Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3

Article abstract of DOI:10.1016/S0960-894X(03)00644-9

Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC₅₀) for PKC-β and GSK-3β were identified, and compounds showed good selectivity over PKC-α, -γ, -δ, -ε, and -ζ. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-βII and increased glycogen synthase activity by inhibiting GSK-3β.

Full text of DOI:10.1016/S0960-894X(03)00644-9

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3049–3053
Macrocyclic Bisindolylmaleimides as Inhibitors of Protein
Kinase C and Glycogen Synthase Kinase-3
Han-Cheng Zhang,a,* Kimberly B. White,a Hong Ye,a David F. McComsey,a
Claudia K. Derian,a Michael F. Addo,a Patricia Andrade-Gordon,a Annette J. Eckardt,a
Bruce R. Conway,b Lori Westover,b Jun Z. Xu,b Richard Look,b Keith T. Demarest,b
Stuart Emanuelb and Bruce E. Maryanoffa
aDrug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA
bDrug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ 08869-0602, USA
Received 28 March 2003; accepted 24 April 2003
Abstract—Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with
multiple heteroatoms. Potent inhibitors (single digit nanomolar IC50) for PKC-b and GSK-3b were identified, and compounds
showed good selectivity over PKC-a, -g, -d, -e, and -z. Representative compound 5a also had high selectivity in a screening panel of
10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by
PKC-bII and increased glycogen synthase activity by inhibiting GSK-3b.
# 2003 Elsevier Ltd. All rights reserved.
Protein phosphorylation and dephosphorylation are
important processes in the regulation of protein func-
tion. Phosphorylation occurs on serine, threonine, and
tyrosine residues and is catalyzed by protein kinases,
thereby mediating various cellular signaling events that
can be associated with human diseases.1 Given the
>500 protein kinases identified in the human genome,
there is a rich mother lode of drug discovery targets for
exploration.2 We have been interested in finding inhibi-
tors of enzymes in the protein kinase C (PKC) and gly-
cogen synthase kinase-3 (GSK-3) classes as potential
therapeutic agents.
ischemia, inflammation, and CNS disorders.3 The b
isoform, which is induced in response to hyperglycemia
in cardiac, aortic, renal, and retinal tissues, is associated
with diabetic complications, particularly retinopathy,
angiopathy, nephropathy, macular edema, neuropathy,
and cardiomyopathy.4
GSK-3 is a serine/threonine protein kinase composed of
two isoforms (a and b) with high homology (ca. 90%) at
the catalytic domain.5 GSK-3b plays a critical role in
glucose homeostasis, CNS function (via the proteins tau
and b-catenin), and cancer (via angiogenesis, apoptosis,
and tumorigenesis).6 Inhibition of GSK-3-dependent
phosphorylation should activate insulin-dependent gly-
cogen synthesis, thereby mimicking the action of insulin
to lower plasma glucose. Thus, inhibitors of GSK-3b
would afford a novel mode of treating type II diabe-
tes.4b,7 Additionally, GSK-3 inhibitors have therapeutic
potential for treating neurodegenerative diseases, bipo-
lar disorder, stroke, cancer, and chronic inflammatory
diseases.8
PKC represents a family of serine/threonine kinases that
play a critical role in intracellular signal transduction,
gene expression, and the control of cell differentiation
and growth. There are at least 11 isozymes that are
classified into three subfamilies on the basis of their
cofactor requirements: conventional (a, bI, bII, g),
novel (d, e, Z, y, m), and atypical (z, i). PKC enzymes
regulate vascular tone, permeability, and proliferation,
and they are involved in cardiovascular disease, cancer,
Several PKC inhibitors, such as UCN-01, CGP-41251
and LY-317615, are now in clinical trials as anticancer
agents.9 Ruboxistaurin (LY-333531) is a selective inhi-
bitor of PKC-b that is in Phase 3 clinical trials for the
*Corresponding author. Tel.: +1-215-628-5988; fax: +1-215-628-
4985; e-mail: hzhang@prdus.jnj.com
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00644-9

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H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3049–3053
Scheme 1. (a) Me2SO4, K2CO3, acetone, reflux, 41%; (b) O(CH2CH2Br)2 (excess), Cs2CO3, DMF, 45 ꢀC, 53%; (c) EtNH2 (excess), i-Pr2NEt, THF,
90 ꢀC, 16 h; then volatiles evaporated, redissolved in dioxane, reflux, 6 h, 40%; (d) KOH, EtOH, reflux; (e) citric acid, H2O; (f) neat NH4OAc,
140 ꢀC, 54%.
