Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.02.034

Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with the repressor protein CoREST in a transcriptional co-repressor complex, whic

Full text of DOI:10.1016/j.bmcl.2018.02.034

Accepted Manuscript
Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual bind-
ing inhibitors
Andrea Milelli, Chiara Marchetti, Eleonora Turrini, Elena Catanzaro, Roberta
Mazzone, Daniela Tomaselli, Carmela Fimognari, Vincenzo Tumiatti, Anna
Minarini
PII:
S0960-894X(18)30139-2
https://doi.org/10.1016/j.bmcl.2018.02.034
BMCL 25630
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 November 2017
15 February 2018
16 February 2018
Please cite this article as: Milelli, A., Marchetti, C., Turrini, E., Catanzaro, E., Mazzone, R., Tomaselli, D.,
Fimognari, C., Tumiatti, V., Minarini, A., Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual
binding inhibitors, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.
2018.02.034
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Graphical Abstract
Novel polyamine-based Histone deacetylases-
Lysine demethylase 1 dual binding inhibitors
Andrea Milelli, Chiara Marchetti,  Eleonora Turrini,
Elena Catanzaro, Roberta Mazzone, Daniela Tomaselli,
Carmela Fimognari, Vincenzo Tumiatti, Anna Minarini
Leave this area blank for abstract info.
O
O
H
H
N
N
HN
N
N
O
H
H
H
O
N
H2N
N
OH
H
O
HDAC1-CoREST: Ki = 42.52 ± 8.94 nM
LSD1-CoREST: IC50 3.85
MCF7: IC50 39.6
=
M
=
M

Bioorganic & Medicinal Chemistry Letters
Novel polyamine-based Histone deacetylases-Lysine demethylase 1 dual binding
inhibitors
Andrea Milellia*, Chiara Marchettib, Eleonora Turrinia, Elena Catanzaroa, Roberta Mazzonec, Daniela
Tomasellic, Carmela Fimognaria, Vincenzo Tumiattia, Anna Minarinib
a Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921, Rimini, Italy.
b Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
c Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Roma, Italy.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Epigenetic modulators Histone deacetylases (HDACs) and Lysine demethylase (LSD1) are
validated targets for anticancer therapy. Both HDAC1/2 and LSD1 are found in association with
the repressor protein CoREST in a transcriptional co-repressor complex, which is responsible for
gene silencing. Combined modulation of both targets results in a synergistic antiproliferative
activity. In the present investigation, we report about the design and synthesis of a series of
polyamine-based HDACs-LSD1 dual binding inhibitors obtained by coupling Vorinostat and
Tranylcypromine. Compound 4 emerged as the most promising of the synthesized series,
showing good inhibitory activity towards HDAC1 and LSD1 either in vitro and in cell-based assay
(Ki = 42.52 ± 8.94 nM and IC50 = 3.85 M, respectively). Furthermore, at 70.0 µM compound 4
induced a more pronounced cytotoxic effect than Vorinostat (68.6% vs 56.6% of dead cells) in MCF7
cancer cell line.
Keywords:
Dual-binding agents
Epigenetics
Histone deacetylase inhibitors
Lysine demethylase inhibitors
Polyamines
Cancer is a multifactorial disease whose onset derives from
both genetic and epigenetic events; in recent years, epigenetic has
gained notable consideration and epigenetic targets have been
validated in therapy.[1] Epigenetic changes are reversible
chromatin modifications that lead to activation or suppression of
gene expressions. The epigenetic control of gene expressions
takes place through modification of the DNA itself, i.e.
group able to strongly coordinate the Zn2+ located in the active
site of the enzyme. The general structure for hydroxamate-
HDACis comprises three main motifs: a Zn2+ binding group, a
hydrophobic spacer and a cap group able to interact with the
surface of the enzyme. Several clinical evidences reported that
HDACis might be more effective as antiproliferative agents when
used in combination with other chemotherapeutic or epigenetic
drugs. For instance, HDACis potentiate the antiproliferative
activities of Topoisomerase I and II inhibitors [9, 10]; further,
HDACis in combination with the EGFR inhibitor Gefitinib
synergistically induce growth inhibition and apoptosis induction
in gefitinib-resistant cancer cell lines.[11, 12] Recently, Bhalla
and coworkers reported that combined inhibition of HDACs and
Lysine demethylase LSD1 is lethal in human AML cells.[13]
Furthermore, the same combination resulted in a synergistic
increase of apoptotic cell death in glioblastoma multiforme cell
line.[14] LSD1 is a histone demethylase, member of the greater
amine oxidase superfamily, that is responsible, among other
activities, for the specific demethylation of mono- and
dimethylated histone H3-Lys4.[15] LSD1 is overexpressed in
various cancers and binds to several transcription factors,
regulating the expression of a vast array of genes.[16] LSD1 is
found in association with the repressor protein CoREST and
HDAC1/2, in a transcriptional co-repressor complex that is
responsible for gene silencing.[17] Most of the known LSD1
inhibitors developed share structural features with monoamine
oxidase inhibitors. In particular, Tranylcypromine is a known
irreversible LSD1 inhibitor and several Tranylcypromine-based
methylation, or DNA-associated proteins, i.e. methylation and
acetylation. According to the subject and the type of
modification, chromatin can adopt conformational changes that
lead to the activation or suppression of gene expression.[2]
Histone deacetylases (HDACs) are one of the most important
classes of epigenetic enzymes responsible for removing acetyl
groups from histone tails, determining a more closed,
transcriptionally repressed, chromatin structure.[3] Abnormal
HDACs activity has been found to be associated with the
aberrant gene expression and the development of several kinds of
cancer.[4] Inhibition of HDACs activities restore normal gene
expression resulting in cell cycle arrest, apoptotic cell death and
cell differentiation.[5] Different HDAC inhibitors (HDACis)
have been approved by the FDA, i.e. vorinostat, romidepsin,
panobinostat and belinostat, and chidamide in China, and many
others are currently under evaluation in clinical trials (Figure
1).[6] Over the years, several different classes of HDACis have
been identified;[7] among them hydroxamate-based compounds
hold a special interest in spite of their unfavourable ADMET
properties.[8] Hydroxamate-based inhibitors, among the most
potent but rather unselective HDACis, bear the hydroxamic acid

