Expedient Access to 2-Benzazepines by Palladium-Catalyzed C?H Activation: Identification of a Unique Hsp90 Inhibitor Scaffold

Article abstract of DOI:10.1002/chem.201804244

Bioactive 2-benzazepines were accessed in an atom- and step-economical manner through a versatile palladium-catalyzed C?H activation strategy. The C?H arylation required low catalyst loading and a mild base, which was reflected by a broad scope and high functional-group tolerance. The benzotriazolodiazepinones were identified as new heat shock protein 90 (Hsp90) inhibiting lead compounds, with considerable potential for anti-cancer applications.

Full text of DOI:10.1002/chem.201804244

A Journal of
Accepted Article
Title: Expedient Access to 2-Benzazepines by Palladium-Catalyzed C
−H activation: Identification of a Unique HSP90 Inhibitor Scaffold
Authors: Giuseppe Zanoni, Ackermann Lutz, Virelli Matteo, Moroni
Elisabetta, Colombo Giorgio, Fiengo Lorenzo, and Porta
Alessio
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201804244
Link to VoR: http://dx.doi.org/10.1002/chem.201804244
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10.1002/chem.201804244
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COMMUNICATION
Expedient Access to 2-Benzazepines by Palladium-Catalyzed C−H
activation: Identification of a Unique HSP90 Inhibitor Scaffold
Matteo Virelli,[a] Elisabetta Moroni,[b] Giorgio Colombo,[a, c] Lorenzo Fiengo,[d] Alessio Porta,[a] Lutz
Ackermann,[a,e]* and Giuseppe Zanoni[a]*
Abstract: Bioactive 2-benzazepines were accessed in an atom- and
step-economical manner by a versatile palladium-catalyzed C−H
activation strategy. The C−H arylation featured low catalyst loading
The latter activity is remarkable in light of the key role played by
and a mild base being reflected by ample scope and high functional
HSP90 client proteins in oncogenic signaling, and in establishing
group tolerance. Thereby, the benzotriazolodiazepinones were
the hallmark traits of malignancy, including proliferation, evasion
identified as novel HSP90 inhibitor lead compounds, with
of apoptosis, immortalization, invasion, angiogenesis and
metastasis.[3] Targeting Hsp90 by designed low-molecular
considerable potential for anti-cancer applications.
weight compounds, constitutes an exciting therapeutic approach
and, at the same time, provides access to possible targets, such
as specific Hsp90 co-chaperones.[4]
Benzazepines, represent key structural motifs of complex
naturally occurring molecules of relevant to material sciences
and medicinal chemistry (Figure 1a).[1] Indeed, particularly the
heterocycle fused 2-benzazepine displays unique biological and
pharmacological features, such as inhibition of PI3-kinase,
hepatitis C Virus NS5B RNA polymerase, modulation of g-
secretase activity and potential HSP90 inhibition (figure 1b).[2]
Within our program on sustainable palladium-catalyzed C−H
activations,[5] and based on detailed molecular modeling
evaluation of literature reported HSP90 inhibitors specifically
aimed to uncovering HSP90 inhibitors endowed with a new
chemical framework, we identified heterocyclic fused 2-
benzazepine derivatives as particularly powerful lead
compounds.[6]Thus, we herein report on our recent findings on
the step-economical synthesis of multi-annulated rings via a
flexible C–H activation strategy affording a new lead compound
with a HSP90 nano-molar (nM) inhibition activity.[7] We initiated
our studies by exploring approaches towards a general strategy
for the preparation of a variety of 2-benzazepines featuring
ample chemical diversity. However, despite major advances,
classical approaches to access these heterocyclic fused 2-
benzazepine derivatives require tedious multi-step sequence
largely involving conventional condensation-based and
enzymatic strategies.[8] Furthermore, metal-catalyzed cross-
coupling strategies have been devised for the construction of N-
fused heterocycles. However, despite indisputable progress
these cross-couplings require two prefunctionalized starting
materials, leading to stoichiometric amounts of undesired
byproducts.[9] Moreover, these approaches continue to be limited
to specific indoles, pyrroles and arenes, while a flexible strategy
for the construction of chemical diverse heterocycles fused 2-
OH
OMe
a)
O
MeO
Cl
N
N
N
N
Me
O
Me
O
N
HN
S
N
O
O
O
Me2
MeN
Valium
Galanthamine
Beclabuvir
R
b)
N
N
N
N
R
Ar
N
O
N
N
N
N
N
N
MeO2C
Hepatitis C virus inhibitors
PI3-Kinase inhibitors
Potential HSP90 inhibitors
Figure 1. Examples of biologically active 2-benzazepines in nature and
pharmaceuticals.
