Pyrrole- and indole-containing tranylcypromine derivatives as novel lysine-specific demethylase 1 inhibitors active on cancer cells

Article abstract of DOI:10.1039/c4md00507d

On the basis of previous research showing the capability of N-carbobenzyloxy-(Z-)amino acid-tranylcypromine (-TCPA) derivatives to inhibit LSD1, we inserted at the 4-amino-TCPA moiety first a Z-Pro (9) and a Z-Gly (10) residue and then, after the encouraging data obtained for 9, a pyrrole and an indole ring in which the relative N₁ position carried a acetophenone, a N-phenyl/benzylacetamide, or a Z chain (11a-f and 12a-f, respectively). In both series, the Z-pyrrole and indole derivatives 11e, f and 12e, f displayed high LSD1 inhibitory activity. The compounds are able to inhibit LSD1 in NB4 cells, increasing the expression of two related genes, GFI-1b and ITGAM, and to induce cell growth arrest in the AML MB4-11 and APL NB4 cell lines. This journal is

Full text of DOI:10.1039/c4md00507d

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Pyrrole- and indole-containing tranylcypromine
derivatives as novel lysine-specific demethylase 1
inhibitors active on cancer cells†
Cite this: DOI: 10.1039/c4md00507d
a
a
Veronica Rodriguez, Sergio Valente, Stefano Rovida,b Dante Rotili,a Giulia Stazi,a
Alessia Lucidi,a Giuseppe Ciossani,b Andrea Mattevi,b Oronza A. Botrugno,d
Paola Dessanti,d Ciro Mercurio,c Paola Vianello,d Saverio Minucci,de
*
d
af
*
Mario Varasi and Antonello Mai
On the basis of previous research showing the capability of N-carbobenzyloxy-IJZ-)amino acid-
tranylcypromine (-TCPA) derivatives to inhibit LSD1, we inserted at the 4-amino-TCPA moiety first a Z-Pro
(9) and a Z-Gly (10) residue and then, after the encouraging data obtained for 9, a pyrrole and an indole
ring in which the relative N1 position carried a acetophenone, a N-phenyl/benzylacetamide, or a Z chain
(11a–f and 12a–f, respectively). In both series, the Z-pyrrole and indole derivatives 11e, f and 12e, f displayed
high LSD1 inhibitory activity. The compounds are able to inhibit LSD1 in NB4 cells, increasing the expres-
sion of two related genes, GFI-1b and ITGAM, and to induce cell growth arrest in the AML MB4-11 and APL
NB4 cell lines.
Received 8th November 2014,
Accepted 19th December 2014
DOI: 10.1039/c4md00507d
www.rsc.org/medchemcomm
The discovery of the H3K4 demethylase called lysine-
specific demethylase 1 (LSD1 or KDM1A) revealed that his-
Introduction
Lysine (Lys) residues on histone tails can undergo post-
translational methylation and demethylation, and therefore
act as important sites for epigenetic control of gene expres-
sion. These lysine marks can either activate or deactivate gene
expression depending on their position in the histone tail,
and the level of methylation (mono-, di- or trimethylated) on
their ε-amine group.1,2 For instance, methylation at Lys4 and
methylation at Lys36 and Lys79 of histone H3 (H3K4, H3K36
and H3K79) are typical activation marks, whereas methyla-
tion at H3K9, H3K27 and H4K20 normally leads to gene
silencing.1,2 Moreover, such last lysine marks typically act in
concert with DNA methylation at CpG islands near promoters,
reinforcing gene repression.
tone methylation is a reversible process.3,4 Up to now, a large
number of demethylases have been identified, belonging to
either the LSD family or the JmJ-containing enzymes.5,6 As a
member of the amine oxidases, LSD1 is able to remove
methyl groups from H3K4me1/2 through a FAD-dependent
redox process. In specific contexts, LSD1 can catalyze
H3K9me1/2 demethylation, changing its role from a gene
silencer to a gene activator.7 LSD1 is also able to demethylate
non-histone substrates, such as the tumor suppressor p53
and the cell cycle and apoptosis regulator E2F1.8,9 Impor-
tantly, aberrant LSD1 expression and/or activity has been
associated with several human cancers ranging from neuro-
blastoma10 to prostate,11 lung,12 and bladder cancers,13 sar-
comas and hepatocarcinomas.14 Hence, LSD1 has been con-
sidered an attractive target for the treatment of cancer.
