Structure-activity relationship study of arylsulfonylimidazolidinones as anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2011.09.025

In an effort to find novel N-arylsulfonylimidazolidinones as highly potent anticancer agent, the structure-activity relationship of ethyl 2-methyl-4-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)phenylcarbamate was explored through synthesis and evaluation of

Full text of DOI:10.1016/j.bmcl.2011.09.025

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6829–6832
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship study of arylsulfonylimidazolidinones
as anticancer agents
Vinay K. Sharma, Ki-Cheul Lee, Eeda Venkateswararao, Cheonik Joo, Min-Seok Kim, Niti Sharma,
⇑
Sang-Hun Jung
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2011
Revised 28 August 2011
Accepted 7 September 2011
Available online 20 September 2011
In an effort to find novel N-arylsulfonylimidazolidinones as highly potent anticancer agent, the structure–
activity relationship of ethyl 2-methyl-4-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)phenylcarbamate
was explored through synthesis and evaluation of in vitro cytotoxicity of its analogs against HCT116,
A549 and NCL-H460 cancer cell lines. Among the synthesized derivatives, the carbamate analogs
(4a–f and 4k–p) exhibited superior cytotoxicity to doxorubicin for all cancer cell lines. The SAR studies
of these derivatives confirm that the intact 4-phenyl-l-benzenesulfonylimidazolidinone has a pivotal role
as a basic pharmacophore and hydrophobic substitutions only at 2-position of 1-aminobenzenesulfonyl
moiety are beneficial for the enhancement of the activity.
Keywords:
Arylsulfonylimidazolidinone
Anticancer activity
Cytotoxicity
Ó 2011 Elsevier Ltd. All rights reserved.
Since the discovery of anticancer drugs, microtubules have
emerged as one of the main anticancer targets for the development
of new chemotherapeutic agents.1,2 Microtubules are hollow tubular
structures found in all eukaryotic cell types which play an important
role in a variety of fundamental cell functions, including sustaining
cell shape, transportation of vesicles and protein complexes, regula-
tion of motility and cell division.2–4 Tubulin, the major protein com-
limidazolidin-2-one (2a), which not only had the best potency
but also a good pharmacological profile.10,11 However, its toxico-
logical profile with dog hampered further development of this
compound (data not published). Afterward, various derivatives of
2a such as 2b,c and 3a,b (2-CH3 and 2-Cl derivatives) (Fig. 1) were
studied for their anti-tumor activity.17 These derivatives displayed
promising in vitro antiproliferative activity with GI50 values in low
micromolar to nanomolar concentration range. In general, we
found good correlation between their inhibition of tubulin poly-
merization and cytotoxicity. Among these derivatives, compounds
ponent of microtubules, exists as a hetero dimer of
and is the target of numerous anti mitotic drugs.5,6Most of these
anti-mitotic drugs interact with the /b-tubulin dimer rather than
a and b-tubulin
a
a
microtubule associated proteins (MAPs ) which participate in micro-
tubule functions. Over a decade, vinca alkaloids, vinblastine, and vin-
cristine, as well as the taxanes such as taxol and taxotere have been
widely used as important chemotherapeutic agents. However, the
mechanism of action and clinical use of all these anti-tubulin agents
are associated with problems of drug resistance, toxicity, and poor
bioavailability.7 Therefore, it is essential to find and develop small
molecular agents which will be effective not only in treating multi-
drug-resistant (MDR) tumors but also inhibiting tubulin
polymerization.
3a,b (inhibition of tubulin polymerization, IC50 = 6.0 and 5.5 lM,
respectively17) not only showed potent in vitro tumor growth
inhibitory activity correlated with the inhibition of tubulin poly-
merization but also maintained their activity against the multi-
drug-resistant cancer cells.17 These results were encouraging for
us to shift our focus to the scaffold 3 for the new and safer analogs
of arylsulfonylimidazolidinones. Therefore, here in the current
studies, we have designed and synthesized a number of analogs
(4a–t) of 3 (Fig. 1) for the evaluation of their in vitro growth inhib-
itory activities against three human cancer cell lines such as hu-
man colon carcinoma (HCT116), and human non-small cell lung
cancer cell lines (A549, and NCI-H460).
Accordingly, we have investigated various derivatives of the
4-phenyl-l(N)-arylsulfonylimidazolidinones 1 (Fig. 1) and some of
them showed potent cytotoxicity against the various cancer cell
lines.8–11 It was revealed that 4-phenyl-l-benzenesulfonylimidazo-
lidinone is the basic scaffold11–16 which is primarily responsible for
the potent anticancer activity. Later, modifications in structure of 1
lead to (S)-1-(1-(4-aminobenzoyl)indolin-6-ylsulfonyl)-4-pheny-
All N-arylsulfonylimidazolidinones 4a–t listed in Table 1 were
prepared as illustrated in Schemes 1 and 2. The compounds 4a–n
were prepared from the substituted anilines 5. Anilines 5 were
acylated with the appropriate acyl chlorides in presence of pyri-
dine at room temperature to give the corresponding compounds
6, which were converted to 7 by the reaction with chlorosulfonic
acid at room temperature. The treatment of 7 with ammonia gas
at room temperature gave the intermediate sulfonamides 8.
⇑
Corresponding author. Tel.: +82 42 821 5939; fax: +82 42 823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.025

