Optimizing the control of apoptosis by amide/triazole isosteric substitution in a constrained peptoid

Article abstract of DOI:10.1016/j.ejmech.2013.03.004

Apoptosis is a biological process relevant to several human diseases that is strongly regulated through protein-protein complex formation. We have previously reported a peptidomimetic compound as potent apoptotic modulator. Structural studies of this comp

Full text of DOI:10.1016/j.ejmech.2013.03.004

European Journal of Medicinal Chemistry 63 (2013) 892e896
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Optimizing the control of apoptosis by amide/triazole isosteric
substitution in a constrained peptoid
,
d
Miriam Corredor a, Jordi Bujons b, Mar Orzáez c, Mónica Sancho c, Enrique Pérez-Payá c
,
,
Ignacio Alfonso b, Angel Messeguer a
*
a Department of Chemical and Biomolecular Nanotechnology, Institute of Advanced Chemistry of Catalonia, IQAC-CSIC, E-08034 Barcelona, Spain
b Department of Biological Chemistry and Molecular Modelling, Institute of Advanced Chemistry of Catalonia, IQAC-CSIC, E-08034 Barcelona, Spain
c Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
d Instituto de Biomedicina de Valencia, IBV-CSIC, E-46010 Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Apoptosis is a biological process relevant to several human diseases that is strongly regulated through
proteineprotein complex formation. We have previously reported a peptidomimetic compound as
potent apoptotic modulator. Structural studies of this compound showed the presence of cis/trans
isomers of the exocyclic tertiary amide bond in slow exchange. This information encouraged us to
perform an isosteric replacement of the amide bond by a 1,2,3-triazole moiety, where different substi-
tution patterns would mimic different amide rotamers. The syntheses of these restricted analogs have
been carried out using the Ugi multicomponent reaction followed by an intramolecular cyclization.
Received 15 November 2012
Received in revised form
25 February 2013
Accepted 1 March 2013
Available online 14 March 2013
Keywords:
Apoptosis inhibitors
Triazole
Unexpectedly, for one of the proposed structures, a novel
b -lactam compound was formed. All com-
pounds showed to efficiently inhibit apoptosis, in vitro and in cellular extracts, with slight differences for
the corresponding regioisomers. We propose the binding to Apaf-1 as the inhibition mechanism.
Ó 2013 Elsevier Masson SAS. All rights reserved.
b-lactam
Ugi-4CC
Click chemistry
Molecular docking
1. Introduction
mitochondrial intermembrane space into the cytosol when
apoptosis-inducing signals are perceived by the cell [1]. The for-
Apoptosis is a highly regulated cellular pathway responsible for
programmed cell death to remove DNA damaged, virally infected,
or otherwise unneeded cells. Diverse apoptotic stimuli, including
activation of cell surface death receptors, anti-cancer agents, irra-
diation, lack of survival factors, and ischemia, induce signaling
cascades that activate the caspase family of cysteine aspartyl pro-
teases. These caspases are essential to the apoptotic process, as they
are required for the initiation and execution of programmed cell
death. Effector caspases (e.g., caspases-3 and -7) are responsible for
the disassembly of cellular components, while initiator caspases
(e.g., caspases-8, -9 and -10) are responsible for the activation of
effector caspases. In particular, caspase-9 is activated upon the
release to the cytosol of proapoptotic proteins from the
mation of the apoptosome is a key event in the intrinsic apoptosis
pathway. The apoptosome is a holoenzyme multiprotein complex
formed by cytochrome c-activated Apaf-1, dATP, and procaspase-9.
When cytochrome c is released from the mitochondria it binds to
Apaf-1, triggering a conformational change and the hydrolysis of
the Apaf-1 bound dATP/ATP. In a process dependent on the hy-
drolysis of ATP or dATP to ADP or dADP respectively, the Apaf-1-
cytochrome c heterodimers assemble into the apoptosome, which
provides a platform for the activation of the initiator procaspase-9.
Then, the activated caspase-9 cleaves and activates executioner
caspases such as caspase-3 [2,3].
Defects in the regulation of apoptosis are related to diseases.
The development of new anti-cancer therapies importantly relies
on inducing apoptosis. In contrast, tissue infarction, ischemiae
reperfusion damage, degenerative diseases, and AIDS showed
in common excessive apoptosis-mediated unwanted cell death.
