); 127.5
CH Ar); 119.6 (C5); 71.2 (CH O); 58.8 (CH O); 47.2 (CH
iPr); 40.3 (CH N); 26.8 (CH CO); 22.7 (2CH iPr). HRMS
(
2
3
2
3
3
Calcd m/z: 360.1489 [M+H]. Found m/z: 360.1491. Anal.
Calcd for C H N O S: C, 56.80; H, 5.89; N, 19.48; S,
5
. Wan, Z.; Boehm, J. C.; Bower, M. J.; Kassis, S.; Lee, J. C.;
Zhao, B.; Adams, J. L. Bioorg. Med. Chem. Lett. 2003, 13,
1
7
21
5
2
8
.92. Found: C, 56.88; H, 5.75; N, 19.55; S, 8.75.
1
191.
1
2. Meijer, L.; Flajolet, M.; Greengard, P. Trends Pharmacol.
Sci. 2004, 25, 471.
6
7
. Chapman, E.; Ding, S.; Schultz, P. G.; Wong, C.-H.
J. Am. Chem. Soc. 2002, 14524.
. Pitts, W. J.; Vaccaro, W.; Huynh, T.; Leftheris, K.;
Roberge, J. Y.; Barbosa, J.; Guo, J.; Brown, B.; Watson,
A.; Donaldson, K. Bioorg. Med. Chem. Lett. 2004, 14,
1
3. Meijer, L.; Skaltsounis, A.-L.; Magiatis, P.; Polychronop-
oulos, P.; Knockaert, M.; Leost, M.; Ryan, X. P.; Vonica, C.
A.; Brivanlou, A.; Dajani, R.; Crovace, C.; Tarricone, C.;
Musacchio, A.; Roe, S. M.; Pearl, L.; Greengard, P. Chem.
Biol. 2003, 10, 1255.
2955.