Synthesis of paramagnetic ligands that target the C-terminal binding site of Hsp90

Article abstract of DOI:10.1016/j.bmcl.2020.127303

Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Our strategy is based on the preparation of paramagnetic analogs of KU-596, an investigational new drug that is currently undergoing clinical trials for the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In particular, we report the design and synthesis of three novel paramagnetic analogs of KU-596, which will be used to obtain long range distances for NMR structural studies of Hsp90 in complex with C-terminal ligands.

Full text of DOI:10.1016/j.bmcl.2020.127303

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Synthesis of paramagnetic ligands that target the C-terminal binding site of
Hsp90
Vishal C. Birar, Ioannis Gelis, Ang Zuo, Brian S.J. Blagg
PII:
S0960-894X(20)30414-5
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127303
BMCL 127303
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
9 April 2020
28 May 2020
31 May 2020
Please cite this article as: Birar, V.C., Gelis, I., Zuo, A., Blagg, B.S.J., Synthesis of paramagnetic ligands that
target the C-terminal binding site of Hsp90, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://
doi.org/10.1016/j.bmcl.2020.127303
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Bioorganic & Medicinal Chemistry Letters
Synthesis of paramagnetic ligands that target the C-terminal binding site of
Hsp90
Vishal C. Birara, Ioannis Gelisb, Ang Zuoa and Brian S. J. Blagg*a
a Department of chemistry and biochemistry, University of Notre Dame, Indiana, USA
b Department of Chemistry, University of South Florida, Tampa, FL 33620
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Identification of the ligand binding site represents the starting point for a structure-
based drug development program. Lack of a binding site hampers the development of
improved ligands that modulate the protein of interest. In this letter, we describe the
development of chemical tools that will allow for elucidation of the Hsp90 C-terminal
ligand binding site. Our strategy is based on the preparation of paramagnetic analogs
of KU-596, an investigational new drug that is currently undergoing clinical trials for
the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In
particular, we report the design and synthesis of three novel paramagnetic analogs of
KU-596, which will be used to obtain long range distances for NMR structural studies
of Hsp90 in complex with C-terminal ligands.
Keywords:
Paramagnetic ligand
HSP90
C-terminal
KU-596
2009 Elsevier Ltd. All rights reserved.
ESR
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular
chaperone that modulates cell signalling processes through the
folding of nascent polypeptides and the rematuration of
denatured proteins1. Hsp90 is responsible for the activation and
maturation of more than 300 client protein substrates, many of
which are directly linked to the ten hallmarks of cancer2. In fact,
Hsp90 inhibition results in the simultaneous degradation of client
proteins that serve as oncogenic signals, and as a result, Hsp90 is
considered a promising target for the development of new anti-
cancer agents3.
On a molecular level, Hsp90 is a homodimer that consists of
three domains; the N-terminal domain (N-Hsp90), the middle
domain (M-Hsp90) and the C-terminus (C-Hsp90). Each region
is well characterized, and their role elucidated. For example, the
N-terminal domain binds and hydrolyzes ATP to afford the
energy necessary for the protein folding process, whereas the
middle region interacts with client and partner proteins, and the
C-terminal domain is responsible for formation of the Hsp90
homodimer4. Studies to inhibit Hsp90 function have identified
numerous small molecules, including the natural products
geldanamycin and radicicol, which have led to the generation of
clinic
ally
evalu
ated
inhibi
tors5.
Mech
anisti
cally,
all of
these
ligand
s
inhibi
t
Hsp9
0
by
bindin
Figure 1. Hsp90 C-terminal inhibitors