To date, a number of small molecules, such as phenelzine
(1), tranylcypromine (TCPA) (2)15 and related compounds
(3–5),16–18 some polyamines (such as 6)19 and amidines
(such as 7),20 as well as some peptides21–23 have been described
as LSD1 inhibitors (Fig. 1).
a Department of Drug Chemistry and Technologies, Sapienza University of Rome,
P.le A. Moro 5, 00185 Rome, Italy. E-mail: antonello.mai@uniroma1.it
b Department of Biology and Biotechnology, University of Pavia, Via Ferrata 1,
27100 Pavia, Italy
c Genextra Group, DAC s.r.l. Via Adamello 16, 20139 Milano, Italy
d Department of Experimental Oncology, European Institute of Oncology IEO,
Via Adamello 16, 20139 Milan, Italy
e Department of Biosciences, University of Milan, 20100 Milan, Italy
f Pasteur Institute - Cenci Bolognetti Foundation, Sapienza University of Rome,
P.le A. Moro 5, 00185 Rome, Italy
Recently, we described some TCPA-based compounds
as novel LSD1 inhibitors by introducing acyl and
N-IJcarbobenzyloxy)-IJZ-)amino acyl moieties in the aniline
NH2 group of 4-IJ2-aminocyclopropyl)aniline.24 Among them,
† Electronic supplementary information (ESI) available: Synthesis of 11a–f and
12a–f and intermediates. LSD1 enzyme inhibition assay. Crystallographic
analysis. Gene modulation assays. Cell growth assays. See DOI: 10.1039/
c4md00507d
the Z-phenylalanine (Z-Phe) derivative
8 (Fig. 1) was
described as one of the most potent and selective LSD1
inhibitors (Ki = 1.3 μM, IC50 = 0.15 μM).24 Compound 8 also
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Fig. 1 Known LSD1 inhibitors.
showed relevant biological activities in cellular models,
exhibiting antiproliferative and differentiating effects in acute
promyelocytic leukemia (APL) cells including primary murine
APL blasts.24 On this basis, pursuing our research in this
field,23–29 we prepared the Z-Pro and Z-Gly analogues of 8,
compounds 9 and 10, and after the encouraging results
obtained with 9 in terms of LSD1 inhibition (see below),
we synthesized compounds 11a–f and 12a–f in which
novel pyrrole and indole compounds 11 and 12 were tested
against LSD1, in comparison with 8 used as a reference drug.
In cellular assays, 11 and 12 were tested to assess their
capability to induce mRNA expression of the growth factor
independent 1 (GFI-1b),25,30–32 a gene that is a direct tran-
scriptional target of LSD1,30 and integrin alpha M (ITGAM),24
a gene related to differentiation, and to affect cell prolifera-
tion in leukemia cell lines.
either
a pyrrole or an indole ring, carrying an aceto-
phenone, a N-phenyl/benzylacetylamide or a carbobenzyloxy
moiety at their N1 position, was inserted at the
4-IJ2-aminocyclopropyl)aniline scaffold (Fig. 2).
In such compounds, the substituted pyrrole/indole por-
tions could mimic the amino acid portion of our TCPA-based
LSD1 inhibitors, without bearing the additional chiral centre,
thus simplifying the stereochemistry of such derivatives. The
Results and discussion
As the first step in our studies, we synthesized two analogues
of 8 in which the Z-Phe moiety was replaced by a Z-Pro (9) or
a Z-Gly (10) residue (Scheme S1 in the ESI†). Particularly,
compound 9 exhibited a two-fold improved inhibitory potency
against LSD1 (IC50 of 0.06 μM; Table 1). Furthermore,
Fig. 2 Novel TCPA analogues based on Z-Pro (9), Z-Gly (10), pyrrole (11a–f) and indole (12a–f) structures.