Scheme 2. (a) ClCH2CH2Br (excess), Cs2CO3, DMF, 45 ꢀC; (b) KI, i-Pr2NEt, THF, 120 ꢀC; (c) KOH, EtOH, 80 ꢀC; (d) citric acid, H2O; (e) neat
NH4OAc, 140 ꢀC, 41% overall from 2.
treatment of diabetic retinopathy, macular edema, and
neuropathy.10 However, inhibitors of GSK-3 are limited
to preclinical evaluation.4b,8,11 Herein, we report the
synthesis and biological evaluation of a novel series of
macrocyclic bisindolylmaleimides12 that provide inter-
esting dual inhibitors of PKC-b and GSK-3b.
only a trace of the desired cyclized product 4a. Use of
more ethylamine accelerated the reaction, leading to
more product 4a along with some undesired acyclic
diamine product. Finally, treatment of 3 with 13 mol-
equiv of ethylamine for 16 h resulted in cyclized product
4a, along with acyclic monoamine (the precursor to the
cyclized product), and acyclic diamine side product in a
ratio of ca. 2:1:1. To avoid further conversion of acyclic
monoamine to the undesired diamine, the excess ethyl-
amine and other volatiles were evaporated in vacuo, and
the residue was refluxed in dioxane for 6 h to allow
complete conversion of the monoamine to the cyclized
product, providing 4a in 40% isolated yield. Deprotec-
tion of the N-methyl group in maleimide 4a was carried
out by using a routine process.14 Thus, 4a was hydro-
lyzed with KOH/EtOH and the resulting diacid was
treated with citric acid to form a maleic anhydride,
which was converted to the desired product 5a (54%
yield from 4a) by reaction with neat NH4OAc at 140 ꢀC.
By using a similar process, symmetrical amine-contain-
ing macrocycles, such as 5b–d, were prepared. When a
less volatile amine was used, such as in the preparation
of 4d, less of an excess was needed.
Synthetic Chemistry
Our novel series of macrocyclic bisindolylmaleimides
contains linkers with multiple heteroatoms. Efficient
syntheses were developed to obtain target compounds in
this class. One or more basic nitrogen atoms, usually
required for biological and/or physicochemical pur-
poses, were introduced into the linker in the last syn-
thetic step via ring-closing N-alkylation. This approach
allowed us to introduce diverse amino groups and syn-
thesize both symmetrical and unsymmetrical macro-
cyclic bisindolylmaleimides. In an approach to
monoamine-containing macrocycles, bisindolylmalei-
mide 1, readily prepared from indole-3-acetamide and
methyl indole-3-glyoxylate in the presence of t-BuOK,13
was treated with Me2SO4 and K2CO3 in acetone to give
N-methylated maleimide 2 (Scheme 1), along with some
di- and tri-N-methylated products. Bis-N-alkylation of 2
with the excess of 2-bromoethyl ether using Cs2CO3 as a
base in DMF afforded dibromide 3. An attempt to treat
dibromide 3 with 1 mol-equiv of ethylamine in the pre-
sence of i-Pr2NEt/THF in a pressure tube at 90 ꢀC gave
Through a similar strategy, a symmetrical macrocyclic
bisindolylmaleimide with a triamine-containing linker
(9) was prepared. Thus, bisindolylmaleimide 2 was
treated with the excess of 1-bromo-2-chloroethane to
give dichloride 6, which was macrocyclized with tri-
amine 7 (1.2 mol-equiv) in the presence of KI/

H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3049–3053
3051
Scheme 3. (a) Cs2CO3, DMF, 50–75 ꢀC, 68–82%; (b) Cs2CO3, DMF, 78 ꢀC, 82%; (c) t-BuOK, THF, 0–23 ꢀC; then concd HCl; (c) Ms2O, pyridine,
THF, 50 ꢀC; (d) i-Pr2NEt, DMF, 90 ꢀC, 11–20% overall from 15.
Scheme 4. (a) NaH, DMF, 60%; (b) t-BuOK, THF, 0–23 ꢀC, then concd HCl, 83%; (c) Ms2O, pyridine, THF, 50 ꢀC, quantitative yield;
(d) i-Pr2NEt, DMF, 100 ꢀC, 15–30%.
i-Pr2NEt/THF at 120 ꢀC to afford 8 (Scheme 2). De-
protection of the N-methyl maleimide by the procedure
described above provided product 9 in 41% overall
yield from 2.
