Rapid preparation of triazolyl substituted NH-heterocyclic kinase inhibitors via one-pot Sonogashira coupling-TMS-deprotection-CuAAC sequence

Article abstract of DOI:10.1039/c1ob05586k

The one-pot, three-component Sonogashira coupling-TMS-deprotection-CuAAC ("click") sequence is the key reaction for the rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, and imidazole. Subsequently, the protective group was readily removed to give the corresponding triazolyl derivatives of these tremendously important NH-heterocycles. All compounds have been tested in a broad panel of kinase assays. Several compounds, 8f, 8h, 8k, and 8l, have been shown to inhibit the kinase PDK1, a target with high oncology relevance, and thus they are promising lead structures for the development of more active derivatives. The X-ray structure analysis of compound 8f in complex with PDK1 has revealed the detailed binding mode of the molecule in the kinase. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05586k

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PAPER
Rapid preparation of triazolyl substituted NH-heterocyclic kinase inhibitors
via one-pot Sonogashira coupling–TMS-deprotection–CuAAC sequence†‡
Eugen Merkul,a Fabian Klukas,a Dieter Dorsch,b Ulrich Gra¨dler,b Hartmut E. Greinerb and
Thomas J. J. Mu¨ller*a
Received 12th April 2011, Accepted 13th May 2011
DOI: 10.1039/c1ob05586k
The one-pot, three-component Sonogashira coupling–TMS-deprotection–CuAAC (“click”) sequence is
the key reaction for the rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such
as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, and
imidazole. Subsequently, the protective group was readily removed to give the corresponding triazolyl
derivatives of these tremendously important NH-heterocycles. All compounds have been tested in a
broad panel of kinase assays. Several compounds, 8f, 8h, 8k, and 8l, have been shown to inhibit the
kinase PDK1, a target with high oncology relevance, and thus they are promising lead structures for the
development of more active derivatives. The X-ray structure analysis of compound 8f in complex with
PDK1 has revealed the detailed binding mode of the molecule in the kinase.
molecules.34 In particular, 7-azaindoles are predestined to be
promising scaffolds for investigations as kinase inhibitors due to
Introduction
Indoles represent one of the most prominent privileged structures1
because they are widespread in nature2 and pharmaceutically
relevant compounds.3 Among them, indoles bearing 5- and 6-
membered heterocycles as substituents in the 3-position repre-
sent a conspicuously frequently occurring substitution pattern.
In particular, the heterocyclic ring found in natural products
or their bioactive analogues can be pyrimidine (meridianins,4
hyrtinadine A5), tetrahydropyrimidine (aplicyanins6), piper-
azine and (dihydro)pyrazine (dragmacidins,7 hamacanthins8),
oxazinone (oxazinins9), oxadiazinone (alboinon10), imida-
zole (nortopsentins,11 topsentins12), imidazolone,13,14 oxazole
(diazonamides,15 martefragin A,16 almazoles,17 pimprinine,18
and labradorins19), thiazole (camalexins,20 BE-1098821), imida-
zoline (spongotines,22 discodermindoles,23 trachycladindoles24),
oxazoline,25 maleimide (didemnimides26), isoquinolinequinone
(mensouramycin D27), b-carboline (eudistomin U,28 hyrtioerec-
tine A29), pyrrole (chromopyrrolic acid,30 lynamicins31), pyrroli-
none (violacein32), or another indole.33 Besides indoles, their
aza analogues, i.e. indazole and azaindoles, apparently play an
increasingly important role as scaffolds for biologically active
their pronounced ability to bind to the hinge region of kinases.35
Again, heterocyclic substituents at the C-3 position are very
common. The most prominent examples are the marine natural
products variolins36 and the simplified synthetic analogues of
variolin B, i.e. the meriolins37 (Fig. 1).
aLehrstuhl fu¨r Organische Chemie, Institut fu¨r Organische Chemie und
Makromolekulare Chemie, Heinrich-Heine-Universita¨t Du¨sseldorf, Univer-
sita¨tsstraße 1, D-40225, Du¨sseldorf, Germany. E-mail: ThomasJJ.Mueller@
uni-duesseldorf.de; Fax: ++49 (0)211 8114324; Tel: ++49 (0)211 8112298
bMerck Serono Research & Development, Merck KGaA, D-64271, Darm-
stadt, Germany
Fig. 1 Biologically active (aza)indoles with 5- and 6-membered heterocy-
cles at C-3 (corresponds to C-5 in variolin B).