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Table 1 LSD1, MAO-A and MAO-B inhibiting activity (IC50 values, μM) of
compounds 9, 10, 11a–f and 12a–f. Compound
comparisona
8
was used for
IC50, μM
Compd
LSD1
MAO-A
MAO-B
8
9
10
0.149
0.061
0.304
0.163
1.323
0.125
0.155
0.032
0.050
0.065
0.853
0.087
0.308
0.040
0.086
11a
11b
11c
11d
11e
11f
12a
12b
12c
12d
12e
12f
0.26
0.11
75.8
3.9
Scheme 1 Synthesis of novel pyrrole and indole derivatives 11a–d and
12a–d. Reagents and conditions: (a) 2-bromoacetophenone or
2-bromo-N-phenylacetamide or N-benzyl-2-bromoacetamide, K2CO3,
dry CH3CN, 2 h, 85 °C. (b) 2 N LiOH, THF, 4 h, rt. (c) trans-N-Boc-2-IJ4-
aminophenyl)cyclopropylamine (13), PyBop, Et3N, dry DMF, N2
atmosphere, overnight, rt. (d) 4 N HCl, dry dioxane/THF, overnight, rt.
0.16
0.46
>60
>70
a
The IC50 values reported are based on two separate curves, wherein
each data point is the average of two determinations. The resulting
IC50 values from these curves were then averaged and reported in the
table. The error is within 10%.
available. Such intermediates were then treated with NaH in
dry THF and benzyl chloroformate to furnish the Z-pyrrole
and Z-indole esters 22a, b and 23a, b, which were hydrolyzed
with trifluoroacetic acid in dry DCM to furnish the acids
24a, b and 25a, b. Such acidic intermediates 24a, b and 25a,
b were coupled with 13 to give the Boc-protected derivatives
26a, b and 27a, b. Further cleavage of their Boc function
with 4 N HCl yielded the desired compounds 11e, f and
12e, f (Scheme 2).
the crystal structure confirmed that the inhibitor binds
covalently to the flavin with the same conformation as the
parent compound24 (coordinates deposited in the Protein
Data Bank with code 4UXN). These initial results encouraged
us to pursue our goal – the synthesis and analysis of deriva-
tives with substituents (e.g. pyrrole or indole) that restrain
the conformation and simplify the stereochemistry by
lacking the chiral centre of the Z-amino acid. The final
step required for the synthesis of 9–12 is the coupling
of the appropriate carboxylic acids with trans-N-Boc-2-
IJ4-aminophenyl)cyclopropylamine (13)24 in the presence of
benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluoro
phosphate (PyBop) and triethylamine, with dry N,N-dimethyl-
formamide as a solvent, followed by Boc cleavage with 4 N
HCl in dioxane and dry THF.24 To prepare 9, 10, 11a and
12a, Z-Pro, Z-Gly, 1H-pyrrole-2-carboxylic acid and 1H-indole-
2-carboxylic acid were directly coupled with 13 and cleaved at
the Boc moiety as described (Scheme 1). For the synthesis of
11b–d and 12b–d, ethyl 1H-pyrrole-2-carboxylate and ethyl 1H-
indole-2-carboxylate were treated with 2-bromoacetophenone,
2-bromoacetylanilide, or 2-bromoacetylbenzylamide in anhy-
drous CH3CN at 85 °C in the presence of potassium carbonate
to provide the N1-alkylated-pyrrole and -indole ethyl esters
14a–c and 15a–c. After alkaline hydrolysis, the corresponding
acids 16a–c and 17a–c were coupled with 13, giving the Boc-
protected derivatives 18a–c and 19a–c, after treated with 4 N
HCl as described (Scheme 1). To prepare compounds 11e, f
and 12e, f, the 1H-pyrrole-2- and -3-carboxylic acids as well
as the 1H-indole-2- and -3-carboxylic acids, respectively, were
treated with N,N-dimethylformamide di-tert-butyl acetal in
dry toluene at 80 °C to obtain the corresponding tert-butyl
esters 20a, b and 21a, b, which are also commercially
Scheme 2 Synthesis of 11e, f and 12e, f. Reagents and conditions:
(a) N,N-dimethylformamide di-tert-butyl acetal, toluene, 1 h, 80 °C;
(b) 60% NaH, dry THF, benzyl chloroformate, 1 h, rt; (c) trifluoroacetic acid,
dry DCM, 5 h, rt; (d) trans-N-Boc-2-IJ4-aminophenyl)cyclopropylamine
(13), PyBop, Et3N, dry DMF, N2 atmosphere, overnight, rt; (e) 4 N HCl, dry
dioxane/THF, overnight, rt.