By applying similar chemistry, the symmetrical, dia-
mine-containing macrocyclic targets 22 could be pre-
pared in reasonable yields, as shown in Scheme 4.
Considering the absence of protection and deprotection
of the maleimide nitrogen, this route presents a sig-
nificant advantage over the previous methods shown in
Schemes 1 and 2.
Application of the above processes to an unsymmetrical
macrocyclic target, such as 18, was less successful due to
the difficulty of selective N-alkylation of 2 with two dif-
ferent alkylating agents. Therefore, we adopted an
alternate approach. Methyl indole-3-glyoxylate 10 was
N-alkylated with 11 by using Cs2CO3 as a base to afford
12, while indole-3-acetamide 13 was N-alkylated with 14
by using NaH as a base to give 15 (Scheme 3). Mal-
eimide condensation of 12 and 15 in the presence of
t-BuOK was followed by treatment of concd HCl to
remove the silyl group to derive product 16. Given that
protection and deprotection of the maleimide nitrogen
are cumbersome, as seen above, an effort was made to
convert diol 16 to cyclized product without protecting
the maleimide nitrogen. Thus, treatment of 16 with
Ms2O (4 mol-equiv) in the presence of pyridine/THF at
50 ꢀC selectively produced dimesylate 17 in quantitative
yield. Ring-closing of 17 with a primary amine was
successful in DMF at 90 ꢀC to afford unsymmetrical
macrocycle 18, although the yield was relatively low
(11–20% overall from amide 15), along with some
acyclic diamine that could be easily separated.
Enzymatic Activity
Given the high homology of PKC isozymes in their
catalytic domain, identification of a selective, ATP-
competitive inhibitor for a particular isozyme can be
challenging. Our original interest was to identify selec-
tive PKC-b inhibitors, in the same vein as the promising
clinical candidate LY-333531.10 Thus, we screened our
macrocyclic bisindolylmaleimides in enzymatic assays
involving the calcium-dependent (conventional) PKC
isozymes a, bI, bII, and g to determine activity and
selectivity within the same subfamily (Table 1). In gen-
eral, the compounds potently inhibited PKC-bI and
PKC-bII, while being selective over PKC-a and PKC-g.
The reference compound staurosporine was very potent,
but it did not show significant selectivity for PKC-b.
Compound 5a, an amine-containing, symmetrical, 19-
membered macrocyclic bisindolylmaleimide, potently

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H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3049–3053
Table 1. Enzymatic activity of macrocyclic bisindolylmaleimdesa
Compd
m
n
X
Y
Z
PKCb IC50 (mM)
PKC-bII PKC-g
GSK-3bc
PKC-a
PKC-bI
PKC-d PKC-e PKC-z
IC50 (mM)
5a
5b
5c
5d
9
18a
18b
22a
22b
22c
23
24
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
0
1
2
1
1
O
O
O
O
O
O
O
O
NEt
NMe
N(i-Pr)
0.11Æ0.02
0.30Æ0.04
0.17
0.014Æ0.003 0.009Æ0.004 0.30Æ0.04
0.35
40%
n.d.
n.d.
1.16
n.d.
0.075 34% 0.025Æ0.003
0.047Æ0.009 0.041Æ0.011
n.d. 0.017
28%
0.40
0.25
n.d.
n.d.
0.17
n.d.
34% 0.071Æ0.002
n.d. n.d.
N(CH2CH2OH) 0.44Æ0.06
0.068Æ0.006 0.040Æ0.013 1.57Æ0.13
n.d. 0.040Æ0.003
40% 0.043Æ0.005
n.d. 0.004Æ0.0004
4% 0.004Æ0.0005
NMe NMe
O
O
NMe NMe
NMe NMe
NMe NMe
NMe
NEt
NMe
O
0.29Æ0.11
0.25Æ0.08
0.031Æ0.008 0.027Æ0.007 1.57Æ0.02
NMe
NEt
0.073Æ0.006 0.046Æ0.016
0.98
O
None
O
0.29Æ0.007 0.031Æ0.01 0.019Æ0.004 1.00Æ0.5
0.61Æ0.05 0.31
35%
0.49Æ0.31
0.77
0.25Æ0.14
0.20Æ0.11
23%
1.56
37%
n.d.