To identify molecules that could ameliorate disease-associated
excessive apoptosis, drug discovery efforts were directed toward
the inhibition of caspase activity, particularly the effector caspase-3
[4]. However, caspase-3 inhibitors have encountered problems in
Abbreviations: Ugi-4CC, Ugi four-component coupling reaction; CuAAC, cop-
per(I)-catalyzed azideealkyne cycloaddition reaction; RuAAC, ruthenium-catalyzed
azideealkyne cycloaddition reaction; IBX, 2-iodoxybenzoic acid; DKP, 2,5-
diketopiperazine.
* Corresponding author. Tel.: þ34 400 61 00x2186.
E-mail address: angel.messeguer@iqac.csic.es (A. Messeguer).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.03.004

M. Corredor et al. / European Journal of Medicinal Chemistry 63 (2013) 892e896
893
their pharmacological development [5]. Alternatively, proteine
protein interactions upstream of caspase activation can also be
relevant points of intervention for the development of modulators
of apoptosis pathways. In particular, recent data propose the for-
mation of the apoptosome as an interesting target for the devel-
opment of apoptotic modulators.
synthetic procedures (see Supplementary data). However, the key
triazole aldehydes bearing different substitution patterns (5aec)
had to be synthesized through modifications of synthetic
methods described in the literature (Scheme 2).
The Cu(I)-catalyzed azideealkyne cycloaddition (CuAAC),
perhaps the most powerful click reaction providing 1,4-
disubstituted 1,2,3-triazoles [18,19] has quickly found many appli-
cations in synthetic and medicinal chemistry [20,21], bio-
conjugations [22,23], materials science [24], and polymer chemistry
[25]. The success of the CuAAC highlights the need for selective
access to the complementary regioisomers. However, 1,5-isomers
have been only scarcely explored so far [26,27], although Fokin
and coworkers [28,29] recently reported that their preparation can
be accomplished by a ruthenium-catalyzed azideealkyne cycload-
dition reaction (RuAAC). This reaction furnishes the triazole de-
rivatives with a virtually total 1,5-regioselectivity [30]. Considering
these two complementary catalysts, we envisioned the synthesis of
both triazole isomers from the common pair of alkyne (propargyl
alcohol) and azide 8. This approach would render the correspond-
ing alcohols, which can be easily transformed into the aldehydes
5a,b by mild oxidation with IBX (Scheme 2). Thus, the 1,4-
disubstituted-1,2,3-triazole was formed using CuSO4/ascorbic acid
in water/THF. For the case of the 1,5-disubstituted 1,2,3-triazole, the
Cp*RuCl(PPh3)2 catalyst was used, showing to be less efficient and
selective than the CuAAC process. In addition to the low conversion
(40%) of the Ru-catalyzed reaction, the yield was additionally
hampered by the exhaustive chromatographic separations neces-
sary to obtain pure material.
Understanding the mechanism of functional activation of the
apoptosome has helped to define prospective targets for treating
deregulated apoptosis associated with human pathologies. One of
these targets is the Apaf-1 protein. Our group has developed an
efficient in vitro and ex-vivo methodology for detecting activity of
molecules inhibiting the apoptosome formation [4]. Within this
project, we identified some active compounds after screening of a
diversity-oriented chemical library of N-alkylglycine oligomers [4].
Then, geometrical restrictions were devised to increase the selec-
tivity [2] by reducing the conformational freedom. A hit compound
(1) was obtained [6], and structural studies of 1 showed the pres-
ence of cis/trans isomers of the tertiary amide bond exchanging at
slow rates (Fig. 1) [7]. The occurrence of these cis/trans isomers has
led us to freeze the cis and trans configuration by isosteric substi-
tution using a triazole moiety [8]. 1,2,3-Triazoles offer an appealing
motif in peptidomimetic research [9,10] because their structural
and electronic characteristics are similar to those of a peptide bond
and general methods are now available for their synthesis [11e13].
In this regard, we hypothesized that the 1,4- and 1,5-disubstituted
triazole moieties could mimic the spatial disposition of the residues
for the cis and trans configuration of 1, respectively (Fig. 1, 2a and
2b). As an intermediate situation, we also envisioned the prepa-
ration of the 2,4-disubstituted triazole derivative (2c).