derivatives have been reported so far (Figure 1). The synergistic
activity obtained combining HDACs and LSD1 inhibitors
together with the finding that LSD1 is associated with CoREST
and HDAC1/2 provided the rational for designing dual binding
agents able to simultaneously modulate HDAC and LSD1.
Herein, we report the design, the synthesis and the preliminary
biological evaluation of a series of polyamine-based
For the synthesis of target compounds 3-5 a stepwise linear
synthetic approach was developed (Scheme 1). Suberic anhydride
7 was condensed with methyl 4-aminobenzoate 6 to generate the
corresponding acid 8. This was coupled to O-(Tetrahydro-2H-
pyran-2-yl)hydroxylamine in order to obtain the protected
hydroxamic acid 9, using EDC as coupling agent. Basic
hydrolysis of the methyl ester of 9 furnished the carboxylic acid
10 that was coupled with the suitable protected polyamines 11-
13. Many efforts were carried out in order to optimize the
coupling conditions of 10 with 11-13 [25, 26]: after variation of
solvents (DCM, DMF, THF), reaction times and coupling
auxiliary (EtOCCl and Et3N, IBCF and Et3N, DCC and HOBt,
DCC and DMAP, EDC and HOBt) and it was found that the use
of EDC and DMAP gave the best yields. Basic deprotection of
the trifluoromethyl protecting group led to the primary amines
17-19, which further reacted with succinic anhydride leading to
the corresponding acids 20-22. Coupling of the latter with Boc-
protected tranylcypromine [27] generated the fully-protected
dimers 24-26. Also in this case, several reaction conditions were
evaluated with the aim to optimize the coupling reaction and
again better yields were obtained using EDC as coupling agent.
Final acidic hydrolysis of the Boc-protecting groups gave the
target compounds 3-5 as hydrochloride salts.
HDAC/LSD1 dual binding inhibitors.
As summarized in Table 1, the target compounds 3-5 as well as
the reference compounds Vorinostat and Tranylcypromine were
profiled for their HDAC1-CoREST3 and LSD1-CoREST3
inhibitory activities in vitro. Unfortunately, compound 5 was
endowed with poor solubility in the media and, therefore, could
not be evaluated. Compounds 3 and 4 retain the activity of the
parent compounds being both active in the nanomolar and in the
micromolar range of concentrations against HDAC1 and LSD1,
respectively. However, by a closer look to the HDAC1 inhibitory
activity, it appears that introduction of a polyamine chain and a
second pharmacophore in the para position of the aromatic ring
induces a slightly decrease in the activity compared to
Vorinostat. Indeed, compounds 3 and 4 are respectively 9 and 14-
fold less active than Vorinostat (3: Ki = 26.87 ± 7.87 nM; 4: Ki =
42.52 ± 8.94 nM; Vorinostat: Ki = 3.04 ± 0.6 nM). An opposite
trend was observed considering the inhibitory activity towards
LSD1; in this case, the introduction of the polyamine chain and a
second pharmacophore has a positive effect on the inhibitory
activity with compounds 3 and 4 being respectively 37 and 23-
fold more active than Tranylcypromine (3: IC50 = 2.40 μM; 4:
IC50 = 3.85 μM; Tranylcypromine: IC50 = 89.08 μM).
Figure 1. Structures of known HDACis, Vorinostat, Romidepsin,
Panobinostat, Belinostat and Chidamide, and LSD1 inhibitors,
Tranylcypromine, 1 and 2.
The design of these new compounds began with the observation
that various substituents may be introduced at the para position of
the aromatic ring of both Vorinostat and Tranylcypromine
without a dramatic drop in the inhibitory activity. The two
pharmacophores have been linked through a polyamine chain
since it has been previously demonstrated that a) protonated
nitrogen atoms can establish interactions with negatively charged
amino acids[18, 19] and b) polyamines interact with both HDAC
and LSD1 proteins.[20-22] Three different polyamine chains
have been chosen differing in the number of the nitrogen atoms
and in the distance between them; indeed, compound 3 has a
spermidine-like linker (3-3), compound 4 has a spermine linker
(3-4-3) and compound 5 carries a spermine-like connecting unit
characterized by longer (6-8-6) polymethylenes chain between
the nitrogen atoms (Figure 2).
During the drafting of this manuscript, two papers reporting
about novel dual HDAC-LSD1 inhibitors appeared.[23, 24]
However, these compounds turned out to be structurally slightly
different than those reported in the present manuscript.
Table 1. HDAC1-CoREST3 and LSD1-COREST3 Inhibiting
Activity of the Dual Binding Agents 3-5 in Comparison with
Vorinostat and Tranylcypromine.
HDAC1-CoREST3
Ki (nM)
26.87 ± 7.87
42.52 ± 8.94
n.d.
LSD1-CoREST3
IC50 (μM)
2.40
3.85
Compounda
H
N
O H
N
H
H2N
O
3
4
5
Tranylcypromine
Vorinostat
n.d.
Vorinostat
3.04 ± 0.6
n.d.
n.d.
89.08
linker
Tranylcypromine
acompounds as hydrochloride salts. bn.d. = not determined
O
H
N
Compounds 3 and 4 were then evaluated in cell-based assay.
First, compounds 3 and 4, together with Vorinostat and
OH
H2N
O
N
H
H
H
N
X
n
N
O
N
H
n
Tranylcypromine, were evaluated for their cytotoxic activity in
MCF7 breast cancer cell line. Vorinostat induced a dose-
dependent decrease in cell viability with an IC50 of 38.2 µM (data
not shown). Higher concentrations of Tranylcypromine were
necessary to decrease MCF-7 viability and the concentration
required to reach the IC50 value was 2518.9 µM (data not shown).
O
O
3: n = 1, X = NH
4: n = 1, X = NH(CH2)4NH
5: n = 4, X = NH(CH2)8NH
Figure 2. Drug design leading to dual binding agents 3-5.

