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dimethoxy-phenyl)-3-cyano-4,7-dihydro-pyrano[2,3-
e]indole (0.998 g, 2.34 mmol) in anhydrous THF (40 mL) at
t
À30 ꢁC was added butylnitrite (1.00 mL, 7.58 mmol) via a
syringe under argon. The light yellow solution was stirred
between À20 and À10 ꢁC for 4 h, then warmed up to 0 ꢁC.
The reaction mixture was cooled to À10 ꢁC and NaBH4
(0.259 g, 6.84 mmol) was added in one portion. The reaction
mixture was warmed up to room temperature slowly and
stirred overnight (15 h). The THF solvent was evaporated
and the residue was dissolved in EtOAc (100 mL). The
mixture was washed with saturated NaHCO3 (15 mL) and
brine (15 mL), dried over MgSO4, and evaporated to give a
brown residue. It was purified by flash column chromatog-
raphy (silica gel, EtOAc:hexanes/1:2) to give 3c as an off-white
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1
solid (0.39 g, 40%): H NMR (CDCl3, 300 MHz) d 8.30 (bs,
1H), 7.45 (m, 1H), 7.24 (m, 1H), 7.13 (m, 1H), 6.96 (d,
J = 2.1 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.70 (d, J = 8.1 Hz,
1H), 6.67 (m, 1H), 4.81 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H).
18. Experimental procedure for the synthesis of 4-(3-bromo-
4,5-dimethoxy-phenyl)-3-cyano-4,7-dihydro-7-methyl-pyr-
ano[2,3-e]indole (3d). A mixture of 4-(3-bromo-4,5-dime-
thoxy-phenyl)-3-cyano-4,7-dihydro-pyrano[2,3-e]indole (51
mg, 0.12 mmol), iodomethane (23 lL, 0.37 mmol), and
cesium carbonate (120 mg, 0.37 mmol) in THF (2 mL) was
stirred at room temperature in a sealed tube for 2.5 days.
The reaction mixture was diluted with EtOAc (20 mL).
The mixture was filtered, and the solid was washed with
EtOAc (30 mL). The EtOAc solution was combined,
washed with brine (2· 5 mL), dried over MgSO4, and
evaporated to give an off-white solid. It was purified by
column chromatography (silica gel, EtOAc:hexanes/1:1) to
give 3d as an off-white solid (51 mg, 97%): 1H NMR
(CDCl3, 300 MHz) d 7.43 (m, 1H), 7.07 (d, J = 3.3 Hz,
1H), 7.05 (m, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.76 (d,
J = 2.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.58 (m, 1H),
4.81 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H).
19. Cai, S. X.; Nguyen, B.; Jia, S.; Herich, J.; Guastella, J.;
Reddy, S. J.; Tseng, B.; Drewe, J.; Kasibhatla, S. J. Med.
Chem. 2003, 46, 2474.
15. Kuppens, I. E.; Witteveen, P. O.; Schot, M.; Schuessler, V.
M.; Daehling, A.; Beijnen, J. H.; Voest, E. E.; Schellens, J.
H. Invest. New Drugs 2007, 25, 227.
16. Doyle, M. P.; Dellaria, J. F.; Siegfried, B.; Bishop, S. W.
J. Org. Chem. 1977, 42, 3494.
17. Experimental procedure for the synthesis of 4-(3-bromo-
4,5-dimethoxy-phenyl)-3-cyano-4,7-dihydro-pyrano[2,3-
e]indole (3c). To a solution of 2-amino-4-(3-bromo-4,5-
20. For example, compound 3a, with an EC50 value of 5 nM
in the caspase activation assay, was found to have an IC50
value of 500 nM in the tubulin polymerization assay. In
comparison, the 4-phenyl analog of 3a, 2-amino-4-phenyl-
3-cyano-4,7-dihydro-pyrano[2,3-e]indole, with an EC50
value of 270 nM in the caspase activation assay, was
found to have an IC50 value of 3000 nM in the tubulin
polymerization assay.