Design and synthesis of cyclic urea compounds: A pharmacological study for retinoidal activity

Article abstract of DOI:10.1016/j.bmcl.2004.06.038

Retinoids are natural and synthetic analogues of all-trans retinoic acid (ATRA). Cancer and other serious hyperproliferative diseases are attractive therapeutic targets for retinoids. We report here the design and synthesis of novel cyclic urea compounds with retinoidal activity. YR105 exhibited potent differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells at the concentration of 10^-9M: its potency was almost equal to that of the native ligand, all-trans retinoic acid.

Full text of DOI:10.1016/j.bmcl.2004.06.038

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4131–4134
Design and synthesis of cyclic urea compounds:
a pharmacological study for retinoidal activity
Masaaki Kurihara,a,* Abu Shara Shamsur Rouf,a Hisao Kansui,a Hiroyuki Kagechika,b
Haruhiro Okudaa and Naoki Miyatac
aDivision of Organic Chemistry, National Institute of Health Sciences, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
bGraduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
cFaculty of Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabedori, Mizuho-ku, Nagoya 467-8603, Japan
Received 23 March 2004; revised 11 June 2004; accepted 11 June 2004
Available online
Abstract—Retinoids are natural and synthetic analogues of all-trans retinoic acid (ATRA). Cancer and other serious hyperpro-
liferative diseases are attractive therapeutic targets for retinoids. We report here the design and synthesis of novel cyclic urea
compounds with retinoidal activity. YR105 exhibited potent differentiation-inducing ability toward human promyelocytic leukemia
HL-60 cells at the concentration of 10À9 M: its potency was almost equal to that of the native ligand, all-trans retinoic acid.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Retinoids, natural and synthetic analogues of all-trans
retinoic acid (ATRA), have a variety of potent biologi-
cal activities, such as induction of cell differentiation,
proliferation, and apoptosis, as well as developmental
changes.1
In earlier studies, a number of synthetic retinoid ana-
logues were prepared, and a few of them showed
potential biological effects several times higher than all
natural retinoids (Fig. 1).6 Some were selected as
promising lead compounds for retinoidal activity. All
the compounds consisted of two parts: a lipophilic
portion fused with a hydrophilic benzoic acid moiety via
amide or alkene or keto linkage. The biological activity
depended on the linker type as well as the presence or
absence of lipophilic moieties. Considering these aspects
we selected the lipophilic moieties and the amido or
alkene was changed to a urea linker, which may act as a
suitable ligand for retinoid receptors. however Ur80,7
Retinoids also have potential chemotherapeutic and
chemopreventive applications in the fields of dermato-
logy and oncology.2 Retinoic acid has a remarkable
remedial effect on acute promyelocytic leukemia (APL).3
Further, the inhibitory effect of retinoids on IL-6 pro-
duction suggests their possible usefulness in various IL-6
associated diseases, including psoriasis and rheumatoid
arthritis.4
It has been shown that the biological effects of retinoids
are mediated by the activation of retinoic acid receptors
(RARs), which are ligand-dependent gene transcription
factors. There are three distinct receptor subtypes
(RARa, b, c), which possess considerable homology in
their ligand binding domains.5
COOH
H
N
COOH
O
Am80
Retinoic Acid (ATRA)
COOH
H
N
COOH
We report here the design and synthesis of novel cyclic
urea compounds, which have retinoidal activity.
Si
O
O
Si
Ch55
Keywords: Cyclic urea; Retinoid; Cell differentiation; Drug design.
* Corresponding author. Tel.: +81-3-3700-1141; fax: +81-3-3707-6950;
e-mail: masaaki@nihs.go.jp
Am555S
Figure 1. Structures of typical retinoid agonists.
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.038