O
O
O
O
O
O
O
O
O
O
i
ii
H
OH
N
H2N
N
O
O
O
N
5
H
H
5
O
O
7
6
9
8
O
O
O
X
HO
O
F3C
N
N
O
iv
H
N
iii
n
n
H
H
H
N
O
O
N
O
O
N
5
H
H
5
O
O
14: n=2 X=NBoc
15: n=2 X=NBoc(CH2)4NBoc
16: n=5 X=NBoc(CH2)8NBoc
10
O
O
O
X
v
H2N
N
O
vi
HO
X
n
n
H
H
N
N
O
N
H
n
H
H
n
O
O
N
O
N
H
5
O
O
N
H
O
5
17: n=2 X=NBoc
18: n=2 X=NBoc(CH2)4NBoc
19: n=5 X=NBoc(CH2)8NBoc
O
20: n=2 X=NBoc
21: n=2 X=NBoc(CH2)4NBoc
22: n=5 X=NBoc(CH2)8NBoc
O
O
H
N
N
H
O
X
vii
N
O
n
H
H
n
N
BocHN
NH2
O
O
N
H
5
O
BocHN
24: n=2 X=NBoc
25: n=2 X=NBoc(CH2)4NBoc
26: n=5 X=NBoc(CH2)8NBoc
23
O
X
O
O
F3C
N
NH2
H
H
n
n
N
X
N
N
O
viii
H
n
H
11: n=2 X=NBoc
H
N
n
O
H2N
12: n=2 X=NBoc(CH2)4NBoc
13: n=5 X=NBoc(CH2)8NBoc
OH
N
H
5
O
3: n=2 X=NH
4: n=2 X=NH(CH2)4NH
5: n=5 X=NH(CH2)8NH
Scheme 1. i) THF, rt, 12h; ii) NH2OTHP, EDC, DMAP, Et3N, DCM, rt, 12h; iii) NaOH, MeOH, 50 °C, 2h; iv) 11-13, EDC, HOBt, Et3N, THF, rt, 16h; v) NaOH,
MeOH, rt, 16h; vi) succinic anhydride, Et3N, DCM, rt, 16h; vii) 23, EDCI, DMAP, DCM, rt, 24h; viii) HCl 4M/dioxane, DCM rt, 12h.
Compounds 3 and 4 significantly decreased MCF-7 viability
starting from the lowest tested concentration and in a dose-
dependent manner. The concentration required to reach the IC50
value was 60.2 μM for compound 3 and 39.6 μM for compound 4
(Figure 3). The cytotoxic activity of compound 4 was similar to
that of Vorinostat: at 4.0 µM, Vorinostat and compound 4
induced 20.8% and 16.3% decrease in cell viability, respectively,
compared to control cells. Increasing treatment concentrations
showed an analogue trend. A 49.3% and 52.7% decrease in cell
viability was recorded after 24 h incubation with either
Vorinostat or compound 4 at 16.0 µM and 35.0 µM, respectively.
At the highest concentration tested (70.0 µM), 4 induced a more
pronounced cytotoxic effect than Vorinostat (68.6% vs 56.6% of
dead cells, respectively). Compound 3 exhibited a lower
cytotoxic activity with only 52% decrease in cell viability
recorded at the highest concentration tested (Figure 3).
Tranylcypromine showed cytotoxic effects at concentrations
much higher than the other compounds (data not shown).
Figure 3. Cell viability after 24 h treatment of MCF-7 cells
with a) compound 3, b) compound 4 and c) compounds 3 and 4
in comparison with Vorinostat.

