C. Aubry et al. / Tetrahedron Letters 46 (2005) 1423–1425
1425
The CDK4 activities of compounds 8e–k were assayed
Acknowledgements
in vitro; IC50 values (Table 1) were measured for inhibi-
tion of CDK4 using RB-152 fusion protein as a sub-
strate.16 These results confirm our predictions that the
indolyl-ethyl indole derivatives 8f,h–k are CDK4 active;
8e and 8g are, contrary to our predictions, inactive.
Interestingly, the two most active compounds, 8f and
8i, contain a fluorine atom in the R1 and R2 position,
respectively. Our modelling suggests that a fluorine at
R1 (8f) is close enough to interact with the guanidinium
of Arg 101,17 and that in contrast Cl or Me are too
bulky to occupy this position, resulting in an alternative
binding mode for 8g and 8h. The in silico results indicate
that the R2 substituents (8i,j,k) lie in a region lined by
Val 72, Phe 93, Ala 157 and the Lys 35/Asp 158 salt
bridge. The importance of the electronic and steric
effects of substituents is demonstrated by the inactivity
of the parent system 8e.
This work was supported by Cancer Research UK.
References and notes
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All the CDK4-active indolyl-ethyl indole derivatives
synthesised are also CDK4 selective compared to
CDK2 (Table 1). This suggests that the indolyl-ethyl in-
dole scaffold is, as we postulated, a good starting point
for the development of CDK4 selective compounds.
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In conclusion we have designed, modelled, synthesised
and tested a series of 3-[2-indol-1-yl-ethyl]-1H-indole
structures as inhibitors of CDK4. The best compound,
8f, has an IC50 of 50 lM. The compounds prepared
are conceived as non-planar analogues of fascaplysin,
and all the CDK4-active compounds are also selective
for CDK4 compared to CDK2. Compounds with sub-
stituents in both indole rings of the 3-[2-indol-1-yl-
ethyl]-1H-indole including the difluoro derivative are
under investigation.
6. Soni, R.; Muller, L.; Furet, O.; Schoepfer, J.; Stephan,
Ch.; Zumstein-Mecker, S.; Fretz, H.; Chaudhuri, B.
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9. Since no experimentally determined 3-dimensional struc-
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Typical experimental for the final step in the synthesis of
8e: To a solution of 7e (0.90 g, 3.41 mmol) in 19.5 mL of
chloroform, under nitrogen atmosphere, was added acti-
vated MnO2 (2.08 g, 24 mmol). The mixture was heated
under reflux for 60 h. After being cooled to room tem-
perature, the resulting mixture was filtered on Celite
and the filtrate was evaporated under reduced pressure.
Purification of the crude product by column chromato-
graphy on silica gel (EtOAc/petroleum ether = 10/90
then 30/70 as gradient of eluant) gave the 3-[2-indol-1-
yl-ethyl]-1H-indole 8e (0.49 g, 1.88 mmol, 55% yield)
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1blx.
1
as a yellow solid. H NMR (300 MHz, CDCl3): d ppm
3.31 (2H, td, J 7.2 and 0.6 Hz), 4.46 (2H, t, J 7.2 Hz),
6.48 (1H, dd, J 3.3 and 0.6 Hz), 6.77 (1H, d, J 2.1 Hz),
6.99 (1H, d, J 3.3 Hz), 7.12–7.29 (4H, m), 7.38–7.42
(2H, m), 7.63–7.69 (2H, m), 7.92 (1H, s). 13C NMR
(75 MHz, CDCl3): d ppm 26.33 (CH2), 46.99 (CH2),
100.83 (CH), 109.39 (CH), 111.30 (CH), 112.63 (Cq),
118.48 (CH), 119.26 (CH), 119.58 (CH), 120.99 (CH),
121.37 (CH), 122.20 (CH), 122.30 (CH), 127.17 (Cq),
128.02 (CH), 128.68 (Cq), 135.85 (Cq), 136.24 (Cq). Rf
(EtOAc/petroleum ether = 20/80) 0.33. Melting point
154–155 °C. Mass spectroscopy FAB+: M+ 260, MH+
261. Accurate mass found M+, 260.13122; C18H16N2
requires 260.13135.
12. Shaw, K. N. F.; McMillan, A.; Gudmundson, A. G.;
Armstrong, M. D. J. Org. Chem. 1958, 23, 1171.
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Billimoria, A. D.; Culpepper, J. S.; Cava, M. P. J. Org.
Chem. 1995, 60, 1800.
16. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor,
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PyMOL Molecular Graphics System DeLano Scientific,
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17. Bo¨hm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn,
B.; Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem
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