A trifluorinated thiazoline scaffold leading to pro-apoptotic agents targeting prohibitins

Article abstract of DOI:10.1002/anie.201405758

A new class of small molecules, with an unprecedented trifluorothiazoline scaffold, were synthesized and their pro-apoptotic activity was evaluated. With an EC₅₀ in the low micromolar range, these compounds proved to be potent inducers of apopt

Full text of DOI:10.1002/anie.201405758

Angewandte
Chemie
DOI: 10.1002/anie.201405758
Drug Discovery
A Trifluorinated Thiazoline Scaffold Leading to Pro-apoptotic Agents
Targeting Prohibitins**
Alba Pꢀrez-Perarnau, Sara Preciado, Claudia Mariela Palmeri, Cristina Moncunill-Massaguer,
Daniel Iglesias-Serret, Diana M. Gonzꢁlez-Gironꢂs, Miriam Miguel, Satoki Karasawa,
Satoshi Sakamoto, Ana M. Cosialls, Camila Rubio-PatiÇo, Josꢀ Saura-Esteller, Rosario Ramꢃn,
Laia Caja, Isabel Fabregat, Gabriel Pons, Hiroshi Handa, Fernando Albericio,* Joan Gil,* and
Rodolfo Lavilla*
Abstract: A new class of small molecules, with an unprece-
dented trifluorothiazoline scaffold, were synthesized and their
pro-apoptotic activity was evaluated. With an EC50 in the low
micromolar range, these compounds proved to be potent
inducers of apoptosis in a broad spectrum of tumor cell lines,
regardless of the functional status of p53. Fast structure–activity
relationship studies allowed the preparation of the strongest
apoptosis-inducing candidate. Using a high performance
affinity purification approach, we identified prohibitins 1 and
2, key proteins involved in the maintenance of cell viability, as
the targets for these compounds.
A new paradigm in scaffold design was provided by
Hamilton and co-workers,[4] who reported an avenue for the
development of new bioactive compounds based on the
structural analogy of polyarylic compounds with a-helices.
Furthermore, fluorinated compounds have unique biological
and physicochemical properties which generate important
chemical products and pharmaceuticals.[5–7] Although organo-
fluorine compounds are scarce in natural products, 20–25% of
drugs in the pipeline have at least one fluorine atom. Hence
the introduction of fluorine in bioactive structures often leads
to improved pharmacological properties. This observation
therefore highlights the need for new chemical approaches to
generate such compounds in an efficient manner. Thus, we
reasoned that fluorinated diarylthiazoles could be a promising
scaffold to mimic complex natural products displaying potent
and selective bioactivity (Figure 1A).
A series of fluorinated thiazole derivatives containing
distinct aryl groups was prepared through a synthetic
sequence which comprises the arylation of the corresponding
thiazole precursor by transition-metal couplings and the
subsequent fluorination of the formed diarylthiazole 2 (Fig-
ure 1B). The Suzuki–Miyaura cross-coupling[8] is the best
synthetic approach to obtain symmetric 2,5-diaryl thiazoles
(Figure 1Ba). In contrast, the preparation of unsymmetrical
Natural products provide an invaluable source of medicinal
leads and thus have a significant impact on drug develop-
ment.[1,2] During the last decades, several bioactive natural
products containing oxazole and/or thiazole rings in their
structures have been isolated.[3] Those heterocyclic moieties
arise from enzymatic modifications (cylodehydrations) and
are essential for bioactivity. However, synthetic access to
these compounds is challenging: long synthetic sequences are
required, they are non-parallelizable, and present great
difficulties for the preparation of analogues, thus representing
a major impediment for medicinal chemistry.