† Dedicated to Prof. K. Barry Sharpless on the occasion of his 70th
birthday.
‡ Electronic supplementary information (ESI) available: experimental
procedures and analytical data of compounds 1a–l, 1n, 8a–s, 9a–b, 10,
and 11. See DOI: 10.1039/c1ob05586k
Recently, we reported a practical approach to indoles and
7-azaindoles substituted with azines via a one-pot Masuda
borylation–Suzuki coupling sequence.38 Using this approach,
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concise total syntheses of meridianins A and G could be realized.
Previously, we synthesized some members of the meridianin family
and a 7-azaindole analogue of variolin B (later called meriolin
1),37 using a carbonylative Sonogashira coupling as a key step.39
In these compounds, as well as in variolin B, the key structural
feature responsible for the observed biological activity is the 2-
aminopyrimidine ring at C-3, even though meridianins, meriolins,
and variolins bind differently to the hinge region of kinases.37,40
Notably, isomeridianins,41 possessing the 2-aminopyrimidine moi-
ety at C-2, and variolin D, lacking a heterocycle substituent at C-5,
are not biologically active.
Surprisingly, triazolyl substituted indoles have hardly been
explored,42 although the 1,2,3-triazole ring as an electron-poor
metabolically stable43 5-membered heterocyclic substituent has
attracted considerable attention in bioconjugate chemistry, medic-
inal chemistry, and drug discovery.44 In addition to its function
as a convenient linker,45 1,4-disubstituted 1,2,3-triazole is a
peptidomimetic,46 has a large dipole moment and is an H-acceptor
over N-2 and N-3 atoms. Here, we report a diversity-oriented
synthetic concept to access 3-triazolyl-substituted (aza)indole
scaffolds in a one-pot fashion. In addition, the potential of the title
compounds as kinase inhibitors47,48 and cytostatics is explored.
Scheme 1 Synthetic concept for triazolyl N-Boc protected heterocycles
(X = CH or N; R = alkyl or aryl, may be generated in situ).
easily introduced on the nitrogen atoms of 5-membered NH-
heterocycles64 or it can be installed directly in the course of their
synthesis.65,66 If not further required, this group can be removed
easily and cleanly under various conditions.67 Previously, we have
demonstrated the enormous utility and versatility of 3-iodo N-Boc
protected indoles, 7-azaindoles, and pyrroles as easily accessible
synthetic building blocks.38,39,66
The Sonogashira coupling of iodo N-Boc NH-heterocycles68
1 with TMSA proceeded smoothly under standard Sonogashira
conditions (PdCl2(PPh3)2/CuI/NEt3).69 The obtained TMS-
alkynes were not isolated but directly deprotected with TBAF
and subsequently reacted with one equivalent of the commercially
available and stable benzyl azide (5a) to furnish N-Boc 3-triazolyl
(aza)indoles 2a–l and azoles 2m–o in a one-pot fashion (Scheme 2).
The yields were very similar for (aza)indoles and pyrrole regardless
of the number and position of nitrogen atoms.