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Compounds 9 and 10, as well as the new pyrrole and
indole derivatives 11 and 12 were tested against LSD1 in bio-
chemical assay, and their IC50 values were determined. Com-
pound 8 was used for comparison (Table 1). The highly
potent compounds 11e, f and 12e, f were also assayed against
MAO-A and MAO-B to assess their selectivity profiles.
Among the pyrrole derivatives 11a–f, the N1-unsubstituted
11a displayed slightly lower LSD1 inhibition with respect to
the Z-Phe-TCPA compound 8, while the analogue with the
acetophenone moiety at N1 (11b) was 10-fold less effective.
However, the ability to inhibit LSD1 was fully restored when a
N-phenyl/benzylacetamide group was inserted at the pyrrole N1
position (see IC50 values for 11c and 11d in Table 1). The intro-
duction of the carbobenzyloxy (Z) substituent at the N1 position
of the pyrrole ring, in either the 2- or the 3-substituted
analogue (11e or 11f), yielded the highest enzyme inhibition,
leading to compounds 5- (11e) or 3-fold (11f) more potent
than 8, which was used as the reference drug.
In the indole series, the NH analogue 12a showed
improved LSD1 inhibitory activity with respect to both 8 and
the pyrrole counterpart 11a, and similarly to what was
observed in the pyrrole series, the substitution at the N1 posi-
tion with the acetophenone moiety (12b) was detrimental to
LSD1 inhibition. However, the replacement of this group with
the N-phenylacetamide portion (12c) restored the LSD1 inhibi-
tion at an IC50 value similar to that of the NH analogue 12a.
Differently from the pyrrole series, the insertion at the
indole N1 position of the N-benzylacetamide chain (12d)
resulted in 3.5-fold lower potency than the N-phenyl counter-
part (12c), likely for steric reasons. Finally, similarly to what
was seen with pyrroles, also with 2- and 3-substituted indoles
the introduction of the Z substituent at the N1 position gave
high LSD1 inhibition, compounds 12e and 12f being 3.7- and
1.7-fold more potent than 8, respectively. However, by com-
paring the Z-containing pyrroles 11e, f and the Z-containing
indoles 12e, f with the corresponding unsubstituted pyrrole
(11a) and indole (12a) analogues, it is clear that the
N-substituent only enhances the activity of the pyrrole series.
The highly potent LSD1 inhibitors 11e, f and 12e, f, when
tested against MAOs, exhibited up to 8-fold lower activity
against MAO-A, and were practically inactive against MAO-B,
with the sole exception of 11f which showed MAO-B inhibi-
tion at the low μM range.
Fig. 3 GFI-1b and ITGAM gene expression induction in NB4 cells by
selected 11 and 12 derivatives. The inhibitors were tested at their
biochemical anti-LSD1 IC50 values. Fold-inductions were calculated
with respect to DMSO, which was used as a control.
Table 2 Antiproliferative activities of the Z-pyrrole- and Z-indole-TCPA
derivatives 11e, f and 12e, f in human AML MV4-11 and human APL NB4
cells. Compound 8 was used for comparisona
IC50, μM
Compd
MV4-11 cells
NB4 cells
8
10.2
6.8
15.2
5.9
17.4
56%b
22.3
6.5
11e
11f
12e
12f
2.5
9.3
a
The IC50 values reported are based on two separate curves, wherein
each data point is the average of two determinations. The resulting
IC50 values from these curves were then averaged and reported in the
table. The error is within 10%. b Percentage of inhibition at 100 μM.
indole compounds are able to induce GFI-1b and, to a lesser
extent, ITGAM gene expression in NB4 cells, thus demonstrat-
ing their capability to inhibit LSD1 in cells.