benzazepine has unfortunately thus far proven elusive.[10]
Y
N
H
R
X
Y
R
N
[a]
[b]
M. Virelli, Prof. G. Colombo, Prof. A. Porta, Prof. L. Ackermann and
Prof. Zanoni
Department of Chemistry
N
N
Z
Z
University of Pavia
Viale Taramelli 10, 27100 Pavia, Italy
E-mail: gz.@unipv.it
X = Br, Cl
Y = N, CH
Z = CH2, C=O, O, S
E. Moroni
Figure 2. Palladium-Catalyzed C-H arylation towards bioactive azepines.
IRCCS MultiMedica
via Fantoli 16/15, 20138 Milano
Istituto di Chimica del Riconoscimento Molecolare, CNR
Via Mario Bianco 9, 20131 Milano, Italy
L. Fiengo
Department of Pharmacy
University of Salerno
Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
Prof, L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstraße 2, 37077 Göttingen, Germany
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de/
[c]
[d]
Our modular strategy for the atom- and step-economical
approach for the synthesis of seven-membered azepines
derivatives is depicted in Figure 2. Hence, our C−H arylation
approach exhibited ample scope and flexibility as to N-
heterocycles, functional groups and spacer between the two
aromatic moieties. Heteroatoms and carbonyl groups in the side
[e]
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COMMUNICATION
R2
chains, halogen substituted aromatic rings and a variety of
heterocycles were well tolerated.
Pd(OAc)2
PCy*HBF4 (3.8-7.5 mol %)
(2.5-5.0 mol %)
R1
Br
H
R1
N
N
R2
We commenced our studies by exploring various ligands, bases
and solvents for the envisioned C−H arylation of 1,2,4-triazole
1a with Pd(OAc)2 as the catalyst. Ultimately ligand and other
parameters (See Supporting Information) established that
catalytic Pd(OAc)2 in the presence of PCy3*HBF4, using DMF as
solvent, was effective for the formation of the new C-C bond
leading to compound 2a in 95 % yield (Scheme 1). It is important
to note that the amount of the catalyst could be reduced to only
1 mol % with a mild base, while the C−H arylation occurred with
a comparable yield on gram scale. With the optimized conditions
for the C−H arylation in hand, we extended the scope of the
C−H activation by varying the substituents on the aryl motif and
inducing various heteroatoms in the spacer between the two
reaction partners.
N
KOAc
DMF
140 °C, 20 h
(1.2 equiv)
N
Y
Y
2
1
Y= CH2 , O, S
R2
R2
N
N
N
R1
N
O
R2 = H
R2 = Ph
2j: 76 %b
2k: 63 %b
R2 = C6H3(OMe)2 2l: 59 %
R1 = H,
R1 = Me, R2 = H
R2 = H
2m: 81 %b
2n: 86 %b
R1 = Me, R2 = Ph 2o: 75 %
R1 = Et,
R1 = Et,
R1 = Cl,
R1 = Cl,
R2 = H
R2 = Ph 2q: 76 %
R2 = H
2r: 77 %b
R2 = Ph 2s: 65 %
2t: 88 %b
2p: 86 %b
R2
N
R1 = NO2 , R2 = H
N
O
O
R1 = NO2
,
R2 = Ph 2w: 63 %
R2
Pd(OAc)2
PCy*HBF4
(1.0 mol %)
(1.5 mol %)
N
H
R
Br
N
R
N
N
N
R2 = H
2x: 67 %b
R2 = C6H3(OMe)2 2y: 77 %b
N
KOAc
DMF
140 °C, 20 h
(1.2 equiv)
N
N
Y
Y
S
2
1
Y= CH2 , O, S
R2 = H
2ab: 54 %
R2 = Ph 2ac: 51 %
R2
N
N
N
N
N
O
N
N
N
R
N
N
BnO
O
O
R2 = H
R2 = Ph
2z: 65 %
2aa: 64 %
2ad: 68 %
2a: 95 %
R = H
2c: 88 %
a Reactions conditions: 1 (0.5 mmol), Pd(OAc)2 (5.0 mol %), PCy3*HBF4 (7.5 mol %),
KOAc (0.6 mmol, 1.2 equiv) in DMF (0.07 M, 7.1 mL) at 140 °C for 20 h.b Pd(OAc)2 (2.5 mol %)
and PCy3*HBF4 (3.8 mol %)
N
R = Me 2d: 85 %
N
N
N
O
O
R = Et
R = Cl
2e: 91 %
2f: 96 %
Scheme 2. Substrate scope for the pyrazole intramolecular C−H activationa.
