Synthesis and receptor binding studies of some new arylcarboxamide derivatives as sigma-1 ligands

Article abstract of DOI:10.1016/j.bmcl.2014.01.032

We describe here the synthesis and the binding interaction with σ₁ and σ₂ receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on σ binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward σ₁ and σ₂ receptors. Two out of 16 derivatives showed an interesting σ₁ affinity (21.2 and 13.6 nM - compounds 2m and 2p) and a good selectivity (K_i(σ ₂)/K_i(σ₁) >140 and >40, respectively).

Full text of DOI:10.1016/j.bmcl.2014.01.032

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1021–1025
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and receptor binding studies of some new arylcarboxamide
derivatives as sigma-1 ligands
b,
a
a
b
b,
Daniele Zampieri a, , Erik Laurini , Luciano Vio , Samuel Golob , Maurizio Fermeglia , Sabrina Pricl
⇑
⇑
⇑
,
Maria Grazia Mamolo a
a Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy
b Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe here the synthesis and the binding interaction with r1 and r2 receptors of a series of new
arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaf-
fold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution
Received 9 December 2013
Revised 9 January 2014
Accepted 12 January 2014
Available online 20 January 2014
on
toward r1 and r2 receptors. Two out of 16 derivatives showed an interesting r1 affinity (21.2 and
13.6 nM—compounds 2m and 2p) and a good selectivity (Ki( 2)/Ki( 1) >140 and >40, respectively).
Ó 2014 Elsevier Ltd. All rights reserved.
r binding. The synthesized compounds have been tested to estimate their affinity and selectivity
r
r
Keywords:
r
-Receptors
Arylcarboxamide derivatives
Radioligand binding assays
More than thirty years ago Martin and co-workers introduced
r
receptor subtype is involved in cellular apoptotic response,11,12
and in the release of Ca2+ though an IP3-independent manner.13,14
The elevated expression of both -R subtypes in cancer cell
sigma receptors (
Currently, it has been conclusively ascertained that
a unique binding site with two distinct subtypes (r1 and
r
-Rs) as a novel subtype of opioid receptors.1
r
-Rs represent
r
r
2),2,3
membranes has led to the speculation that these proteins may
serve as markers for certain tumors15 whilst, concomitantly, con-
certed efforts are currently being focused on the development of
widely distributed in the central nervous system (CNS) and periph-
eral organs and tissues.4,5
So far, only the r1 subtype has been purified and cloned.6 The
r1 receptor shares 90% identity and 95% similarity across species,
and the guinea pig receptor shares 30% identity and 67% similarity
with the yeast enzyme C8-C7 sterol isomerase (ERG2) involved in
postsqualene synthesis.7 Despite this, however, the r1 receptor is
not endowed with sterol isomerase activity.7 Several reports con-
curred to show that the r1 receptor is a membrane protein of
25.3 kDa, recognized in recent year as a small-ligand operated
chaperone essential for the regulation of the passage of Ca2+ form
the endoplasmic reticulum (ER) to the mitochondria.8Additionally,
the r1 protein can modulate voltage-gated K+, Ca2+, Na+, and ClÀ
channels,9 while many transduction systems, such as the
N-methyl-D-aspartate (NMDA), muscarinic, dopaminergic, and
r
-R targeting anticancer agents and imaging tools.16,17
The endogenous ligand for r1 receptors has not been unequiv-
ocally identified to date. Progesterone18,19 and N,N dimethyltrypta-
mine (DMT)20 were suggested as putative
r1-R endogenous
ligands; however, other steroids (e.g., pregnenolone, dehydropi-
androsterone, and testosterone) show only moderate affinity for
this receptor, thus making the attribution rather ambiguous.
Some
r-Rs ligands displaying preferential affinity for the r1
receptor subtype are (+)-benzomorphans such as (+)-pentazocine
and (+)-N-allylnormetazocine (NANM, SKF-10,047) whereas halo-
peridol and 1,3-di-(2-tolyl)guanidine (DTG) exhibit high affinity
for both receptor subtypes.21 (+)-Pentazocine shows a very low
affinity for the
r2-Rs and, as such, represents a prototypical selec-
serotoninergic systems,10 are sensitive to
r
1-mediated neuromod-
tive agonist used (in its tritiated form) to label r1 receptors.