26%
n.d.
n.d.
0.61
n.d.
0.080
n.d.
n.d.
0.11Æ0.003
0.027
0.14Æ0.06 0.075Æ0.010
0.041Æ0.014
6% 0.006Æ0.001
n.d. 0.008Æ0.001
7% 0.033Æ0.002
n.d. 0.031Æ0.001
O
NMe
–OCH2CH2NEt–
O
O
0.57Æ0.033 0.010Æ0.002 0.009Æ0.001 0.39Æ0.3
1.50
n.d.
0.049
n.d.
0.91
0.028Æ0.0001
n.d.
0.30Æ0.005 0.11Æ0.04
36%
0.010Æ0.004 0.059Æ0.007
n.d. n.d.
Staurosporine
SB-216763d
0.063
n.d.
0.012 10%
n.d.
n.d.
n.d. 0.007Æ0.0001
aIC50 values are expressed as meanÆSEM (nꢁ2; n=1 for values without error limits). % Inhibition was measured at 1 mM. n.d. denotes not determined.
bFor PKC-a, -bI, -bII, and -g isozymes, the assay was performed essentially as previously described10b (histone as a substrate) with the following modifi-
cations: the reaction volume was reduced to 100 mL, the assay was run in a 96-well format, and [g-33P]ATP was substituted for [g-32P]ATP. For d, e, and z
isozymes, the PKC-e pseudosubstrate hexadecapeptide ERMRPRKRQGSVRRRV was employed in place of histone as a substrate and CaCl2 was eliminated
from the reaction mixture.
cPerformed at Upstate Biotech Inc. using a filtration assay. Recombinant human GSK-3b was used with a peptide derived from glycogen synthase as a
substrate.
dGSK-3 inhibitor reference compound.11g
inhibited PKC-bI and PKC-bII with IC50 values of 14
and 9 nM, respectively, and was 12- to 33-fold selective
for PKC-bII over PKC-a and PKC-g. Replacement of
the Et group attached to the linker nitrogen in 5a with
Me, i-Pr or hydroxyethyl groups (5b–d) caused some
loss of potency versus PKC-b. An unsymmetrical ana-
logue with the N-Et moved from the Z to Y position
(18b) showed no loss of potency or selectivity. Intro-
duction of diamines (22b and 23) or triamines (9) into
the linker was well tolerated, but changing the macro-
cyclic ring size from 19 to 16 (22a) or 22 atoms (22c and
24) led to a decrease of potency.
assessing kinase selectivity (Table 2). High selectivity
was observed across the panel except for CDK1
(IC50=0.24 mM) and GSK-3b (IC50=0.018 mM). The
outstanding potency against GSK-3b triggered us to
profile other compounds in a GSK-3b assay. Thus,
the series generally turned out to show potent dual
action against PKC-b and GSK-3b. Certain non-
macrocyclic maleimides are able to inhibit GSK-
3b.11f,g,15 However, no GSK data has been disclosed for
LY-333531.
Cellular Activity
Selected compounds were further tested in PKC iso-
zyme assays representing other subfamilies, such as cal-
cium-independent (novel) isozymes PKC-d and PKC-e,
and the atypical isozyme PKC-z. Most of the tested
compounds showed some activity against PKC-e, bu t
weak inhibition of PKC-d and PKC-z (Table 1).
We developed a stable HEK293 cell line expressing
PKC-bII to evaluate the functional activity of inhibi-
tors. When stimulated by the phorbol ester PMA
(phorbol-12-myrisate-13-acetate), these cells synthesize
and release the cytokine interleukin-8 (IL-8). Selected
compounds with good PKC-bII inhibition were studied
in this assay to gain information on their ability to
penetrate cell membranes and inhibit intracellular PKC-
Compound 5a, as a representative lead compound, was
further screened against a panel of 11 other kinases for
Table 2. Kinase selectivity, IC50 (mM)a
Compd
VEGF-R2 CDK1 EGF-R
Protein
kinase A kinase 1 kinase 2
Casein
Casein Calmodulin GSK-3b MAP kinase Insulin receptor PDGF-R
kinase 2
ERK-2
kinase-b
5a
Staurosporine
1.41
0.014
0.24
0.008
>100
0.049
14.5
0.004
>100 >100
1.40 >100
7.8
0.006
0.018
0.089
>100
>100
4.4
0.002
1.38
0.20
aThe values are the average of duplicate determinations. Assays were performed as described in ref 16.