[*] Dr. A. Pꢀrez-Perarnau,[+] Dr. C. M. Palmeri, C. Moncunill-Massaguer,
Dr. D. Iglesias-Serret, Dr. D. M. Gonzꢁlez-Gironꢂs,
Dr. A. M. Cosialls, Dr. C. Rubio-PatiÇo, J. Saura-Esteller,
Dr. I. Fabregat, Dr. G. Pons, Prof. J. Gil
and
Institute for Biomedical Research Barcelona and CIBER-BBN
Baldiri Reixac 10–12, 08028 Barcelona (Spain)
E-mail: albericio@irbbarcelona.org
Departament de Ciꢂncies Fisiolꢃgiques II, University of Barcelona
Institut d’Investigaciꢄ Biomꢂdica de Bellvitge (IDIBELL)
L’Hospitalet de Llobregat (Spain)
Dr. S. Karasawa, Dr. S. Sakamoto, Prof. H. Handa
Tokyo Institute of Technology, Yokohama (Japan)
[+] These authors contributed equally to this work.
E-mail: jgil@ub.edu
[**] We thank the Scientific and Technological Centers of the Bellvitge
Campus at the University of Barcelona for their technical support.
This study was supported by grants from the “Ministerio de
Economꢅa y Competividad” and ERDF (SAF2010-20519 and
CTQ2012-30930), the “Instituto de Salud Carlos III” (RTICC RD12/
0036/0029), Fundaciꢄ Bosch i Gimpera (AVCRI-PPV022-08) and the
“AGAUR-Generalitat de Catalunya” (2009SGR395, 2009SGR312 and
2009SGR1024).
Dr. L. Caja, Dr. I. Fabregat
Institut d’Investigaciꢄ Biomꢂdica de Bellvitge (IDIBELL)
L’Hospitalet de Llobregat (Spain)
Dr. S. Preciado,[+] Dr. M. Miguel, Dr. R. Ramꢄn, Prof. R. Lavilla
Barcelona Science Park
Baldiri Reixac 10-12, 08028 Barcelona (Spain)
E-mail: rlavilla@pcb.ub.es
Prof. R. Lavilla
Laboratory Organic Chemistry
Faculty of Pharmacy, University of Barcelona (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405758.
Prof. F. Albericio
Department of Organic Chemistry
University of Barcelona (Spain)
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Figure 1. Structural and synthetic aspects of fluorinated thiazolines. A) Fluorinated diarylthiazoles as triaryl scaffolds. B) Synthetic access to
trifluorinated thiazolines. C) Mechanistic hypothesis for the trifluorination reaction. D) Chemical and three-dimensional structure of 1c from the
X-ray diffraction of a monocrystal.[27] ACN=acetonitrile, MW=microwave.
derivatives was achieved by a sequential Suzuki coupling
The induction of apoptosis is closely related to p53
activation.[15] This is a key protein in cancer treatment, since
the p53 gene is mutated in roughly 50% of cancers, therefore
leading to serious drug resistance. We next assessed the pro-
apoptotic effects of 1a and 1b in an extended panel of cancer
cell lines with defined mutational status, gene expression, and
other molecular characteristics, including either wild-type or
altered p53 pathway (http://p53.free.fr/). The EC50 was
calculated at 24 hours after treatment for all these cell lines
(see Figure S2). All 20 cell lines analyzed displayed substan-
tial sensitivity to 1a with an EC50 in the low micromolar range
(< 10 mm), independently of p53 status. In comparison, the 1b
analogue was at least twofold less active in the cell-based
apoptosis assay, thus demonstrating the improvement in
potency achieved in the SAR studies (see Figure 2 and
Table S1). Furthermore, normal human T cell lymphocytes
were found to be more resistant to 1a than primary leukemic
B cells from chronic lymphocytic leukemia (CLL) patients
(Figure 2D).