More recently, new different structures endowed with sigma
affinity and selectivity were identified by various research groups,
such as arylalkylamines,22a–f benzooxazolones,23 and spirocyclic
pyranopyrazoles.24
ulation. Far less is known about the r2 receptor subtype, a
18–21.5 kDa protein not yet cloned.6 It has been proposed that this
In a previous work25 we have synthesized the series of acetam-
ide derivatives 1 showing an excellent affinity (Ki = 0.09 nM) to-
ward the r1 receptor.
⇑
Corresponding authors. Tel.: +39 0405587858 (D.Z.).
E-mail addresses: dzampieri@units.it (D. Zampieri), erik.laurini@di3.units.it
(E. Laurini), sabrina.pricl@di3.units.it (S. Pricl).
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2014.01.032

1022
D. Zampieri et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1021–1025
All new arylcarboxamide derivatives 2a–p have been synthe-
R1
sized starting from the commercially available 4-aminomethylpi-
peridine and acetaldehyde according to the pathway illustrated
in Scheme 1. A typical Shiff reaction led to the imine derivatives
3 which were further alkylated to the piperidine nitrogen atom
with benzyl chloride or 4-chlorobenzyl chloride to obtain interme-
diates 4 and 5, respectively. Subsequently, the Shiff bases were re-
duced with NaBH4 and the corresponding derivatives (6, 7)
acylated on the nitrogen atom of the secondary amine to afford
the final arylcarboxamide compounds 2a–p. All the derivatives
were obtained as hydrochlorides.
N
N
O
CH3
R2
R1= H, Cl
R2= H, Cl, CH3
1
The acetamide derivatives 1 were characterized by the presence
of chemical features matching the requirement of a 1 receptor 3D
Intriguingly, the presence of a furyl group and an unsubstituted
benzene (or an aromatic group bearing a small substituent as chlo-
rine atom) produced compounds 2m and 2p, gifted with the higher
r
pharmacophore model recently developed by our group.26 Briefly,
the two benzene rings map two hydrophobic aromatic pharmaco-
phore features, the piperidine basic nitrogen fits the positive ioniz-
able model site, the carbonyl oxygen of the acetamide group
overlaps the hydrogen bond acceptor feature and, lastly, the small
substituents at the para position of the benzyl moiety linked to the
basic nitrogen atom (e.g., –Cl, –CH3, or –H) match the last hydro-
phobic feature of the pharmacophore model. Accordingly, a 3D
pharmacophore model mapping of compound 1 (R1 = Cl, R2 = H) re-
r
1-R affinity (Ki(r1) = 21.2 and 13.6 nM) and the best selectivity
(Ki( 2)/Ki( 1) >140 and >40, respectively) of the series.
r
r
In general, all compounds showed very low r2 affinities, with
values ranging from 270 up to 3000 nM (Table 2).
The decrease in r1 receptor affinity of the new arylcarboxa-
mides 2a–p with respect to the acetamide derivatives 1 was ratio-
nalized via a well-validated computational approach based on the
3D-pharmacophore model26 and the 3D homology model25 for r1
receptor recently developed by our group. Although compounds
2a–p possess the typical chemical functions required for binding
sulted in predicted affinity for the
agreement with the corresponding experimental value (Ki(-
1) = 1.87 nM).26 Based on this encouraging result, a number of
r1-R of 1.04 nM, in excellent
r
the
r1 protein, the introduction of a bulkier substituent at the car-
other variously substituted derivatives 1 were synthesized, some
of which were indeed found endowed with high r1 affinity.
On the spur of this favorable result, and with the twofold aim of
(i) designing a second generation of stronger r1 binders and (ii)
understanding the effect of the aromatic portions of the original
molecular scaffold (compound 1) on r1 affinity, we went further
and replaced the substituted benzyl moiety linked to the acetam-
ide group by a small ethyl chain while the acetyl residue was con-
verted into a number of aroyl moieties, ultimately yielding the new
derivatives 2a–p (Table 1).
boxamide moiety results in a suboptimal mapping of the pharma-
cophore features onto the 3D pharmacophore model in comparison
with the lead compounds 1, as showed in Figure 1.