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M. Kurihara et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4131–4134
COOH
(a)
O
NH Br
2a-h
NH
2
R
R
N
H
N
H
1a-d
Ur80
Br
(b)
N
C NH
O
COOEt
R
COOH
O
3a-h
Me
H
N
N
H
N
N
O
(c)
(d)
N
N
COOEt
COOH
Me
R
O
4a-h
COOH
Ur100
Ur90
Figure 2. Conformations of methylated Ur80.
N
N
R
O
which has a urea linker, exhibited low bioactivity.
Introduction of substitutes to urea nitrogen would cause
flipping of stereochemistry to form Ur90 and Ur100 like
Am808 (Fig. 2). Because of fix of conformation and
lipophilicity, we chose a cyclic urea structure as the
linker (Fig. 3).
5a-h
tBu
NH
2
NH
NH
NH
2
2
2
tBu
1a
1b
1c
1d
Scheme 1. Reagents and conditions: (a) 1,2-dibromoethane or 1,3-
dibromopropane, CH3CN, 50–70 ꢁC, 72 h, 25–60%; (b) ethyl 4-iso-
cyanatobenzoate, benzene, 60–70 ꢁC, 48 h, 60–80%; (c) NaH, THF, rt,
3 h, 75–97%; (d) 5% NaOH, MeOH–H2O (7:3), 60 ꢁC, 1 h, 90–96%.
A very simple method was developed to synthesize all
desired cyclic urea derivatives. The synthesis of urea
derivatives (5a–h) was accomplished via the following
reaction sequences (Scheme 1). A number of different
aromatic amines (1a–d) were utilized as the starting
materials for the preparation of the desired cyclic urea
compounds.
amines were allowed to react with ethyl 4-iso-
cyanobenzoate in anhydrous benzene to form urea
derivatives (3a–h). The intramolecular cyclization of the
urea derivatives was performed utilizing sodium hydride
as the base to obtain cyclic urea derivatives (4a–h). Fi-
nally, the ethyl ester of cyclic urea derivatives was con-
verted to free acid form (5a–h) under basic conditions.
Various primary aromatic amines (1a–d) alkylated with
1,2-dibromoethane or 1,3-dibromopropane in acetoni-
trile resulted in formation of the respective secondary
amines (2a–h). The synthesized secondary aromatic
The biological activities of compounds 5a–h were eval-
uated in terms of induction of differentiation of HL-60
cells into mature granulocytes. The results are summa-
rized in Table 1. YR105 (5e) exhibited potent differen-
tiation-inducing activity toward HL-60 cells, with an
EC50 value of 8.3 · 10À9 M. The activity of YR105 was
one order weaker than that of retinobenzoic acid Am80,
and comparable to that of all-trans retinoic acid. YR106
hydrophobic interaction
(Ile-275, Phe-304)
N
N
COOH
R
O
hydrohobic interaction
hydrogen bond
(Trp-227, Phe-230, Leu-268,
Phe-304, Leu-307, Ala-397,
Ile-412, Leu-416)
(Arg-278, Ser-289)
Table 1. HL-60 differentiation-inducing activity of cyclic urea com-
pounds (5a–h)
n
n
Compound
Activity (ED50) (M)
N
N
COOH
N
N
COOH
5a (YR101)
5b (YR102)
5c (YR103)
5d (YR104)
5e (YR105)
5f (YR106)
5g (YR107)
5h (YR108)
Retinoic acid
Am80
Inactive
Inactive
Inactive
Inactive
8.3 · 10À9
4.9 · 10À7
1.2 · 10À7
Inactive
2.4 · 10À9
7.9 · 10À10
>10À6
O
O
n=1: 5a (YR101)
n=2: 5b (YR102)
n=1: 5c (YR103)
n=2: 5d (YR104)
n
n
N
N
COOH
N
N
COOH
O
O
n=1: 5e (YR105)
n=2: 5f (YR106)
n=1: 5g (YR107)
n=2: 5h (YR108)
Ur80
Inactive means there was no activity at 10À6 M, and >10À6 M means
there was slight activity at 10À6 M.
Figure 3. Design of cyclic urea compounds.

M. Kurihara et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4131–4134
4133
energy-minimized structure Am80. YR105 is better
overlapped with Am80 than YR107.
A docking model of YR105 (5e) bound to RARc
(1EXA) was constructed by molecular dynamics (MD)
simulation at high temperature (1000 K) and molecular
mechanics (MM) energy minimization. AMBER* was
used as force field. Calculations were performed by
MacroModel (ver. 6.5 and 8.0).9 YR105 was well fitted
to the cavity of the ligand binding domain (LBD) of
RARc, as shown in Figure 5. The bulky alkylated
phenyl moiety fits well to the hydrophobic region of the
LBD (Trp-227, Phe-230, Leu-268, Phe-304, Leu-307,
Ala-397, Ile-412, Leu-416). The carboxylate group of the
ligand interacted with Arg-278, Ser-289 by hydrogen
bonds.
In conclusion, we have discovered a new class of cyclic
urea compounds that exhibit retinoidal activity.
Figure 4. (A) Superimposition of energy-minimized conformations of
YR105 (green) and Am80 (red). (B) Superimposition of energy-mini-
mized conformations of YR107 (green) and Am80 (red).
Acknowledgements
This work was supported in part by a grant (MF-16)
from the Organization for Pharmaceutical Safety and
Research and by the Budget for Nuclear Research of the
Ministry of Education, Culture, Sports, Science and
Technology, based on the screening and counseling by
the Atomic Energy Commission.
(5f), YR107 (5g) decreased the activity by two orders of
magnitude, compared with YR105.
Figure 4 shows superimposition of the energy-mini-
mized structures of YR105 (5e) and YR107 (5g) on the
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