Mitochondrial outer membrane permeabilization
(MOMP) and release of mitochondrial intermembrane pro-
teins, such as cytochrome c, are critical steps in the control of
apoptosis.[13] We evaluated whether pro-apoptotic effects
induced by fluorinated thiazolines occurred through cyto-
chrome c release from mitochondria to the cytosol. To this
end, Jurkat cells were treated with either 1a or 2a, and
cytochrome c release was analyzed in cytosolic and mitochon-
drial extracts. The compound 1a induced the release of
cytochrome c from mitochondria to the cytosol while 2a did
not (Figure 2E).
from 2-bromothiazole, followed by a second arylation step, by
[9]
À
C H activation (Figure 1Bb). Related strategies were
useful for specific compounds (see the Supporting Informa-
tion). Both protocols are suitable for the introduction of
a high degree of chemical diversity, thus allowing a wide
variety of substituents on the phenyl rings. The diarylthiazoles
2 were fluorinated using Selectfluor in acetonitrile by means
of conventional or microwave-assisted heating. Unexpectedly,
this process afforded the trifluorinated compounds 1.[10–12]
This unprecedented transformation presumably takes place
through a stepwise mechanism involving the initial electro-
philic fluorination of the unsubstituted thiazole position
followed by a second electrophilic process, thus yielding
a fluorinated carbenium ion, which is then trapped by the
À
BF4 anion and leads to the final trifluorothiazolines 1 (Fig-
ure 1C). The connectivity of the trifluorothiazoline moiety
was elucidated through NMR studies. In addition, X-ray
diffraction analysis of a single crystal of 1c (Figure 1D)
unequivocally confirmed the proposed structure.
Although the yields obtained were moderate (17–55%), it
À
should be noted that three C F bonds were formed in this
single treatment. Interestingly, when using a stoichiometric
amount of Selectfluor, monofluorinated thiazoles were
obtained as the main products. Also, under standard reaction
conditions, the electronically deactivated diarylthiazoles 2
only afforded the monofluorinated thiazoles 4.
Since one hallmark of cancer development and progres-
sion is the resistance of cancer cells to apoptosis,[13,14] we
analyzed the biological activity of a primary series of
fluorinated thiazoline compounds by means of a cell-based
apoptosis screening. While the thiazolines 1a–f (Figure 2A)
demonstrated important pro-apoptotic activities in Jurkat and
HeLa cells in a dose-dependent manner (Figure 2B), the
related thiazoles 2a and 4c did not display significant
cytotoxic effects (see Figure 2C and Figure S1). These results
showed a relevant cytotoxicity associated with the novel
scaffold, where small chemical modifications introduced
along the series triggered relevant differences regarding the
biological effects.
As the trifluorinated thiazolines 1 are generated as
racemic mixtures, we considered that their resolution and
the subsequent study of the biological activity of each
enantiomer would provide relevant information. In this
context, we successfully separated the racemic mixture of
1b by means of chiral-phase HPLC on a semipreparative
scale and determined the structure and optical activity of both
enantiomers (X-ray diffraction and polarimetric analyses; see
Figure S3A). Interestingly, the eutomer (À)-1b induced
a considerable loss of cell viability in HeLa cells, while its
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MitoTracker. Cells treated with the vehicle for 4 hours and
cells treated with racemic 1b or (+)-1b presented filamentous
mitochondrial structures. Only those cells incubated with (À)-
1b showed extensive disruption of the mitochondrial network
(see Figure S3C).
To study the mechanism by which fluorinated thiazolines
induced apoptosis, we sought to identify potential target
proteins by performing an affinity-based proteomic screening
using polymer-coated magnetic nanobeads (FG beads).[16,17]
The pro-apoptotic fluorinated thiazoline 1a was selected for
pull-down experiments. Thus, to ensure its immobilization
onto the beads, we synthesized a trifluorothiazoline derivative
with a carboxylic acid attached to the aryl ring linked to the
thiazole 2-position (1g; Figure 3A). This derivative was
suitably conjugated with the amino-functionalized FG beads
through an amide bond.