g to the N-terminal ATP binding pocket competitively versus
ATP6. As a result, the protein folding cycle is disrupted and
consequently, the clients are degraded via the ubiquitin-
proteasome pathway5.
study demonstrated that removal of amino acids 657-677
severely compromised novobiocin binding, and a synthetic
peptide that mimicked amino acids 663-676 was found to
compete for novobiocin binding to Hsp908,14. Other studies
utilized photoaffinity analogs of novobicin that interacted with
the Hsp90 C-terminal domain21, whereas another approach by
Sogba and co-workers22 used homology modelling and molecular
dynamics simulation to identify cavities on the surface that could
bind a nucleotide or novobiocin. Ultimately, the data suggests
that ATP interacts with amino acids 609-632, 676-681, and/or
497-501 and supports the existence of three potential binding
sites within the Hsp90 C-terminus22.
Hsp90 contains a nucleotide binding site within its N- and C-
terminal domains. Hsp90 inhibitors that bind and displace ATP
from the N-terminus have been evaluated in clinical trials for the
treatment of cancer5. However, these N-terminal inhibitors also
induce the pro-survival heat shock response7, resulting in
increased levels of Hsp90 that require an escalation in dose and
frequency and ultimately, pushes the patient towards the
maximum tolerated dose.
More recently, saturation transfer difference (STD) NMR
spectroscopy was used to probe for molecular insights into the
mode by which KU-32 and KU-596 bind Hsp9023. These
researchers reported the primary binding epitope for both ligands
is localized to the central core (coumarin or biphenyl), and
suggested specific locations on KU-596 that can be modified to
increase interactions with Hsp90. In addition, methyl-TROSY
NMR data were obtained and provided insight into the
mechanism by which these ligands bind and modulate Hsp90
function23. Similar to other C-terminal inhibitors, KU-32 and
KU-596 were found to elicit long range structural rearrangements
In 2000, Neckers and co-workers reported that novobiocin binds
the C-terminus to inhibit Hsp90 function in SKBr3 cells with an
EC50 of approximately 700 μM.8,9 Instead of binding to the N-
terminal ATPase domain, novobiocin was found to bind a
previously unrecognized C-terminal domain, which also
disrupted cancer cell growth similar to N-terminal inhibitors10,11
.
However, subsequent studies revealed that novobiocin does not
induce the HSR, and thus represents an alternative to Hsp90 N-
terminal inhibition. The C-terminal binding pocket to which
novobiocin binds was localized to amino acids 542-738, and
subsequent experiments revealed amino acids 657-677 to be
essential, as removal of these residues significantly diminished
affinity for novobiocin.8,9 Furthermore, these residues are also
required for Hsp90 dimerization and co-chaperone binding.12,13
As a result, derivatives of novobiocin have been pursued to
increase efficacy, establish SAR, and to elucidate the location of
the C-terminal binding pocket14,15. In addition to novobiocin and
novobiocin analogs, epilgallocatechi-3-gallate (EGCG), silybin,
and cisplatin were also found to bind the Hsp90 C-terminus and
to inhibit chaperone function in cells.16-20 Although several C-
terminal inhibitory scaffolds have been reported in the literature,
the exact location to which these ligands bind Hsp90 has not
been elucidated. Consequently, clarity regarding the location and
the mode by which these ligands bind Hsp90 remains unknown
and significantly hinders the development of improved analogs.
upon binding Hsp90 that are propagated to the N-terminus23,24
.
In this communication, the design and synthesis of KU-596
paramagnetic ligands are reported, which can be used to identify
the exact location to which these ligands bind Hsp90. In
particular, carboxy TEMPO (2,2,6,6-tetramethylpiperidine1-
oxyl) and tetramethylpyrroline-1-oxyl appendages were chosen
to be incorporated into the KU-596 scaffold, which is undergoing
clinical evaluation for neuropathy.
Studies with KU-596 using STD experiments provided evidence
that the noviose sugar exhibits the lowest STD effect and thus
provides minimal interaction with Hsp90, highlighting an
opportunity to install additional moieties. Therefore, we designed
a paramagnetic ligand at this location in an effort to reveal nearby
residues upon binding to Hsp90. Paramagnetic ligands such as
Studies have reported various binding modes for Hsp90 C-
terminal inhibitors, but none are consistent with all of the
2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) and 2,2,5,5-
tetramethylpyrroline-1-oxyl are widely used in structural studies
by NMR. The presence of the paramagnetic center on a small
acquired biochemical data8-9,14
.
Prior studies utilized
computational approaches, biochemical analyses, and/or affinity
labelling to identify putative binding sites. For example,
mutational analysis suggested that the novobiocin binding site is
contained within amino acids 538-728.8 Moreover, a related
ligand or other protein partner causes a dramatic increase in the
R2 relaxation rates of protons in a radius of 28 Å. In turn, this is
manifested as a significant signal attenuation, which can be very
accurately converted into a large set of long-range distance
restr
aints
for
struc
ture
calc
ulati
on
prot
ocol
s25.
Ther
efor
e,
we
soug
ht to
Figure 2. Retrosynthetic analyses of KU-596 paramagnetic ligands.
inco