On the other hand, the 2-substituted-2H-1,2,3-triazoles can be
obtained by alkylation of NH-1,2,3-triazoles with the suitable
electrophilic reagents, although a mixture of the isomeric products
is often produced. A general and simple method for the synthesis of
the 2H-isomers is not still available. In 2008, Fokin and coworkers
reported an elegant three-component one-pot synthesis of 2-
hydroxymethyl-2H-1,2,3-triazoles [31]. These compounds are ver-
satile intermediates that can be used for the preparation of NH-
1,2,3-triazoles. In their method, formaldehyde, sodium azide and a
terminal alkyne (propargyl alcohol in our case) react in a one-pot
two-steps process under acid conditions. A mixture of the 1-
hydroxymethyl-1,2,3-triazole and the 2-hydroxymethyl isomer
was obtained, being the desired isomer the major and the most
stable one. Basic hydrolysis of the N-hydroxymethylalcohol led to
the parent NH-compound (Scheme 2B). Finally, a simple SN2 reac-
tion at N-2 of the triazole with the corresponding bromide afforded
the 4-hydroxymethyl-2,4-disubstituted-triazole derivative, which
was also transformed into the corresponding aldehyde (5c) by
oxidation with IBX (Scheme 2). The substitution patterns of the
three isomeric triazoles were unambiguously established by a
complete NMR assignment of the signals of 5aec and those of their
corresponding alcohol precursors, including the 15N NMR signals
from 1He15N gHMBC 2D experiments (see Supplementary data).
Once all the reagents of the Ugi-4CC reaction were available, the
final products could be synthesized. The Ugi reaction requires a
high concentration in the mixture and a specific order of addition.
Considering that the formation of the imine is a key step for the
progress of the overall reaction, it was monitored by 1H NMR. We
concluded that the imine was formed in 6 h; afterward, the addi-
tion of the isocyanide and the carboxylic acid must be done within
30 min. The addition of the acid before this period of time produced
the hydrolysis of the imine and prevented the formation of the Ugi
products. To afford the final DKP products from 3aec, two different
basic treatments were used due to the different reactivity of the
structures. For 3a, a KOH/MeOH mixture was used and the desired
product 2a was formed; but when the same method was used for
3b, the hydrolyzed product was obtained. Then, a NaH/THF system
2. Chemistry
For the syntheses of 2aec, we planned a common strategy
(Scheme 1) based on an Ugi four-component coupling reaction
(Ugi-4CC) [14e17] comprising a primary amine 4, an aldehyde 5, an
isocyanide 6 and a carboxylic acid 7, which are condensed to yield
a single product (3). After the formation of the open products, a
base-promoted intramolecular cyclization would yield the final
compounds. Most of the corresponding starting materials are
commercially available (4 and 7) or easily accessible (6) by simple
O
O
O
A
R1
R1
O
N
O
N
R2
N
N
N
R2
H2NOC
N
R2
R2
O
CONH2
1-cis
O
1-trans
B
O
N
O
R1
4
R1
4
R1
N
N
N
N
1
N
N
5
R2
R2
R2
R2
N
2N
R2
N
N
N
O
N
O
N
O
N
1
R2
2a
2c
2b
Cl
Ph
R1
=
R2
=
Ph
Cl
Fig. 1. A) Structure of apoptosis inhibitor 1. B) Proposed conformationally restricted
analogs bearing the 1,2,3-triazole residue.

894
M. Corredor et al. / European Journal of Medicinal Chemistry 63 (2013) 892e896
Ugi-4CC
intramolecular
O
O
O
cyclization
Cl
Cl
N
Cl
N
H
N
N
Cl
Cl
N
N
N
O
N
N
N
Cl
Cl
3a-c
2a-c
Cl
Cl
CHO
N
NC
NH2
O
+
N
+
+
N
Cl
Cl
OH
7
Cl
Cl
4
6
Cl
5a-c
Scheme 1. Retrosynthesis of 2aec comprising an Ugi-4CC reaction followed by an intramolecular cyclization.
was assayed and the cyclic compound 2b was isolated after
preparative TLC purification. Noticeably, when using any of these
methods with 3c, an unexpected product was formed. This com-
pound had the same mass of 2c in the ESI-MS spectrum
(m/z ¼ 720.14 for MHþ), but the 1H NMR spectrum showed an
amide NH signal that should disappear when forming the DKP,
while the CH of the chiral center of the DKP was absent, suggesting
that the intramolecular cyclization had occurred through the
corresponding carbon atom. After carefully analyzing the NOESY,
1He13C gHSQC/gHMBC, and 1He15N gHMBC NMR spectra, as well
as the FT-IR spectrum, the proposed structure 9 was confirmed
(Fig. 2). We also included compound 9 in the biological assays as
apoptosis inhibitors.
shown in Fig. 3, an improvement of the activity was obtained in the
triazole compounds, with slight differences for the two
regioisomers 2a,b. It is also worth mentioning that the b-lactam
structure 9 elicited the best activity. Similar inhibitory trends were
observed in cellular extracts (Supplementary data). This is an
interesting starting point to further study this new scaffold in the
design of optimized apoptosis inhibitors. In addition, these results
support our initial hypothesis that a more rigid structure could
favor the interaction with the target protein. On the other hand, we
deem that the more restricted conformational freedom of these
compounds will reduce the risks associated to interaction with
non-desired targets.