In this context, we prepared the compound 1h, the amide
derivative of the carboxylic acid 1g, which mimics the probe
and therefore served to demonstrate its suitability. We first
tested the target-binding capacity of 1g and 1h in a cell
viability assay, and compared it to that of the primary hit
compound 1a. While 1g failed to induce apoptosis in Jurkat
and in HeLa cells, probably because of limited cell perme-
ability, 1h retained the pro-apoptotic activity of 1a (see
Figure S4). This result indicates that target proteins likely
interact with 1h in a similar way to that with the parent
thiazoline 1a.
Next, to identify the 1a-target proteins, we conjugated 1g
to amino-functionalized FG beads (Figure 3B). To purify 1g-
interacting proteins, unconjugated and 1g-conjugated FG
beads were exposed to whole HeLa cell lysates. After
extensive washing, proteins bound to the surface-immobilized
compound were eluted under harsh conditions, separated by
SDS-PAGE, and visualized by silver staining (see Fig-
ure S5A). The pattern of bands obtained was further con-
firmed in Jurkat cell lysates (Figure S5B). For selectivity
profiling against potential off-targets, we followed a drug
competition strategy. Increasing concentrations of active 1a
or an excess of the inactive analogue 2a were incubated with
protein lysates from HeLa cells before the pull-down assay
was carried out. The yields of two proteins present in the
standard purification were significantly reduced or even
absent in the 1a-competition sample, thus suggesting poten-
tial specific targets. Remarkably, the free compound 2a,
which showed no pro-apoptotic activity, was unable to impair
the interaction of these potential target proteins with the 1g-
conjugated FG beads (Figure 3C). Additional competition
affinity purification was carried out with the active thiazoline
1b, and confirmed the same putative target proteins. We next
obtained these candidate protein bands and identified them
as prohibitin 1 (PHB1) and prohibitin 2 (PHB2) by means of
tandem mass spectrometry (MS/MS). The target identity was
confirmed by SDS-PAGE immunoblotting using specific
antibodies, where the disappearance of the target protein
bands in the competition sample with the unmodified
compound 1a was visible. Notably, target proteins remained
bound to the immobilized probe at the lower concentrations
of the free active competitor, thus revealing a dose-dependent
interaction. Furthermore, the inactive probe 2a was unable to
Figure 2. Effects of fluorinated thiazolines on cancer cells viability.
A) Chemical structures of thiazoline-derived compounds. B) Jurkat and
HeLa cells were exposed to DMSO or to a range of doses of the
indicated compounds and cell viability was assessed after 24 h. C) Cell
lines were treated with DMSO (CT) or a single dose of 10 mm 1a or 2a
for different time periods. D) B and T lymphocytes from CLL patients
(n=4) were incubated with a range of doses of 1a for 24 h and cell
viability was assessed. E) Thiazoline-induced apoptosis occurs through
cytocrhrome c release. Jurkat cells were treated for 8 h with either 1a
or 2a and cytochrome c release was analyzed. Viability data represent
the percentage of non-apoptotic cells (Annexin V negative) versus
DMSO-treated controls, shown as mean values Æ SEM of at least
three independent experiments. Differences between paired values are
statistically significant as determined by Student’s t-test. * p<0.05;
** p<0.01; *** p<0.001 1a-treated cells versus DMSO- or 2a-treated
cells (in C) or B lymphocytes versus T lymphocytes (in D).
distomer (+)-1b was considerably less potent. These results
were confirmed in the mantle cell lymphoma Z-138 cell line
(see Figure S3B). Although not exclusively, the fluorescence
emitted by 1b co-localized with mitochondria stained with
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Figure 3. Identification of prohibitins as the main targets for pro-apoptotic fluorinated thiazolines. A) Synthesis of the trifluorinated precursor 1g,
and the positive control 1h for the affinity probes. B) Scheme of drug immobilization of 1g onto the magnetic nanobeads. C) Drug competition
binding assay and purification of 1g-interacting proteins. 200 mg of HeLa cell lysate was pre-treated with either 5% DMSO (Vehicle), different
concentrations of free active compound 1a (0.01, 0.1, 1 mm), or the highest concentration of free 1b or free inactive compound 2a (1 mm).