6830
V. K. Sharma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6829–6832
O
O
O
O
O
O
O
O
O
R1
S
S
S
N
N
N
HN
HN
HN
N
R
NH
R
O
R2
O
1
2
3
1a (R=H), 1b (R = CH3)
1c (R = OCH3), 1d (R = NHCOCH3)
3a (R1 = CH3, R2 = OEt),
3b (R1 = Cl, R2
4-Aminophenyl
2a (R = C6H4(4-NH2)),
2b (R = Thiophen-2-yl)
=
)
2c (R = CH2-thiophen-2-yl)
O
O
O
S
R2
N
HN
R1
NH
R3
O
R4
4
Fig. 1. Structural modification on diarylsulfonylureas.
Table 1
finally treated with the appropriate acyl chloride or p-nitrobenzoyl
chloride in the presence of pyridine at room temperature to give
4o–q and 4s. Further, the compounds 4q and 4s were transformed
to the corresponding amino compounds 4r and 4t using catalytic
hydrogenation in the presence of Raney-Ni in methanol.
The in vitro cytotoxicity of compounds 4a–t was measured
against human lung carcinoma (A549), human colon cancer (HCT
116) and small lung cancer (NCI-H460) cell lines using MTT
assay.18,19 The results from these tests are shown as IC50 values
in Table 1.
To explore the structure–activity relationship of N-arylsulfony-
limidazolidinone 3, methyl group at 2-position of 1-amino-
benzenesulfonyl moiety in 3a was initially replaced with ethyl
(4a), fluoro (4b) or chloro (4c) groups. The activity was retained
in analogs 4a and 4c and was decreased in case of fluoro analog
4b against all cell lines. This proves that the highly hydrophobic
and relatively large sized substituent at 2-position of 1-amino-
benzenesulfonyl moiety are beneficial for the good activity. There-
fore, in our further experiments, we studied the optimal size of
carbamate moiety at 4a, by keeping ethyl group at the same
position. The methyl (4d), n-propyl (4e), isopropyl (4f) n-butyl
(4g) and isobutyl (4h) carbamate analogs were tested against
A549, HCT 116 and NCI-H460 cell lines. Similar level of activity
was observed for 4d–h compared to the activity of 4a and 3a. Thus,
this indicates that the variation of alkyl moiety in carbamate group
does not cause any change in the activity of 4a.
In vitro cytotoxicity of N-arylsulfonylimidazolidinones 4
R1
R2
R3
R4
IC50
(lM)
a
No.
A549 HCT116 NCl-H460
3a17
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH2CH3
F
H
H
H
H
H
H
H
H
H
H
H
H
H
OEt
OEt
OEt
OEt
0.05
0.06
3.8
0.07
0.07
5.0
0.07
0.07
4.5
Cl
0.02
0.25
0.06
0.06
0.20
0.07
0.10
0.50
0.20
0.20
0.06
0.06
0.20
0.06
0.06
0.30
0.50
0.46
0.35
>10
5.5
0.02
0.30
0.06
0.06
0.20
0.08
0.07
0.30
0.80
0.67
0.30
>10
5.0
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
OMe
OPr-n
OPr-i
OBu-n
OBu-i
NHPr-i
NHcyHex
C6H4(4-NO2) 0.70
C6H4(4-NH2) 0.22
3-CH3 OEt
6-CH3 OEt
0.30
>10
5.0
CH3
CH3 CH3
CH3 Cl
CH3 CH3
CH3 CH3
CH3 Cl
H
H
H
H
H
H
OEt
OEt
6.0
5.5
6.0
C6H4(4-NO2) >10
C6H4(4-NH2) >10
C6H4(4-NO2) >10
C6H4(4-NH2) >10
>10
>10
>10
>10
>10
>10
>10
>10
0.456
4s
4t
CH3 Cl
Doxb
0.477 0.400
a
IC50 values are taken as a mean from three experiments. The SE (standard error)
in all cases is lower than 0.002.
b
Dox: doxorubicin.
In another set of experiments, the isopropylcarbamoylamino 4i
and cyclohexylcarbamoylamino 4j derivatives showed less potent
inhibition than the carbamate analogs. The benzoyl analogs such
as 4k and 4l also showed less inhibition than the carbamates.
However, their activities were still comparable to doxorubicin.
These results supported the importance of carbamate group at
N-arylsulfonylimidazolidinone derivatives.
In addition, the compounds 4m and 4n with extra methyl group
on benzene ring showed totally different behavior towards cancer
cell lines. Introduction of methyl group at 3-position of benzene
ring such as in 4m reduced the activity, whereas introduction at
6-position as in 4n totally abolished the activity. Thus, the
presence of an additional hydrophobic group on benzenesulfonyl
moiety of 4a exerts an adverse effect on the activity.
Another intermediate 9 was prepared using (S)-(+)-2-phenylgly-
cine as reported earlier.17 The reaction of mesylate 9 with various
aryl sulfonamide 8a–k and 8m,n17 in the presence of sodium
hydroxide in DMF–water mixture at 0 °C gave the final compounds
4a–k, 4m,n. The nitro compound 4k was transformed to compound
4l containing terminal amino group using catalytic hydrogenation
in the presence of Raney-Ni in methanol as shown in Scheme 1.
Other final compounds 4o–t were prepared as shown in Scheme
2. Intermediate 10 was synthesized by our previously reported
procedure.8 The reaction of 10 with the appropriate arylsulfonyl
chlorides17 (11o–t) in the presence of sodium bicarbonate in ace-
tone/water (1:1) produced 12. After the removal of the trifluoro-
acetyl group of 12 using sodium hydroxide in aqueous methanol
at room temperature, the resulting imidazolidine 13 was dispersed
in ether and then treated with hydrochloric acid for 3 h at room
temperature to get the compounds 14. The compound 14 was
To explore the influence of substitution at imidazolidinone ring
of 4, a methyl group was introduced at 5-position of imidazolidi-
none as shown in 4o–t. Surprisingly, 4o–t showed very weak inhi-
bition against all cell lines. As compared to 3a, the disappearance of