We see that, while all chemical groups of 1 (R1 = Cl, R2 = H) per-
fectly overlay the corresponding features of our 3D pharmacophore
model, the different orientation assumed by the oxygen atom of
derivatives 2f and 2p results in an imperfect fit of the H-bond
acceptor feature which, in turn, negatively influences the mapping
of the hydrophobic features by their proximal aromatic portion. On
the other hand, the original N-benzylpiperidine scaffold still as-
sumes the conformation required for an apt positioning of the
remaining chemical groups onto the corresponding pharmaco-
phoric features (Fig. 1). Taking again compounds 2f and 2p as a
proof-of-concept, further details of the interactions of compounds
N
R
N
Ary
O
2a–p with the
r1 receptor were gathered from extensive MM/PBSA
molecular dynamics (MD) simulations25,27 performed on the corre-
sponding compound/protein complexes, as shown in Table 3.
According to our predictions the two molecules show quite dif-
2a-p
R= H, 4-Cl
Ary= Ph, 4-ClPh, 4-CH3Ph, 4-OCH3Ph,
1-Naphtyl, 2-Naphtyl, 2-Furyl
ferent affinities towards the receptor, as
mol for 2f and
Gbind = À10.95 0.31 kcal/mol for 2p, respectively.
Importantly, the corresponding 1Ki,calc values nicely compare
with the affinity values experimentally tested toward the 1 recep-
D
Gbind = À9.09 0.29 kcal/
D
r
r
tor (220 nM vs 155 nM for 2f, and 9.4 vs 13.6 nM for 2p). The
deconvolution of the total free energy of binding into its different
Table 1
contributions (Table 3) reveals that the solvation (
DGSOL) and the
Compds
R
Ary
Yield (%)
mp (°C)
C H N
entropic (ÀT
D
Sbind) terms for these two compounds are similarly
unfavorable, a result somewhat expected since 2f and 2p are very
similar from a structural viewpoint. The difference in r1 affinity
between the two compounds hence stems mainly from the more
favorable enthalpic contribution exhibited by the furyl-substituted
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
H
H
H
H
–Ph
4-Cl-Ph
4-CH3-Ph
1-Naphtyl
2-Naphtyl
–Ph
77
73
85
89
96
74
47
70
61
87
76
92
64
86
74
59
80–84
76–80
108–112
94–98
90–94
126–130
140–144
120–124
75–78
110–114
104–108
94–97
C
C
22H29ClN2O
22H28Cl2N2O
C23H31ClN2O
C
C
C
C
26H31ClN2O
26H31ClN2O
22H28Cl2N2O
22H27Cl3N2O
H
2p (
tive 2f (
This difference in the enthalpically-driven affinity of 2f and 2p
for the 1-R was further investigated by performing a per residue
D
Hbind = À36.06 kcal/mol) with respect to the phenyl deriva-
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
H
H
4-Cl
4-Cl
D
Hbind = À34.04 kcal/mol).
4-Cl-Ph
4-CH3-Ph
4-OCH3-Ph
1-Naphtyl
2-Naphtyl
–Ph-4-Ph
2-Furyl
4-OCH3-Ph
–Ph-4-Ph
2-Furyl
C23H30Cl2N2O
C23H30Cl2N2O2
C26H30Cl2N2O
r
binding free energy decomposition, as detailed in Figure 2.
As well illustrated in Figure 2A, both molecules assume a simi-
lar binding pose within the receptor binding site. Similarly to the
previously reported acetamide derivatives 1, the N-chlorobenzylpi-
peridine moiety satisfies two important pharmacophore require-
ment: (1) a polar interaction via a salt bridge between the
piperidine –NH+ atom and the side chain of Asp126 (Fig. 2B),
C
C
C
26H30Cl2N2O
28H33ClN2O
20H27ClN2O2
86–90
88–92
106–110
82–85
C23H31ClN2O2
C28H32Cl2N2O
C
20H26Cl2N2O2
Characterization of derivatives 2a–p.

D. Zampieri et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1021–1025
1023
Scheme 1.
Table 2
Affinities and selectivities towards r1 and r2 receptors of compounds 2a–p
a
b
Compds
Kir1 (nM)
Kir2 (nM)
Selectivity Kir2/Kir1
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
66.8 10c
n.d.
n.d.
>17
>3
59.1
7
>1000
>500
>1000
270 121
n.d.