Afterwards control beads (non-conjugated) or 1g-beads (1 mm 1g-conjugated beads) were incubated with pre-treated HeLa cell lysates. Arrows
indicate the 1g-interacting proteins selectively kept by 1a. D) Target identity validation by Western blot analysis using specific antibodies.
DMF=N,N-dimethylformamide, dppf=1,1’-bis(diphenylphosphino)ferrocene, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt=
hydroxybenzotriazole.
impair the binding of prohibitins to the immobilized com-
pound (Figure 3D).
coveries have emphasized their role in other cellular compart-
ments, thus showing that these proteins contribute to the
regulation of several signaling pathways.[22] Prohibitins have
recently emerged as key elements in the maintenance of
cellular quiescence and in determining whether cells should
proliferate or enter programmed cell death.[23] There are
To further test whether prohibitins were bona fide targets
for fluorinated thiazolines, and given that PHB1 and PHB2
are closely related proteins which interact in vivo to form
complexes,[21,22] we expressed isolated GST-tagged recombi-
nant prohibitins in Escherichia coli. Protein samples were
obtained and subjected to SDS-PAGE to examine their
binding affinity to 1g. To exclude that this binding was caused
by the reporter, we expressed GST protein and used it as
a control. GST-PHB1 and GST-PHB2 bound to the 1g-
conjugated FG beads (see Figure S6). This binding could not
be ascribed to any complex formation between PHB1 and
PHB2. Taken together, our results support the notion that 1a
engaged both intended targets, thereby revealing a direct
physical interaction.
Prohibitins are specifically required in proliferating cells,
thus indicating a potential role in cancer progression.[18] The
major contribution of prohibitins to the preservation of
mitochondrial integrity[19] and the prevention of apoptosis[20]
and senescence[21] might explain their overexpression in
several types of tumor cells. Prohibitins are invariant compo-
nents of the mitochondrial structure. However, recent dis-
records of natural products (aurilide[24] and rocaglamides[25]
)
which bind to prohibitins.[26] However, the complexity of such
compounds and synthetic/availability issues compromise their
use in biological studies and in therapeutics. In contrast, our
new chemotype is free from these problems and can be
readily used in biological and medicinal chemistry programs.
Finally, these fluorinated thiazolines can be considered useful
probes to further study the functions of prohibitins. In
conclusion, our work describes the successful preparation of
a family of synthetic, easily accessible fluorinated thiazolines
featuring an innovative scaffold. Their p53-independent pro-
apoptotic activity relies on targeting prohibitins and may
represent a promising new therapeutic strategy for cancer
treatment and drug discovery.
Received: May 29, 2014
Published online: && &&, &&&&
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Communications
Drug Discovery
Not one, not two, but three: A novel
fluorination of thiazoles selectively yields
a trifluorinated heterocyclic scaffold.
Robust chemistry leads, in short sequen-
ces, to a family of potent p53-independ-
ent pro-apoptotic antitumor compounds.
Pull-down experiments show that these
derivatives are selective ligands of pro-
hibitins. NP=nanoparticle.
A. Pꢁrez-Perarnau, S. Preciado,
C. M. Palmeri, C. Moncunill-Massaguer,
D. Iglesias-Serret,
D. M. Gonzꢂlez-Gironꢃs, M. Miguel,
S. Karasawa, S. Sakamoto, A. M. Cosialls,
C. Rubio-PatiÇo, J. Saura-Esteller,
R. Ramꢄn, L. Caja, I. Fabregat, G. Pons,
H. Handa, F. Albericio,* J. Gil,*
R. Lavilla*
&&&& — &&&&
A Trifluorinated Thiazoline Scaffold
Leading to Pro-apoptotic Agents
Targeting Prohibitins
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