Results and discussion
The Sonogashira coupling–TMS-deprotection–CuAAC sequence
The Sonogashira–Hagihara cross-coupling49 is among the most
reliable C–C bond forming reactions and has become the method
of choice for the construction of internal alkynes from (het-
ero)aryl halides and terminal alkynes.50 Upon coupling halides
with trimethylsilylacetylene (TMSA), TMS-protected alkynes are
formed, which can be easily deprotected to give (hetero)aromatic
terminal alkynes.51 The latter are perfectly suited for the copper(I)-
catalyzed azide–alkyne cycloaddition (CuAAC),52,53 the most re-
markable Cu(I)-catalyzed process developed in the last decade. The
transformation belongs to click-type reactions,54 which proceed
with a high degree of atom economy.55 This process is also very
reliable, mild, general, and highly tolerant to diverse functional
groups. All these features render this reaction highly practical.56
In the past, many efforts have been made to develop one-
pot methodologies based upon the in situ generation of the
azide component,57 the in situ utilization of TMS-acetylenes,58
or the direct sequential Cu(I)-catalyzed C–H-bond arylation of
the obtained triazoles.59 Surprisingly, only little attention has been
paid to the in situ construction of terminal alkynes.60
As a continuation of our program directed to develop new
one-pot multi-component reactions initiated by metal-catalyzed
cross-coupling as an entry for the synthesis of heterocycles61,62
we envisioned the possibility of performing Sonogashira coupling
and CuAAC in a one-pot fashion. Coupling of N-Boc protected
3-iodo NH-heterocycles 1 with TMSA would furnish the inter-
mediate TMS-protected heterocyclic alkynes 3, which after in situ
deprotection would give terminal alkynes 4, the starting material
to accomplish CuAAC with an azide 5, resulting in another Cu(I)-
catalyzed reaction. It was hoped the strategy would give direct
access to triazoles 2 in the sense of sequential catalysis (Scheme 1).
Boc (tert-butoxycarbonyl) is one of the cheapest and most
frequently used nitrogen protective groups.63 Either it can be
Scheme 2 Sonogashira coupling–TMS-deprotection–CuAAC sequence
for the synthesis of N-Boc 3-triazolyl (aza)indoles 2a–l and azoles 2m–o
(X = CH or N; R = Bn, Ph; R¢ = Me, OMe, O(CH2)2OMe, p-MeOC6H4).
No further addition of CuI was required in the CuAAC step.
The reaction progress can be conveniently monitored by TLC
and the steps cleanly proceed as “spot-to-spot” reactions without
noticeable amounts of byproducts. No Glaser-type homodimer-
ization products70 were detected because the CuAAC reaction was
performed under an argon atmosphere. It is worth mentioning
that the electron-withdrawing Boc protective group renders the
(aza)indolyl iodides 1 stable to storage,71 whereas the unprotected
iodides are frequently sensitive to light and temperature and
therefore inconvenient to handle.72 Moreover, the Sonogashira
coupling is greatly facilitated, or even becomes feasible, due to
the diminished electron density of these heterocycles.
For the synthesis of triazoles with different substituents on
the N-1 atom of the triazole moiety, the sequence was extended
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to a four-component reaction with N-Boc protected 3-iodo 7-
azaindole (1f) as a substrate. This sequence additionally includes
the in situ generation of the azide 5 via nucleophilic substitution
of a halide with caesium azide (Scheme 3). Hence, not only
electronically diverse benzyl substituents (2p and 2q), and even
a-phenylethyl substituents (2s), but also the homobenzyl group
can be introduced with a comparable yield (2r).
Scheme 5 Deprotection of N-Boc 3-triazolyl heterocycles 2 and 7
to 3-triazolyl NH-heterocycles 8 and 9 (X = CH or N; R = Me,
OMe, O(CH2)2OMe, p-MeOC6H4; R¢ = Ph, homobenzyl, Bn, or benzyl
derivatives).
Scheme 3 Four-component Sonogashira coupling–TMS-deprotection–
Finkelstein-type reaction–CuAAC sequence for the synthesis of N-Boc
protected triazolyl 7-azaindoles 2p–s (R = alkyl; Hal = Br, Cl).
For 4- and 5-bromo 7-azaindoles (6a and 6b), which are
commercially available and stable compounds, a four-component
Boc-protection–Sonogashira
coupling–TMS-deprotection–
CuAAC sequence was developed to give N-Boc protected 4- and
5-triazolyl azaindoles (7a and 7b) in very good yields (Scheme 4).
The Sonogashira coupling was performed at room temperature
using Fu’s catalytic system.73
Scheme
4 Boc-protection–Sonogashira coupling–TMS-deprotection–
CuAAC sequence for the synthesis of N-Boc 4- and 5-triazolyl 7-azaindoles
7a and 7b.
The possibility to easily adopt the whole synthesis to a
specific substrate and a flexible incorporation of additional steps
into the sequence is an additional advantage of this one-pot
methodology.