>1000
>500
283 54
>1000
n.d.
>500
>3000
n.d
n.d.
>500
160 136
161 23
198 35
155 33
91 18
>6
1.36
n.d.
>11
>3
1.30
>4
n.d.
>1
>140
n.d.
n.d.
>40
140
9
217 14
215 35
225 55
301 65
21.2 11
192 45
373 57
13.6
1
a
r1 Affinities were determined in rat liver homogenates using [3H](+)-
pentazocine.
Figure 1. Mapping of compounds
pharmacophore model developed for r1 ligands.
1
(R1 = Cl, R2 = H), 2f, and 2p onto the 3D
b
r2 Affinities were determined in guinea pig brain using [3H]-DTG in the
presence of (+)-pentazocine to block r1 receptors.
c
The values are means SEM of three experiments performed in duplicate.
Table 3
Binding free energy (
receptor
DGbind) and its components for 2f and 2p in complex with the r1
responsible for a favorable contribution to binding of À2.39 kcal/
mol for 2f and À2.47 kcal/mol for 2p (Fig. 2C and D); and (2) the
encasement of the aromatic phenyl ring of both derivatives by
the side chains of the r1 receptor residues Arg119, Tyr120 and
Trp121, contributing stabilizing van der Waals and hydrophobic
interactions of À3.39 kcal/mol for 2f and À3.72 kcal/mol for 2p,
respectively (Fig. 2C and D). Contrarily to 1, however, the new aryl-
carboxamide scaffold is only partially inserted into the protein
binding cavity; consequently, this molecular portion establishes
weaker interaction with the clustered residue Ile128, Glu172, and
Compds
2f
À43.21 0.08
2p
À44.65 0.07
D
D
D
D
D
D
D
EVDW
EELE
EMM
GPB
GNP
GSOL
Hbind
À149.29 0.11
À192.50 0.14
165.45 0.13
À6.99 0.02
158.46 0.13
À34.04 0.19
24.95 0.31
À9.09 0.36
155 33
À152.20 0.12
À196.85 0.14
167.47 0.14
À6.68 0.01
160.79 0.14
À36.06 0.20
25.11 0.29
À10.95 0.35
13.6 1.3
ÀT
DSbind
Gbind
D
r
r
1Ki,exp
1Ki,calc
a
Tyr173 with respect to the best
r1-R binder 1. Interestingly, the
220
9.4
binding conformation of the arylcarboxamide moiety is such that
the carbonyl oxygen atom is hindered from establishing the topi-
cal, stabilizing H-bond interaction with any of the surrounding
r1 residues (Fig. 2A and B). However, in the case of 2p, the
All energy values are in kcal/mol. The experimental and calculated Ki values (nM)
are also reported for comparison.
a
The
r
1Ki,calc values were obtained from the corresponding
Gbind = ÀRTln(1/ 1Ki).
DGbind values using
the relationship
D
r

1024
D. Zampieri et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1021–1025
Figure 2. (A) Superposition of equilibrated MD snapshots of the r1 receptor in complex with 2f (sandy brown) and 2p (steel blue). The images are zoomed views of the
receptor binding site. The ligands are portrayed in sticks-and-ball colored according to the protein in the corresponding complex. Water, ions and counterions are not shown
for clarity. (B) Equilibrated MD snapshots of the r1 receptor in complex with 2p. The image is a zoomed view of the receptor binding site. The ligand is portrayed in green
sticks-and-balls and colored by element, while the protein residues mainly involved in the interaction with 2p are highlighted as colored sticks and labelled. Salt bridge and
H-bonds interactions are shown as dotted black lines. Some water molecules and ions are shown as sphere colored by element. (C) and (D) Per residue binding free energy
decomposition for r1 in complex with 2f and 2p, respectively. Only r1 amino acids from position 100 to 200 are shown, as for all the remaining protein residues the
contribution to ligand binding is irrelevant.
additional oxygen atom of the furyl ring is indeed engaged in a sta-
ble hydrogen bond with the side chain hydroxyl group of Thr151
(Fig. 2B), ultimately yielding a favorable contribution to binding
enthalpy of À1.51 kcal/mol.