2b: 74 %
R = NO2 2g: 66 %
N
N
N
N
Furthermore, the broadly applicable palladium catalyst enabled
the efficient C−H activation on other nitrogen heterocycles
likewise, including imidazole 1ae and 1,2,3-triazole 1af (Scheme
3).
N
O
S
2i: 62 %
2h: 93 %
a Reactions conditions: 1 (0.5 mmol), Pd(OAc)2 (1.0 mo l%), PCy3*HBF4 (1.5 mol %),
N
N
Pd(OAC)2 (2.5 mol %)
PCy3*HBF4 (3.8 mol %)
KOAc (0.6 mmol, 1.2 equiv) in DMF (0.07 M, 7.1 mL) at 140 °C for 20 h.
H
Br
N
N
N
N
KOAc
(1.2 equiv)
Scheme 1. Substrate scope for the 1,2,4-triazole intramolecular C−H
activationa.
DMF, 140°C
20 h
1ae
2ae: 94 %
N
N
H
Pd(OAC)2 (2.5 mol %)
PCy3*HBF4 (3.8 mol %)
Br
A wide range of spacer-motifs could be employed in the C−H
arylation. In particular, the chain containing the sulfur atom is
fascinating because it gave access to different class of
thiazepine in an innovative fashion. Importantly, the C−H
arylation smoothly proceeded with various substituents on both
aryl moieties and the nitrogen-containing heterocycle. The
versatile catalyst thus proved tolerant of valuable electrophilic
functional groups, such as the chloro and nitro substituent.
Subsequently, we explored the robustness of our optimized
catalyst by testing various pyrazole heterocycles (Scheme 2).
N
N
KOAc
(1.2 equiv)
DMF, 140°C
20 h
1af
2af: 67 %
Scheme 3. Other nitrogen heterocycles.
To our delight, under otherwise identical reaction conditions the
palladium catalyst provided versatile access to diversely
decorated benzodiazepine 3, starting from easily accessible 2-
bromoanilines (Scheme 4).
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function, with stricter requirements for ligand-receptor shape
complementarity.
H
N
N
N
Pd(OAc)2
PCy*HBF4
10 mol%
15 mol%
N
O
Table 1. Pseudo-thermodynamic dissociation constants measured by SPR.
Br
N
N
N
3
KD (µM)
KD (µM)
Compound
Compound
N
R
O
KOAc
DMF
20h, 140 °C
1.2 equiv
R
Ph
N
N
N
3a R = Bn 56 % (44%)*
N
N
O
O
TFA
50 mol%
2k
2o
0.105 + 0.012 2b
4.48 + 5
3b R = H 75 %
3c R = Me 68 % (55%)*
Ph
N
N
N
N
*Reaction performed using 5 mol% of Pd(OAc)2 and 7.5 mol% of PCy3*HBF4
5.71 + 0.77
15 + 0.2
2ad
2af
0.63 + 0.16
Me
BnO
O
O
Scheme 4. Synthesis of benzodiazepines.