To explore the ability of compounds 3 and 4 to inhibit HDAC
in cell, nuclear extracts of treated MCF-7 cells were compared to
Vorinostat plus Tranylcypromine-treated cells. Based on the
results of the preliminary evaluation that allowed to define the
cytotoxic activity, cells were treated with concentrations similar
or lower than the IC50: 70.0 µM for compound 3, 17.0 µM for
compound 4, Vorinostat and Tranylcypromine 35 and 1000.0
µM, respectively. The HDAC activity levels of all tested
compounds were significantly lower than the HDAC activity
level of untreated samples (Figure 4). A HDAC enzyme
inhibition of 50.2% was recorded after treatment with 17.0 µM of
compound 4 (Figure 4). The inhibitory activity of compound 4
was similar to that induced by the combination of Vorinostat plus
Tranylcypromine (50.0%). As expected from the cytotoxic
results, compound 3 had the lowest rate of HDAC inhibition:
after 70.0 µM treatment, the reduction of enzyme activity was
35.8% (Figure 4).
synthesis of other analogues are currently pursued in our
laboratories and will be reported in due course.
Acknowledgments
This work has been supported by RFO-University of Bologna.
AM thanks Mr. Mahmoud Haji for proofreading the manuscript.
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Designing dual binding agents is a well establishes strategy in
medicinal chemistry to provide new drug candidates or
biochemical tools. In the present investigation, we explore the
structure-activity relationships data available for HDAC and
LSD1 inhibitors to design the first class of polyamine-based dual
HDAC/LSD1 inhibitors. Indeed, it is well known that HDAC1/2
and LSD1 are associated within the same complex with CoREST.
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structure of two well-known HDAC and LSD1 inhibitors, namely
Vorinostat and Tranylcypromine. As linker different polyamine
chains have been choose. Indeed, polyamines are known to
establish additional interaction with negative charged amino
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Supplementary Material
Supplementary data associated with this article can be found
in the online version.
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