H.-C. Zhang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3049–3053
3053
Table 3. Cellular activitya
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Compd
IL-8 releaseb
IC50 (mM)
GS activityc
EC50 (mM)
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5a
5d
9
18a
23
Staurosporine
SB-216763
0.025
0.058
0.082
0.045
0.046
0.077
n.d.
0.31
0.38
0.39
0.15
0.14
n.d.
0.20
aValues are an average of at least two independent determinations.
n.d. denotes not determined.
bHEK293 cells stably expressing PKC-bII were preincubated with
compounds prior to stimulation with PMA and the amount of IL-8
released in cell supernatant was measured by quantitative ELISA.
cHEK293 cells were treated with compounds and GS activity was
determined in cell extracts by measuring 14C-UDP glucose incor-
poration into glycogen.
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bII. As presented in Table 3, IL-8 release was effectively
inhibited by these molecules, with 5a being a very potent
inhibitor (IC50=25 nM).
10. (a) Sorbera, L. A.; Silvestre, J.; Rabasseda, X.; Castaner,
J. Drugs Future 2000, 25, 1017. (b) Ishii, H.; Jirousek, M. R.;
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Feener, E. P.; King, G. L. Science 1996, 272, 728. (c) Jirousek,
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nald, J. H., III; Neel, D. A.; Rito, C. J.; Singh, U.; Stramm,
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11. (a) Martinez, A.; Castro, A.; Dorronsoro, I.; Alonso, M.
Med. Res. Rev. 2002, 22, 373. (b) Cline, G. W.; Johnson, K.;
Regittnig, W.; Perret, P.; Tozzo, E.; Xiao, L.; Damico, C.;
Shulman, G. I. Diabetes 2002, 51, 2903. (c) Martinez, A.;
Alonso, M.; Castro, A.; Perez, C.; Moreno, F. J. J. Med.
Chem. 2002, 45, 1292. (d) Nikoulina, S. E.; Ciaraldi, T. P.;
Mudaliar, S.; Carter, L.; Johnson, K.; Henry, R. R. Diabetes
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K. A.; Facci, L.; Skaper, S. D.; Reith, A. D. J. Neurochem.
2001, 77, 94. (f) Smith, D. G.; Buffet, M.; Fenwick, A. E.;
Haigh, D.; Ife, R. J.; Saunders, M.; Slingsby, B. P.; Stacey, R.;
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Coghlan, M. P.; Culbert, A. A.; Cross, D. A. E.; Corcoran,
S. L.; Yates, J. W.; Pearce, N. J.; Rausch, O. L.; Murphy,
G. J.; Carter, P. S.; Cox, L. R.; Mills, D.; Brown, M. J.;
Haigh, D.; Ward, R. W.; Smith, D. G.; Murray, K. J.; Reith,
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Selected compounds were also tested for their ability to
increase glycogen synthase (GS) activity in HEK293
cells, a direct functional assay to measure the cellular
activity of GSK-3b inhibitors. The results (Table 3)
indicate effective blockade of GSK-3b and increased GS
activity within cells. For example, 5a has an EC50 of
0.31 mM in this assay.
Conclusion
We developed several efficient synthetic approaches to
novel macrocyclic bisindolylmaleimides containing lin-
kers with multiple heteroatoms. The compounds gen-
erally exhibited potent dual inhibition of PKC-b and
GSK-3b, and good selectivity over PKC-a, -g, -d, -e,
and -z. Representative lead compound 5a had high
selectivity in a screening panel of 10 other kinases. Cer-
tain compounds were effective intracellularly by block-
ing PKC-bII-induced IL-8 release and increasing
glycogen synthase activity via blockade of GSK-3b.
Acknowledgements
We thank Diane Croll, William Jones for excellent
technical assistance, and Drs. Gee-Hong Kuo, Bruce
Damiano and Dennis Hlasta for helpful discussions. We
thank Upstate Biotech Inc. for providing enzymatic
data for GSK-3b.
12. A paper on related macrocyclic polyoxygenated bis-7-azain-
dolylmaleimides as selective GSK-3b inhibitors was submitted
for publication separately: G.-H. Kuo et al., J. Med. Chem. 2003.
13. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. Tetra-
hedron Lett. 1999, 40, 1109.
14. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sulli-
van, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek,
M. R. J. Org. Chem. 1998, 63, 1961.
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