Scheme 1. Reagents and conditions: a) Acetyl chloride, Et3N, 80%; (b) H2, Pd/C, MeOH, 72%; (c) BF3.OEt2 solution, CH2Cl2,
rt; (d) Et3N, MeOH, rt, overnight, 45% e) DCC, DMAP, CH2Cl2, rt.
rporate paramagnetic handles onto the 2’- and 3’-hydroxyls of
noviose as well as onto the amide side chain of KU-596.
Retrosynthetic analysis of the molecules (1 and 2, Figure 2)
suggested that they could be prepared from KU-596, following
modification of the reported synthetic procedure26. In regards to
analog 3, the N-acetyl bromide intermediate 4 was envisioned as
a key intermediate that could undergo nucleophilic displacement
to give the desired analog, 3.
Paramagnetic ligand 3 was prepared from biphenyl ethyl amine
7, the latter of which was synthesized following our previously
reported method.26 Acetylation of biphenylamine
7 with
bromoacetyl bromide gave the α-bromo intermediate 11, which
underwent debenzylation to give the corresponding phenol 5 after
treatment with a solution of boron trichloride. The free phenol of
5 was subsequently coupled with activated noviose carbonate 26,27
in the presence of catalytic boron trifluoride etherate to give the
corresponding noviosylated product, 4. Displacement of the
bromide upon refluxing with 3-amino-pyrrolidine-1-oxyl led to
formation of paramagnetic ligand 12, which underwent solvolysis
to cleave the carbonate and afford the desired product, 3.
Preparation of the paramagnetic ligands is described in Schemes
1 and 2. As mentioned previously, analogs 1 and 2 were
synthesized from KU-596 26. The KU-596 diol was coupled with
an equimolar amount of 4-carboxy-2,2,6,6-tetramethylpiperidine
1-oxyl
(4-carboxy
TEMPO)
using
N,N′-
The synthesized paramagnetic ligands were characterized by
NMR, mass spectroscopy, and ESR spectroscopy. However,
NMR data for the final compounds were not conclusive due to
presence of the paramagnetic spin label. In fact, the NMR signals
exhibited broad peaks due to inclusion of the nitroxide free
radical in addition to missing signals from the protons on the
dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine
(DMAP) to give a 3:1 mixture of regioisomers that upon careful
analysis was found to represent the corresponding 3’- and 2’-
esters, respectively 26,27
.
Scheme 2. Reagents and conditions: a) Bromoacetyl bromide, TEA, DCM, 2Hrs, 40%; b) BCl3SMe2, dry DCM, -20oC, 55%;
c) ) INt, BF3.OEt2, CH2Cl2, rt 6 hrs, 60% d) Radicle, Toluene, reflux overnight, 85% e) ) Et3N, MeOH, rt, overnight, 58%.

nitroxide ring,
The authors gratefully acknowledge the funding support of this
project by NIH CA203175 (B.S.J.B.) and GM115854 (I.G.).
AUTHORS INFORMATION
both of which are consistent with prior reports28-30. Therefore,
incorporation of the paramagnetic residue onto the KU-596
Vishal C Birar -v.birar@nd.edu, & Ang Zuo- azuo@nd.edu,
Figure 3. Continuous wave (CW) electron paramagnetic resonance spectra (EPR) of paramagnetic ligands 1, 2 and 3 in
DCM.
scaffold was confirmed via electron spin resonance (EPR)
spectroscopy and mass spectrometry. The triplet observed in the
ESR spectra was due to the nitroxide signal, which produced
characteristic constants of a = 15.55 G and g = 2.00585. Figure 3
shows the continuous-wave (CW) EPR spectra of spin-labelled
molecules 1-3.
Brian SJ Blagg bblagg@nd.edu, Department of Chemistry,
Notre Dame University, USA.
Ioannis Gelis-igelis@usf.edu, Department of Chemistry,
University of South Florida, Tampa, FL 33620
SUPPLEMENTRY INFORATION
After the discovery of novobicin as an Hsp90 inhibitor,
numerous analogs were prepared that eventually led to the
establishment of preliminary SAR. However, the exact location
of the C-terminal binding site remains unknown, despite the
efforts of several research groups. In an effort to circumvent
these concerns, efforts have shifted from attempting to identify
the binding site via solution of a co-crystal structure, to the use
of NMR to obtain a solution structure of the binding site. Initial
studies demonstrated the key binding motifs for both KU-596
and KU-32 were the central cores, allowing the attachment of
additional moieties onto the sugar and amide side chains. Thus,
paramagnetic ligands were designed and synthesized in this
study, which can now be used to interrogate the location of the
Hsp90 C-terminal binding site, which can then be used to
develop more efficacious analogs for the treatment of cancer
and/or neurodegenerative diseases. The results from such studies
will be reported in due course.
Attached here.
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Synthesis of Paramagnetic ligands that target the C-terminal binding site of HSP-90
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