References and notes
1. Gilbert, P. E.; Martin, W. R. J. Pharmacol. Exp. Ther. 1976, 198, 66.
2. Quirion, R.; Bowen, W. D.; Itzhak, Y.; Junien, J. L.; Musacchio, J. M.; Rothman, R.
B.; Su, T. P.; Tam, S. W.; Taylor, D. P. Trends Pharmacol. Sci. 1992, 13, 85.
3. Walker, J. M.; Bowen, W. D.; Walker, F. O.; Matsumoto, R. R.; De Costa, B.; Rice,
K. C. Pharmacol. Rev. 1990, 42, 355.
4. Su, T.-P.; Junien, J.-L. Sigma Receptors in the Central Nervous System and in the
Periphery. In Sigma Receptors; Itzhak, Y., Ed.; Academic Press: London, 1994; p
21.
In conclusion, the results of our in vitro and in silico investiga-
tion confirm the role of the N-benzylpiperidine core as an excellent
scaffold for r1 ligands. At the same time, this study highlights the
following, specific moieties as beneficial to effective
r1 binding: (i)
5. Wolfe, S. A., Jr.; De Souza, E. B. NIDA Res. Monogr. 1993, 133, 95.
6. Hellewell, S. B.; Bruce, A.; Feinstein, G.; Orringer, J.; Williams, W.; Bowen, W. D.
Eur. J. Pharmacol. 1994, 268, 9.
7. Moebius, F. F.; Striessnig, J.; Glossmann, H. Trends Pharmacol. Sci. 1997, 18, 67.
8. Hayashy, T.; Su, T.-P. Cell 2007, 131, 596; (b) Tsai, S. I.; Hayashy, T.; Mori, T.; Su,
T.-P. Cent. Nerv. Syst. Agents Med. Chem. 2009, 9, 184.
9. Paquette, M. A.; Foley, K.; Brudney, E. G.; Meshul, C. K.; Johnson, S. W.; Berger,
S. P. Psychopharmacology 2009, 204, 743.
10. Cobos, E. J.; Entrena, J. M.; Nieto, F. R.; Cendan, C. M.; Pozo, E. D. Curr.
Neuropharmocol. 2008, 6, 344.
11. Crawford, K. W.; Bowen, W. D. Cancer Res. 2002, 62, 313.
12. Crawford, K. W.; Coop, K. W.; Bowen, W. D. Eur. J. Pharmacol. 2002, 443, 207.
13. Hayashy, T.; Su, T.-P. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 491.
14. Wu, Z.; Bowen, W. D. J. Biol. Chem. 2008, 283, 28198.
15. (a) Mach, R. H.; Smith, C. R.; Al-Nabulsi, I.; Whirrett, B. R.; Childers, S. R.;
Wheeler, K. T. Cancer Res. 1997, 57, 156; (b) Kekuda, R.; Prasad, P. D.; Fei, J.
Y.; Leibach, F. H.; Ganapathy, V. Biochem. Biophys. Res. Commun. 1996, 229,
553.
a tertiary amide possibly substituted with an aromatic group, and
(ii) a small heteroaromatic group like the furyl ring. Indeed, the
presence of this latter substituent on the benzylpiperidine scaffold
leads to a substantial increase of the
r1 receptor affinity and selec-
tivity towards the corresponding derivatives, resulting from opti-
mized interactions between the compounds and some of the
main residues of the r1 binding site.
Taken together, all this information might be exploited in the
future to design and synthesize new molecules featuring a furyl
group or an isoster thereof and characterized by strong binding
contacts toward the r1 receptor subtype.
Acknowledgment
16. Caveliers, V.; Everaert, H.; Lahoutte, T.; Dierickx, L. O.; John, C. S.; Bossuyt, A.
Eur. J. Nucl. Med. Mol. Imaging 2001, 28, 133.
17. (a) Friebe, M.; Mahmood, A.; Bolzati, C.; Drews, A.; Johannsen, B.; Eisenhut, M.;
Kraemer, D.; Davison, A.; Jones, A. G. J. Med. Chem. 2001, 44, 3132; (b) Choi, S.
R.; Yang, B.; Plossl, K.; Chumpradit, S.; Wey, S. P.; Acton, P. D.; Wheeler, K. T.;
Mach, R. H.; Kung, H. F. Nucl. Med. Biol. 2001, 28, 657.