The obtained N-Boc protected triazolyl NH-heterocycles 2 and
7 were readily deprotected under extremely mild conditions using
potassium carbonate in methanol at room temperature or slightly
above (Scheme 5). It should be mentioned that although the Boc
protective group could be removed after the completed sequence in
a one-pot fashion, we preferred to perform the Boc-deprotection
in a separate step to ensure the high purity of the final products 8
and 9 (as determined by HT-LC-MS analysis, the UV purity was
99.9–100% for all presented compounds). The content of Pd and
Cu in compound 8f was determined to be < 1 mg g-1 (< 3 ppm)
and < 2 mg g-1 (< 9 ppm), respectively. Thus, no additional removal
of these heavy metals is required.74
Fig. 2 Scope of the synthetic strategy towards triazolyl NH-heterocycles
8 and 9 (isolated yields over two steps).
The yields are fair to good and are very similar for all
indole analogues 8a–l. They are little affected by the position
and number of additional nitrogen atoms, which is not self-
evident (according to personal observations experienced with
other coupling reactions of these substrates) and emphasizes
the synthetic power gained from the combination of two very
general methods, Sonogashira coupling and CuAAC. Only the
azoles 8n and 8o gave poor yields due to the increased lability of
the Boc protective group in the corresponding starting materials.
Moreover, with tert-butyl 4-iodo-1H-imidazole-1-carboxylate (1n)
the Sonogashira coupling proceeded very sluggishly and required
The scope of the presented methodology includes indole (8a)
and its bioisosters75 such as indazole (8b), all azaindoles (8c–i, 8p–
s, and 9), diazaindole (8j), deazapurines (8k–l), as well as pyrrole
(8m), pyrazole (8n), and imidazole (8o) (Fig. 2).
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Table 2 Comparison of IC50 values of PDK1 inhibition between isomeric
3-triazolyl 7-azaindole compounds 8f and 10, as well as 3-pyrazolyl 7-
azaindole 11
15 d reaction time. The structures of the obtained triazoles 8
and 9 were unambiguously supported by NMR spectroscopy,
mass spectrometry, and combustion analysis, and later by an
X-ray structure analysis of compound 8f, cocrystallized with
kinase PDK1 (vide infra).
PDK1 inhibition/IC50 (mM)
The sequences are very straightforward and preparatively
extremely simple to perform. Generally, all steps proceed at room
temperature, which is especially important if less stable azides
are to be used. However, they can even be generated in situ with
comparable efficiency. It should be noted that while these studies
were in progress two reports appeared in the literature which
described the same synthetic approach with simple aryl iodides.76
However, we used this strategy to synthesize triazolyl NH-
heterocycles, which are more sophisticated chemical targets and
show promising biological activity, thus illustrating the synthetic
utility of this practical synthesis. Since a variety of diverse NH-
heterocycles, which are of paramount importance in many areas of
research, can be decorated with triazoles in a very straightforward
fashion, the sequence is quite general. Starting from these small
lead structures, more potent derivatives can be readily developed
using this synthetic approach.
8f
10
11
0.8
>10
2.6
like template turned out to be broad kinase inhibitors with 8h,
8k, and 8l having the broadest activity. In contrast, compounds
9a and 9b, which possess a benzyltriazole substituent at C-4 and
C-5 of the 7-azaindole, are much less active, thus emphasizing
the importance of C-3 substitution. Furthermore, substitution
at C-2 or a nitrogen atom in the para-position to N-7 of the 7-
azaindole seem to reduce the biological activity of compounds 8i
and 8j.
For determining whether the triazole unit is merely a linker
or possesses an additional function, an analogue of compound 8f
was prepared via the recently reported Masuda borylation–Suzuki
coupling sequence.38 This compound bears a pyrazole moiety
instead of a triazole. Interestingly, the triazole unit seems to be
important for the biological activity, since the pyrazole compound
11 was significantly less active with an IC50 value of 2.6 mM
for PDK1 compared with 0.8 mM for the triazole 8f. Therefore,
triazole does not simply seem to be a linker, as in many applications
of this heterocycle, but rather displays a pharmacophore character.
However, even more exciting was the observation that the isomeric
compound 10,78 differing from 8f only in the permutation of
substituents on N-1 and C-4 of the triazole unit, showed no activity
on kinases, including PDK1 (Table 2).
