ORGANIC
LETTERS
2006
Vol. 8, No. 21
4975-4977
A Practical Method for the Synthesis of
Indolylaryl- and Bisindolylmaleimides
Sudipta Roy, Sujata Roy, and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, HanoVer, New Hampshire 03755
Received August 28, 2006
ABSTRACT
Indolylaryl and indolylheteroarylmaleimides, including bisindolylmaleimides, are easily prepared by the reaction of N-methylindole-3-glyoxylamide
with methyl aryl acetates in the presence of potassium tert-butoxide in THF.
Indolylarylmaleimides have valuable pharmacological prop-
erties.1,2 For example, indolylarylmaleimide derivatives,
particularly bisindolylmaleimides, are reported to be useful
in the control and prevention of cancer, central nervous
system disorders, Alzheimer’s disease, cardiovascular
diseases (thromboses, arteriosclerosis, hypertension), der-
matological diseases (allergies), inflammation, autoimmune
diseases (rheumatoid arthritis), diabetic complications, and
viral diseases. Furthermore, bisindolylmaleimide derivatives,
such as Ruboxistaurin (LY333531) mesylate (Arxxant),
Enzastaurin (LY317615), and Ro 31-7453, are in clinical
trials.3
kinase C (IC50 ) 87 nm). Bisindolylmaleimides are also
useful intermediates in the synthesis of indolocarbazole
alkaloids including arcyriaflavins, staurosporine, rebecca-
mycin, and other indolocarbazoles that have important
biological activities such as anticancer and antiviral activity.5-7
Indolylmaleimides are also potent plant growth regulators.8
Recently, bisindolylmaleimides have found potential ap-
plication as light-emitting diodes.9 They have also been used
(4) Peifer, C.; Stoiber, T.; Unger, E.; Totzke, F.; Schaechtele, C.; Marme,
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Tarrason, G.; Mitjans, F.; Piulats, J. Bioorg. Med. Chem. Lett. 2001, 11,
2701-2703. Bit, R. A.; Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.;
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Wadsworth, J.; Wilkinson, S. E. J. Med. Chem. 1993, 36, 21-29. Davis,
P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.;
Keech, E.; Turner, S. E. J. Med. Chem. 1992, 35, 177-184.
Many derivatives of indolylmaleimide have been synthe-
sized and biologically evaluated.4 The natural bisindolyl-
maleimide arcyriarubin A is a potent inhibitor of protein
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(7) Slater, M. J.; Cockerill, G. S.; Littler, E. PCT Int. Appl., 1993, WO
9318765. Sanchez-Martinez, C.; Shih, C.; Zhu, G.; Li, T.; Brooks, H. B.;
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S. A.; Ogg, C. A.; Considine, E.; Dempsey, J. A.; Zhang, F. Bioorg. Med.
Chem. Lett. 2003, 13, 3841-3846. Faul, M. M.; Engler, T. A.; Sullivan,
K. A.; Grutsch, J. L.; Clayton, M. T.; Martinelli, M. J.; Pawlak, J. M.;
LeTourneau, M.; Coffey, D. S.; Pedersen, S. W.; Kolis, S. P.; Furness, K.;
Malhotra, S.; Al-Awar, R. S.; Ray, J. E. J. Org. Chem. 2004, 69, 2967-
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(8) Bastiaans, H. M. M.; Donn, G.; Knittel, N.; Martelletti, A.; Rees,
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10.1021/ol0621203 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/21/2006