The financial support of ‘FRA 2012 (Research Fund University of
Trieste-Italy)’ is gratefully acknowledged.
Supplementary data
18. Monnet, F. P.; Mahé, V.; Robel, P.; Baulieu, E. E. Proc. Natl. Acad. Sci. U.S.A. 1995,
92, 3774.
19. Waterhouse, R. N.; Collier, T. L. Nucl. Med. Biol. 1997, 24, 127.
20. Fontanilla, D.; Johannessen, M.; Hajipour, A. R.; Cozzi, N. V.; Jackson, M. B.;
Ruoho, A. E. Science 2009, 323, 934.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl. 2014.
01.032.

D. Zampieri et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1021–1025
1025
21. Bertha, C. M.; Vilner, B. J.; Mattson, M. V.; Bowen, W. D.; Becketts, K.; Xu, H.;
Rothman, R. B.; Flippen-Anderson, J. L.; Rice, K. C. J. Med. Chem. 1995, 38, 4476.
22. (a) Collina, S.; Loddo, G.; Urbano, M.; Linati, L.; Callegari, A.; Ortuso, F.; Alcaro,
S.; Laggner, C.; Langer, T.; Prezzavento, O.; Ronsisvalle, G.; Azzolina, O. Bioorg.
Med. Chem. 2007, 15, 771; (b) Rossi, D.; Urbano, M.; Pedrali, A.; Serra, M.;
Zampieri, D.; Mamolo, M. G.; Laggner, C.; Zanette, C.; Florio, C.; Shepmann, D.;
Wünsch, B.; Azzolina, O.; Collina, S. Bioorg. Med. Chem. 2010, 18, 1204; (c) Rossi,
D.; Pedrali, A.; Urbano, M.; Gaggeri, R.; Serra, M.; Fernandez, L.; Fernandez, M.;
Caballero, J.; Rosinsvalle, S.; Prezzavento, O.; Shepmann, D.; Wünsch, B.;
Peviani, M.; Curti, D.; Azzolina, O.; Collina, S. Bioorg. Med. Chem. 2011, 19, 6210;
(d) Rossi, D.; Marra, A.; Picconi, P.; Serra, M.; Catenacci, L.; Sorrenti, M.; Laurini,
E.; Fermeglia, M.; Pricl, S.; Brambilla, S.; Almirante, N.; Peviani, M.; Curti, D.;
Collina, S. Bioorg. Med. Chem. 2013, 21, 2577; (e) Rossi, D.; Pedrali, A.; Gaggeri,
R.; Marra, A.; Pignataro, L.; Laurini, E.; DalCol, V.; Fermeglia, M.; Pricl, S.;
Shepmann, D.; Wünsch, B.; Peviani, M.; Curti, D.; Collina, S. Chem. Med. Chem.
2013, 8, 1514; (f) Rossi, D.; Pedrali, A.; Marra, A.; Pignataro, L.; Shepmann, D.;
Wünsch, B.; Ye, L.; Leuner, K.; Peviani, M.; Curti, D.; Azzolina, O.; Collina, S.
Chirality 2013, 25, 814.
23. Zampieri, D.; Mamolo, M. G.; Laurini, E.; Zanette, C.; Florio, C.; Sollina, S.; Rossi,
D.; Azzolina, O.; Vio, L. Eur. J. Med. Chem. 2009, 44, 124.
24. Schläger, T.; Shepmann, D.; Lehmkuhl, K.; Holenz, J.; Vela, J. M.; Buschmann,
H.; Wünsch, B. J. Med. Chem. 2011, 54, 674.
25. Laurini, E.; Marson, D.; Dal Col, V.; Fermeglia, M.; Mamolo, M. G.; Zampieri, D.;
Vio, L.; Pricl, S. Mol. Pharm. 2012, 9, 3107.
26. Zampieri, D.; Mamolo, M. G.; Laurini, E.; Florio, C.; Zanette, C.; Fermeglia, M.;
Posocco, P.; Paneni, M. S.; Pricl, S.; Vio, L. J. Med. Chem. 2009, 52, 5380.
27. Laurini, E.; Dal Col, V.; Mamolo, M. G.; Zampieri, D.; Posocco, P.; Fermeglia, M.;
Vio, L.; Pricl, S. ACS Med. Chem. Lett. 2011, 2, 834.