Biological data
All compounds 8 and 9 were tested for inhibition of a broad panel
of kinases at the Division of Signal Transduction Therapy (DSTT)
at the University of Dundee, UK. The compounds were screened
against 95–121 kinases at a concentration of 1 mM. In addition, for
all compounds, IC50 values for the inhibition of the kinase PDK1,
a target of high relevance for oncology,77 were determined. The
results for compounds that showed submicromolar activity on at
least one kinase are summarized in Table 1.
For the compounds described here, a hydrogen donor/acceptor
pattern of the 7-azaindole core that can interact with the hinge
region of kinases, is a prerequisite for kinase inhibitory activity. All
compounds in this table possess such a pattern whereas the great
majority of the inactive compounds 8a, 8c, 8d, 8e, 8m, 8n, and
8o, lack this peculiar structural feature. In particular, compounds
with a benzyltriazole group in the 3-position of a 7-azaindole-
X-ray structure of 8f in complex with PDK1
For further characterization of the binding mode, compound 8f
was soaked in crystals of the kinase domain of PDK1. Broad
kinase activity of triazole derivatives is related to PDK1 activity
(Table 1), which suggests that the binding mode in this kinase may
be representative for several other kinases. The crystal structure
Table 1 Biological data of selected compounds 8 and 9
Number of kinases with >50% inhibition
@ 1 mM/number of kinases tested
IC50[PDK1] (mM)
˚
was solved at 1.7 A (Table 3) and reveals the detailed binding mode
8b
8f
8g
8h
8i
8j
8k
8l
8p
8q
8r
8s
9a
9b
4/121
22/121
10/120
48/95
2/120
11/95
54/120
60/102
15/95
3/121
17/121
11/120
12/110
4/110
>10
0.8
5.2
0.1
2.3
4.9
0.2
0.3
1.8
>10
>10
1.1
7.9
>10
of 8f within the ATP-binding site (Fig. 3).
Compound 8f shows two canonical hydrogen bonds to the hinge
region, an H-bond donor contact from azaindole N-1 to Ser160,
and an H-bond acceptor contact from azaindole N-7 to Ala162.
The triazole nitrogen atoms are also involved in hydrogen bonding
interactions: N-3 to the Thr222 side chain (which may explain the
lower activity of the pyrazole 11) and N-2 to a water molecule.
This water molecule is also in the H-bond distance to the catalytic
amino acids Lys111 and Asp223. The molecule binds in an overall
bent conformation with the benzyl group forming hydrophobic
interactions with the glycine-rich region (GC-loop). The reason for
the inactivity of compound 10, which is a bioisostere of compound
8f and differs only in the relative position of the substituents on N-1
and C-4 of the triazole unit and consequently in the dipole moment
IC50: concentration inhibiting kinase activity or reducing cell proliferation
by 50%.
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Table 3 Crystallographic data of compound 8f
with the benzyl substituent in 8f. Since all synthesized compounds
are small molecules, more potent analogues can be envisioned by
derivatization, which can be achieved easily with the presented
method.
PDB ID
3RCJ
Total number of reflections collected
Number of unique reflections
Space group
110193
33266
C2
˚
Cell dimensions a, b, c (A)
148.87, 44.39, 47.10
Experimental
Cell dimensions a, b, g (◦)
Rmerge overall, highest resolution shell (%)
I/s overall, highest resolution shell
Completeness (%)
90, 101.01, 90
55.4, 7.2
20.58, 2.81
99.0
Synthesis of 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-
1H-pyrrolo[2,3-b]pyridine (8f)
Redundancy
Resolution range used in refinement (A)
Number of unique reflections used in refinement
Rfactor (%)
Rfree (%)
Number of molecules per asymmetric unit
Number of ligands per asymmetric unit
Number of protein atoms
Number of ligand atoms
Number of water molecules
3.31
(Compound 2f): PdCl2(PPh3)2 (71 mg, 0.10 mmol, 2 mol%)
and CuI (39 mg, 0.20 mmol, 4 mol%) were placed in a dry
screw-cap Schlenk vessel with a septum. Then, tert-butyl 3-iodo-
1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1f) (1.72 g, 5.00 mmol)
was added in 25 mL of dry tetrahydrofuran under an argon
atmosphere and the reaction mixture was degassed with argon.