V. K. Sharma et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6829–6832
6831
O
O
R2
S
R2
R2
Cl
(a)
(b)
NH
NH
NH2
R4
O
R4
O
7
6
5
(c)
O
O
O
N
O
H2NO2S
R2
S
R2
HN
OPh
OMs
R3
(d)
R3
R1
HN
+
NH
R4
NH
O
O
R4
9
4a-k, 4m-n
8
4k
(e)
4l
Scheme 1. Synthesis of N-arylsulfonylimidazolidinones 4a–n. Reagent and conditions: (a) R4COCl, pyridine, CH2Cl2, rt; (b) chlorosulfonic acid, rt; (c) ammonia gas, rt, CH2Cl2;
(d) NaOH, DMF, 0 °C rt; (e) H2 (40–45 psi), Raney-Ni, MeOH, rt.
O
O
O
O
R2
O
O
S
R2
ClO2S
R3
R1
S
R2
N
R3
R1
N
(a)
N
R3
R1
(b)
N
NH
NH
N
NH
+
NH2
O
CF3
O
CF3
O
H3C
13
(c)
12
11
10
O
O
O
O
O
O
S
R2
N
S
R2
R3
R1
N
HN
(d) or (e)
R3
HN
NH
R4
R1
NH2
O
4o-t
14
Scheme 2. Synthesis of N-arylsulfonylimidazolidinones 4o–t. Reagent and conditions: (a) NaHCO3, acetone/H2O, and then arylsulfonyl chloride; (b) NaOH, EtOH, 0 °C; (c) HCl,
ether, rt.; (d) R4COCl, Py, CH2Cl2, rt; (e) (i) p-NO2-BzCl, Py, CH2Cl2, rt; (ii) H2 (40–45 psi), Raney-Ni, MeOH, rt.
activity in 4o–t indicates that the steric congestion at this position
is unfavorable for the activity of 4. Therefore, phenylimidazolidi-
none motif should be the main pharmacophore of 4.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.09.025.
Taken together, the carbamate analogs showed more potent
inhibition than the carbamoyl group. On increasing the alkyl chain
length at carbamate moiety the activity was not altered. The
substitution of more hydrophobic halogen at 2-position of 1-amino-
benzenesulfonyl moiety showed good effect on the activity of the
N-arylsulfonylimidazolidinones 4. In addition, the presence of
extra methyl group at 3 or 6-position on benzenesulfonyl moiety
of 4a decreases the activity. Therefore, on the basis of our previ-
ous17,20 and current studies, we can conclude that the structural
requirements of N-arylsulfonylimidazolones analogs for their cyto-
toxicity against tested cell lines are as follows: (a) pivotal role of
the intact 4-phenyl-l-benzenesulfonylimidazolidinone as a basic
pharmacophore and (b) hydrophobic substitutions only at 2-posi-
tion of 1-aminobenzenesulfonyl moiety are beneficial for the
enhancement of the activity.
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Acknowledgment
This work was supported by Priority Research Centers Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology
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