N
N
N
N
N
2i
10.2 + 2.3
1.96 + 2.1
S
N
In order to exploit the biological activity of the new benzazepines
3a, 3b and 3c, various biological tests were carried out. First, in
light of the chemical similarity,2a we explored their inhibitory
potential against PI3-β kinase without any positive results.
Thus, we were delighted to find that the newly synthesized
compounds showed considerable binding to recombinant human
Hsp90α protein in a surface plasmon resonance (SPR) assay in
which 17-AAG was used as a positive control.[11] Analysis of the
SPR sensorgrams indicated that the six compounds 2b, 2h, 2o,
2k, 2ae and 3a interacted with the protein in the µM range
(Table 1). Compounds 2k and especially secondary amide 3b
were shown to display a high affinity towards the chaperone, as
reflected by the measured KD values in the nM range. Thus, 5H-
benzo-triazolodiazepinone 3b exhibited an affinity that was even
higher than the one of NVP-AUY922, one of the most active
reference compounds.[12]
In order to gain detailed insights and rationalize the role of the
different functionalities for the ligand affinities at the receptor, we
selected a subset of molecules having the same scaffold of the
most active compound, which interestingly showed a wider
range of KD, for structural studies. In particular, we focused on
molecules 3b, 2i, 3a, 3c, 2b and 2h to model the possible
binding modes with Hsp90. Docking calculations were
performed in the nucleotide binding pocket of the N-terminal
domain of human-Hsp90. The crystal structure of the receptor
was obtained from the RCSB Protein Data Bank (PDB), PDB
code 2CCS (resolution 1.79 Å), where the N-terminal domain of
Ph
N
N
3b
0.005 + 0.026 2w
N
N
O2N
N
H
O
O
N
N
N
N
N
N
3a
3c
15 + 0.7
2h
3.59 + 1.4
3.57 + 1.4
N
Bn
O
N
O
N
N
N
N
13.2 + 1.6
2ae
N
N
Me
O
O
Me
NH
O
17-AAG
HN
O
Ref compound
KD (µM) 0.330 + 0.27
Me MeO
OH
NH2
O
O
MeO
Me
The XP run confirmed that the most represented binding pose
corresponds to the most represented one observed in the SP
run. In this binding pose compound 3b establishes a network of
HB interactions with the critical residue ASP93 and residues
ASN51 and THR184 (Figure 3) and accommodates its benzene
ring in a hydrophobic pocket defined by LEU107, PHE138,
VAL150, VAL186 (pocket A).
Hsp90 was co-crystalized with
a
piperazine-containing
compound. We first set up a docking procedure that was able to
reproduce the binding pose of this crystal structure (see Docking
section in Supporting Information, Figure S-1) and then we used
the same protocol for modelling the binding of molecules 3b, 2i,
3a, 3c, 2b and 2h in the ATP binding site of Hsp90, the
molecular interaction of which is highlighted in Figure S-2.
Hence, a magnesium ion is coordinated by oxygen atoms of the
α-, β-, and γ-phosphate groups, the side chain of ASN51 and
two water molecules. The most active compound 3b showed five
possible binding poses within 3 kcal/mol from the lowest energy
mode. The lowest energy binding pose is also the most
represented among the 20 poses that were retained at the end
of the docking run. Docking calculations of stage (4) described in
the Material and Methods section were performed using two
different methodologies, SP and XP. XP does more extensive
sampling than SP and it uses a more sophisticated scoring
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contrast to cross-coupling-based strategies, our approach
involves the direct activation of otherwise inert C−H bonds
without the need for tedious prefunctionalizations. The identified
compounds are low molecular weight inhibitors of HSP90
featuring a novel, and so far underappreciated, scaffold. Our
computational studies provide a model that not only rationalizes
the distinct activities of the various compounds, but provides
novel guidance for structural modifications aimed to further lead
development.
Figure 3. 3D and 2D best binding pose of compound 3b (green) in complex
with NTD of Hsp90. In the 2D representation, amino acids are colored
according to hydrophobicity, charge, and polarity (Gray- GLY, dark green-
hydrophobic, cyan- polar uncharged, blue – positives, red – negatives). Yellow
dashed lines represent H-bond interactions.