After that, trimethylsilylacetylene (1.08 mL, 7.50 mmol, 1.50
equiv.) and dry triethylamine (1.39 mL, 10.0 mmol, 2.00 equiv.)
were added and the mixture was stirred at room temperature
(in a water bath) for 1 h until the complete consumption of
the starting material (monitored by TLC). Then, 1 M solution
of tetrabutylammonium fluoride in tetrahydrofuran (7.50 mL,
1.50 mmol, 1.50 equiv.) was added dropwise and the mixture
was stirred at room temperature for 0.5 h until the deprotection
was complete (monitored by TLC). After that, benzyl azide (5a)
(679 mg, 5.00 mmol, 1.00 equiv.) in 5 mL of dry methanol
was added and the mixture was stirred at room temperature for
40 h until the complete conversion to the product (monitored
by TLC). After removal of the solvents in vacuo the residue was
˚
70–1.7
33266
19.8
21.7
1
1
2278
21
162
R
absorbed onto Celiteꢀ and purified chromatographically on silica
gel with petroleum ether (boiling range 40–60 ◦C)–ethyl acetate
PE–EtOAc = 2 : 1 (Rf (PE–EtOAc = 2 : 1): 0.20) to give 1.56 g
(4.15 mmol, 83%) tert-butyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-
1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2f) as a yellow foam.
The obtained compound was deprotected without characteriza-
tion and further purification.
˚
Fig. 3 X-ray structure of the complex of 8f with PDK1 at 1.7 A resolution.
The 7-azaindole ring forms H-bonds to the hinge region (Ser160 &
Ala162); two of the triazole N-atoms form H-bonds to Thr222 and a
water molecule. The benzyl ring is oriented towards the GC-loop.
(Compound 8f): tert-Butyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-
1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2f) (1.56 g, 4.15 mmol)
was placed in 21 mL of methanol. Then, potassium carbonate
(1.45 g, 10.4 mmol, 2.50 equiv.) was added and the mixture was
stirred at room temperature (in a water bath) for 1 h (monitored
by TLC). A precipitate formed after a few min. The mixture was
of the molecule, cannot be deduced from this X-ray structure and
still remains obscure.
Conclusions
R
adsorbed on Celiteꢀ and purified chromatographically on silica
A practical and preparatively simple one-pot three-component
Sonogashira coupling–TMS-deprotection–CuAAC sequence was
developed to synthetically access a variety of triazolyl NH-
heterocycles 8 and 9 in high purity and a very concise fashion. The
sequence works very reliably for substrates with nitrogen atoms
in different positions of various indole isosters, arising from the
robustness, the versatility, and the generality of both Sonogashira
coupling and CuAAC. The title compounds were tested for
inhibition of a broad panel of kinases to reveal their kinase
inhibitory activities. Compounds 8f, 8h, 8k, and 8l were found
to inhibit PDK1 kinase with IC50 values below 1 mM. The X-ray
structure analysis of compound 8f in complex with PDK1 reveals
the importance of the benzyl substituent for the binding. The
phenyl and homobenzyl derivatives 8g and 8r were considerably
less active, indicating a suboptimal position of their aromatic
rings for favorable interaction towards the GC-loop compared
gel with dichloromethane–methanol–aqueous ammonia DCM–
MeOH–NH3 = 100 : 1 : 1 → 100 : 2 : 1 → 100 : 3 : 1 (stepwise
gradient). After drying in vacuo overnight, 930 mg (3.38 mmol,
81%) of a pale yellow solid were obtained. The product was
additionally purified by suspension in dichloromethane, sonica-
tion in ultrasonic bath for 0.5 h, filtration and drying in vacuo at
◦
70 C overnight to obtain the analytically pure 3-(1-benzyl-1H-
1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8f) as◦ a colorless
solid. UV purity (HT-LC-MS): 100%. M.p. 234–237 C.1H NMR
(DMSO-d6, 500 MHz): d (ppm) 5.66 (s, 2 H), 7.17 (dd, J = 7.9 Hz,
J = 4.7 Hz, 1 H), 7.32–7.43 (m, 5 H), 7.92 (d, J = 2.5 Hz, 1 H), 8.29
(dd, J = 4.7 Hz, J = 1.6 Hz, 1 H), 8.44 (dd, J = 7.9 Hz, J = 1.6 Hz,
1 H), 8.54 (s, 1 H), 11.9 (br, 1 H, NH). 13C NMR (DMSO-d6,
125 MHz): d (ppm) 52.8 (CH2), 105.0 (Cquat), 115.9 (CH), 116.9
(Cquat), 119.8 (CH), 123.2 (CH), 127.8 (CH), 128.1 (CH), 128.3
(CH), 128.7 (CH), 136.1 (Cquat), 142.4 (Cquat), 143.1 (CH), 148.5
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(Cquat). EI + MS (m/z (%)): 275 (M+, 100), 248 (13), 247 (74), 246
(87), 220 (11), 219 (35), 170 (15), 156 (24), 142 (10), 129 (17), 91
Notes and references
1 For a review on indole scaffold as a privileged structure, see: F. R. de Sa´
Alves, E. J. Barreiro and C. A. M. Fraga, Mini-Rev. Med. Chem., 2009,
9, 782; For a general review on bicyclic privileged structures, see: D. A.
Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893;
For a comprehensive listing of privileged scaffolds, see: M. E. Welsch,
S. A. Snyder and B. R. Stockwell, Curr. Opin. Chem. Biol., 2010, 14,
347.
+
-1
˜
(C7H7 , 19), 44 (19). IR (KBr): n 1584 (s) cm , 1458 (m), 1420
(m), 1220 (m), 941 (m), 799 (m), 771 (s), 722 (s). Anal. calcd for
C16H13N5 (275.3): C 69.80, H 4.76, N 25.44. Found: C 69.71, H
5.02, N 25.44.
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PDK1 biochemical kinase assay
The PDK1 (3-phosphoinositide-dependent protein kinase-1)
assay was carried out in 384-well streptavidin-coated FlashPlates
(PerkinElmer). 3.4 nM His6-PDK1(D1-50), 400 nM biotinylated
PDKtide
(Biotin-bA-bA-KTFCGTPEYLAPEVRREPRILS-
EEEQEMFRDFDYIADWC), and 4 mM ATP (spiked with
0.25 mCi 33P-ATP per well) were incubated in a total volume
of 50 mL (50 mM TRIS, 10 mM magnesium acetate, 0.1%
mercaptoethanol, 0.02% Brij35, 0.1% bovine serum albumin,
pH 7.5) with or without test compound (7–10 concentrations) for
60 min at 30 ◦C. The reaction was stopped by the addition of 25 mL
200 mM EDTA. After 30 min at room temperature the liquid
was removed and each well washed three times with 100 mL 0.9%
sodium chloride solution. Nonspecific reaction was determined
in the presence of 100 nM staurosporine. Radioactivity was
measured in a Topcount (PerkinElmer). Results (IC50 values) were
calculated with e.g. AssayExplorer (Symyx).
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buffer was 50 mM orthophosphoric acid) and dried in air. The dry
Unifilter plates were then sealed on the addition of MicroScint
O and were counted in Packard Topcount NXT scintillation
counters.
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Cocrystallization of compound 8f with PDK1 and X-ray structure
determination
Crystallization of PDK1 was performed as previously described80
and crystals were used for soaking with compound 8f. X-Ray
diffraction data were collected at the PXIII beamline equipped
with a Pilatus detector at the Paul Scherrer Institut in Villingen,
Switzerland. With the detector set at 270 mm, data were collected
◦
˚
in 720 contiguous 0.25 oscillation images at 1 A wavelength. The
˚
data for compound 8f extends to 1.7 A resolution, has an Rmerge
of 7.2% and 3.31-fold multiplicity. The structure was refined using
CNX (Accelrys Inc.) to an Rfactor of 19.8%.
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Acknowledgements
The support of this work by the Merck Serono, Darmstadt,
the Deutsche Forschungsgemeinschaft DFG, and by the Fonds
der Chemischen Industrie is gratefully acknowledged. We thank
Daniel Schro¨der, Merck Serono, for conducting the crystallization
experiments.
5134 | Org. Biomol. Chem., 2011, 9, 5129–5136
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