Finally, the Z-pyrrole (11e, f) and the Z-indole (12e, f)
derivatives were tested in two leukemia cell lines, the human
acute myelocytic leukemia (AML) MV4-11 and the APL NB4
cell lines, using increasing concentration of the inhibitors for
72 h, to assess their antiproliferative potential (Table 2).
In this assay, the Z-pyrrole derivatives 11e, f displayed sim-
ilar or lower antiproliferative activities than 8, while the
Z-indoles 12e, f were from 2- to 4-fold more potent than 8 in
inducing leukemia cell growth arrest, with IC50 values in the
single-digit μM range.
To investigate if the compounds were able to inhibit LSD1
in cells, we tested selected pyrrole and indole compounds
(11a, c–f and 12a, c, e, f) for their capability to induce, in
human acute promyelocytic leukemia (APL) NB4 cells, the
expression of GFI-1b25,30–32 and ITGAM,24 two genes related
to expression and activity of LSD1 and/or to cell differentia-
tion. Compound 8 was included for comparison purposes.
The inhibitors were added to cultures of NB4 cells at a con-
centration equal to their respective biochemical IC50 values,
and after 24 hours the GFI-1b and ITGAM mRNA expression
levels were measured by quantitative RT-PCR and graphed as
fold-induction with respect to the control (DMSO). Data
depicted in Fig. 3 show that all the selected pyrrole and
Conclusions
Recently we reported a series of Z-amino acid-TCPA deriva-
tives as novel potent LSD1 inhibitors.24 From this study, the
Z-Phe-TCPA derivative 8 emerged as the most potent and selec-
tive compound in enzyme assays as well as in leukemia cells.
Pursuing our research in this field, we extended our previous
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work by linking to the 4-amino-TCPA scaffold first a Z-Pro
(9) and a Z-Gly (10) moiety and then, after the encouraging
results obtained for 9 in inhibiting LSD1, some pyrrole- and
indole-2- and -3-carboxylic acids, in which the N1 positions
were substituted with acetophenone, N-phenylacetamide,
N-benzylacetamide, and benzyloxycarbonyl chains, to mimic
the Z-amino acid moiety. The new compounds 11a–f and 12a–f
have the advantage of lacking the third, additional chiral cen-
tre due to the amino acid portion of the previous inhibitors.
Tested against LSD1, the pyrroles unsubstituted at N1 (11a)
or bearing at the same position a N-phenyl/benzylacetamide
chain (11c, d) displayed similar inhibiting activity to 8,
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which was used as
a
reference drug, and the
N1-carbobenzyloxy-substituted analogues 11e, f were up to
5-fold more potent than 8. Among the indole derivatives, the
N1-H (12a) as well as the N1-N-phenylacetamide (12c) and
the two N1-carbobenzyloxy (12e, f) substituted compounds
showed 2/3-fold higher potency than 8 in inhibiting LSD1.
Such inhibitors were then tested in APL NB4 cells to assess
their capability to induce mRNA expression of GFI-1b25,30–32
and ITGAM,24 two genes related to LSD1 activity and/or cyto-
differentiation. At the concentration equal to their bio-
chemical IC50s, all of them induced GFI-1b up to 6-fold, and
ITGAM up to 4-fold, with respect to DMSO which was used as
a control. Finally, the N1-carbobenzyloxy pyrroles and indoles
11e, f and 12e, f were tested in APL NB4 and AML MV4-11
cells to determine their effects on proliferation. In this assay,
in particular the indoles 12e, f displayed single-digit μM cell
growth arrest, them being more efficient than 8 when tested
under the same conditions. Further studies will be under-
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Acknowledgements
This work was supported by Fondazione Cariplo (2010.0778),
AIRC (IG-11342), MIUR (Progetto Epigen and RF-2010-2318330),
FIRB RBFR10ZJQT, Sapienza Ateneo Project 2013, IIT-Sapienza
Project, FP7 Project BLUEPRINT/282510 and A-PARADDISE/
602080, and Regione Lombardia, Fondo per la Promozione di
Accordi Istituzionale, Bando di Invito di cui al Decreto n. 4779
del 14/05/2009, Progetto DiVA.
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