Acknowledgements
Generous support by the Regione Lombardia
- Cariplo
Foundation: avviso congiunto per l'incremento dell'attrattività del
sistema ricerca lombardo e della competitività dei ricercatori
candidati su strumenti ERC – edizione 2015 (2015-0014). GC
thanks AIRC (Associazione Italiana Ricerca sul Cancro) for
support through grant IG 20019.
In the most represented binding pose, compound 2i overlaps
almost perfectly with compound 3b. The N2 and N4 atoms of the
triazole ring are able to establish HB interactions with LYS58
and ASN51, and the benzene ring accommodates in
hydrophobic pocket A as observed for compound 3b, however
compound 2i lacks of the possibility of establishing any
interactions with ASP93 and THR184 (Figure S-4). The binding
pose of compound 3a is slightly different compared to the
binding mode of compound 3b. In particular, compound 3a is
rotated in the binding site so that the carboxyl group in the
azepine ring still engages in HB to THR184, but the benzyl
group accommodates more deeply in the hydrophobic pocket
compared to the benzene ring of compound 3b. The N2 and N4
atoms of the triazole ring can establish HB interactions with
LYS58 and GLY97 (Figure S-5). Compound 3c shows a very
similar binding mode to compound 3a. The N2 atom of the
triazole ring can establish a HB interaction with LYS58, while the
carbonyl group of the azepine ring can bind residue THR184.
The entire scaffold is slightly shifted in respect to compound 3a,
and this shift orients the methyl group in the azepine ring
towards the hydrophobic pocket A. However, this group cannot
accommodate inside pocket A, unlike the long benzyl group of
compound 3a (see Figure S-6). Compound 2h flips the triazole
ring which engages a HB interaction with THR184 and improves
the hydrophobic interaction with pocket A through its benzene
rings; moreover, one of the benzene rings can reach residue
PHE138, with whom it establishes a ꢀ, ꢀ-stacking interaction
(see Figure S-7). Compound 2b still establishes a HB interaction
with THR184 with the triazole ring, while it points the azepine
ring toward the hydrophobic pocket A and it rotates the order to
orient the dioxolane ring into a polar cavity (see Figure S-8).
From this analysis the interactions that appear to foster binding
are the H bonds with ASP93 and THR184 (see the comparison
between 2i and 2b).
Keywords: C-H arylation • HSP90 • Inhibitors • benzazepines •
docking analysis.
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In summary, we have reported on an unprecedented palladium-
catalyzed C−H activation strategy to provide step-economical
access to
a heterocyclic fused 2-benzazepine. The C−H
arylation strategy is characterized by low catalyst loading, a mild
base and ample substrate scope towards various azepines,
benzoxazepines, thiazepines, and even benzodiazepines. In
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This article is protected by copyright. All rights reserved.

10.1002/chem.201804244
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Matteo Virelli, Elisabetta Moroni, Giorgio
Colombo, Lorenzo Fiengo, Alessio
Porta, Lutz Ackermann, * and Giuseppe
Zanoni*
H
R
X
Z
Y
N
N
33 examples
HSP90 inhibitors
X
=
Br, Cl
Y = N, CH
CH2 C=O, O, S
Z
=
,
Page No. – Page No.
Expedient Access to 2-Benzazepines
by Palladium-Catalyzed C−H
activation: Identification of a Unique
HSP90 Inhibitor Scaffold
Bioactive 2-benzazepines were accessed in an atom- and step-economical
manner by a versatile palladium-catalyzed C−H activation strategy. The C−H
arylation featured low catalyst loading and a mild base being reflected by ample
scope and high functional group tolerance. Thereby, one of our
benzotriazolodiazepinones was identified as novel HSP90 nanomolar inhibitor,
with considerable potential for future anti-cancer applications.
H
R
X
Z
Y
N
N
33 examples
HSP90 inhibitors
X = Br, Cl
Y = N, CH
Z = CH2, C=O, O, S
This article is protected by copyright. All rights reserved.