A preliminary blind docking screening for a related 7-membered
cyclic analog of 1 targeting the reported human Apaf-1 1-591
structure [32], revealed potential binding sites at the CARDeNOD
interface (Site 1) and at the reported ADP binding site in the NOD
domain (Site 2). These two predicted binding sites on Apaf-1 were
consistent with experimental results that demonstrated the inter-
action between this analog and Apaf-1 [33]. Interestingly, in the
crystal structure these binding sites are connected through a nar-
row channel (Fig. 4A), which constitutes the only apparent entrance
3. Biological activity and docking studies
All the compounds (1, 2a,b and 9) were potent in vitro inhibitors
of the apoptosome-dependent activation of procaspase-9 activity
(Fig. 3 and Supplementary data). Moreover, none of them was a
direct inhibitor of the activity of recombinant caspase-9, which
suggests that the most probable target is apoptosome formation. As
A
N3
Br
OH
1)
catalyst
NaN3
DMF
Cl
Cl
5a, cat: CuSO4 /ascorbic acid
5b, cat: Cp*RuCl(PPh3)2
2) IBX
Cl
8
Cl
Cl
B
1) Cs2CO3
Br
OH
OH
1) CuSO4 /ascorbic acid
2) NaOH
Cl
+ NaN3 + CH2O
5c
N
N
N
H
2) IBX
Scheme 2. Syntheses of aldehydes 5aec.

M. Corredor et al. / European Journal of Medicinal Chemistry 63 (2013) 892e896
895
part and is disposed on top of a small hydrophobic patch on the
surface of the protein, formed by residues Val125 and Leu297.
Finally, the exocyclic amide and the carbonyl group of the b-lactam
Ph
Ph
Cl
Cl
O
ring contribute to stabilize the docked pose of (R)-9 by participating
on hydrogen-bond interactions with residues Val124 and Arg428.
Analysis of the docking poses obtained for the enantiomeric (S)-9
and the rest of the compounds studied showed similar results (see
Supplementary data). Hence, a common feature of the compounds
N
N
N
N
HN
O
bound at Site 1 was the formation of several p-cation interactions
with different cationic residues (i.e. Lys100, Arg111, Arg122 and
Arg332), as well as hydrogen bond interactions with the polar side-
chains or the backbone of close residues, while the contribution of
hydrophobic interactions at this site was in general less important
(see Table S1, Supplementary data).
Cl
Cl
Concerning the predicted binding Site 2, which as mentioned
above coincides with the nucleotide binding site, it is constituted by
Fig. 2. Compound 9.
a relatively large cavity (Fig.4A) formed by helices
a10, a15 and a17,
to the deeply buried nucleotide binding site (NBS), suggesting that
access to this site requires unpacking of the CARDeNOD interface
[32]. Thus, inhibitor binding at Site 1 could obstruct the access of
dATP to the NBS by blocking the entrance to this channel and,
possibly, by stabilizing Apaf-1 into a “locked” conformation that
would hinder unpacking of the CARDeNOD interface. Alternatively,
binding at Site 2 would directly block the NBS. Therefore, interac-
tion with any of these sites, or both, would hamper dATP binding,
and consequently would interfere with apoptosome formation.
Those docking studies have now been extended to compounds
1, 2a, 2b and 9. Since all of these compounds have a single ster-
eogenic center on their structures, independent docking runs were
carried out for each enantiomer. Fig. 4BeD shows the best poses
obtained for compound (R)-9 at each of the two putative binding
sites.
sheets 2, 6 and 7, and loops between residues 117e129,154e159
b
b
b
and 389e394. The residues that constitute this cavity are mainly
hydrophobic in nature, particularly in the region close to the
location of the purine ring of the bound ADP (ie. residues Pro123,
Val125, Phe126, Val127, Val162, Ile294 and Pro321). The best
docked pose obtained for compound (R)-9 fills most of the cavity
and partially overlaps with the crystallographically determined
ADP molecule (Fig. 4B,D), suggesting that both compounds would
compete for binding at this Site. Its diphenylmethyl moiety oc-
cupies the same location as the purine system of ADP, while one of
the dichlorophenyl rings is disposed in an approximately parallel
orientation, surrounded by residues Pro120, Pro123, Val162 and
Ala165, and the second one extents toward a more hydrophilic
region of the cavity, constituted by the polar residues Lys160,
Asp243, Asp244, Arg265, Asp392, His438 and Asp439. Finally, the
triazole ring of (R)-9 occupies the region where the diphosphate
Site 1 is located on a large cleft at the CARDeNOD interface and
it is formed by helices a2, a3, a5, a7, a8, and the loop between
group of ADP binds, establishing a
His438 and a hydrogen bond with the backbone NH-group of
Gly159, while the -lactam is disposed close to the location of the
p,p-stacking interaction with
residues 117 and 129. According to our docking results, at Site 1
compound (R)-9 is disposed along this cleft covering the entrance
to the NBS access channel, with its diphenylmethyl moiety occu-
pying a cavity formed by residues His28, Asp32, His77, Lys100,
Arg111, and Arg122 (Fig. 4B,C). The two aromatic rings of this
b
ADP-ribose group. On the other hand, the best docked pose of the
stereoisomer (S)-9 shows an inverted geometry where the diphe-
nylmethyl and dichlorophenyl moieties that were occupying the
hydrophobic locations described above have switched places, while
the second dichlorophenyl ring and the linked triazole still occupy
the more hydrophilic region and the diphosphate binding site,
respectively (see Supplementary data). The rest of the compounds
considered show best docked poses which are similar to that of (S)-
9, with the exception of compound (S)-1 which resembles more to
(R)-9 (see Supplementary data). The existence of these alternative
docking geometries is derived from the flexibility of the com-
pounds, as well as the large size of the cavity and the fact that the
main stabilizing interactions with the protein are of hydrophobic,
and therefore less specific, nature.
moiety establish
p-cation and p,p-stacking interactions with resi-
dues Lys100 and His77, respectively. All the other compounds
similarly showed occupation of this cavity by their diphenylmethyl
or one of their dichlorophenyl moieties, which were also stabilized
by similar interactions with the cited residues (see Supplementary
data for details). On the other hand, one of the dichlorophenyl
substituents of (R)-9 extents to the other side of the cleft and forms
a
p-cation interaction with residue Arg332, while the second
dichlorophenyl group is oriented toward the more solvent exposed
After analysis of these results, it is worth noting that the relative
similarity in bound geometries and binding interactions at each site
is in agreement with the comparable biological activities observed
for these compounds. It is also remarkable that, considering the
best poses obtained for all the compounds, the average docking
Apoptosome inhibition
14.0
12.0
10.0
8.0
scores for Sites 1 and 2 are 4.9 ꢀ 1.0 and 8.1 ꢀ 1.7 kcal molꢁ1
.
Although docking scores alone often show little correlation with
experimental binding affinities, this difference would suggest that
binding at Site 2 is stronger than at Site 1. Preliminary prediction of
the affinities using more accurate methodologies (ie. MMGBSA)
confirm this suggestion (results not shown). Therefore it could be
speculated that Site 1 could act as a vestibule where the compounds
studied here could bind with a relatively low affinity before
accessing the higher affinity NBS-Site 2 to exert their apoptosome
inhibitory activity.
6.0
4.0
2.0
0.0
1
2a
2b
9
Fig. 3. In vitro inhibitory activities on the apoptosome formation by the triazole
derivatives 2a, 2b and 9. Activity of DKP 1 is shown for comparative purposes.

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M. Corredor et al. / European Journal of Medicinal Chemistry 63 (2013) 892e896
Fig. 4. A) Human Apaf-1 1-591 structure (PDB 1Z6T) showing the CARD (green) and NOD (light gray) domains, as well as a crystallographically determined ADP molecule (yellow)
bound into the NBS. The inset shows the bound ADP molecule surrounded by Apaf-1 residues, and a mesh representation of the protein surface that reveals a narrow channel
connecting the NBS with the exterior. B) Best docked poses of compound (R)-9 bound at the putative binding sites 1 (orange) and 2 (cyan). C) and D) Detailed view of the above
docked poses at the two sites surrounded by interacting Apaf-1 residues (see Supplementary data for detailed interaction diagrams). Docking was performed with the program
Glide XP [34e37]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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In conclusion, it has been shown that geometrically restricted
analogs of a peptoid derivative by amide/triazole isosteric substi-
tution maintain their activities as apoptosis inhibitors. Moreover,
an unexpected and structurally novel b-lactam derivative showed
the best activity among all the tested compounds.
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This work was supported by grants from the Spanish Ministry of
Science and Innovation (SAF2008-00048, SAF30542-C01-01 and
SAF2010-15512) and a fellowship to M. Corredor from CSIC JAE
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Supplementary data related to this article can be found at http://
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