Synthesis and cytotoxic activities of novel phenacylimidazolium bromides

Article abstract of DOI:10.1016/j.bmcl.2009.02.065

A series of novel phenacylimidazolium derivatives, bearing an aryl or alkyl substituent at position-1 and a phenacyl substituent at position-3 of the imidazole ring, has been prepared and evaluated in vitro against a panel of human tumor cell lines. Phena

Full text of DOI:10.1016/j.bmcl.2009.02.065

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1892–1895
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and cytotoxic activities of novel phenacylimidazolium bromides
a
Xiao-Dong Yang a, , Xiang-Hui Zeng a, , Yan-Li Zhang b, Chen Qing b, , Wen-Jian Song ,
*
Liang Li a, Hong-Bin Zhang a,
*
a Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming 650091, PR China
b Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650031, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel phenacylimidazolium derivatives, bearing an aryl or alkyl substituent at position-1 and a
phenacyl substituent at position-3 of the imidazole ring, has been prepared and evaluated in vitro against
a panel of human tumor cell lines. Phenacylimidazolium bromides bearing a highly sterically hindered
aryl group at position-1 and an electron-rich phenacyl or naphthylacyl substituent at position-3 of imid-
azole ring proved to be more active than imidazolium bromides with other substituted groups. In partic-
Received 5 January 2009
Revised 11 February 2009
Accepted 16 February 2009
Available online 21 February 2009
ular, compound 5j was found to be the most potent compounds with IC50 values lower than 5.0 lM
against 8 strains human tumor cell lines and more active than cisplatin (DDP).
Keywords:
Phenacylimidazolium bromides
Synthesis
Ó 2009 Elsevier Ltd. All rights reserved.
Cytotoxic activities
Structure–activity relationships
Imidazolium salts have attracted considerable interests in re-
cent years for their versatile properties in chemistry and pharma-
cology. They are well-known as room-temperature ionic liquids
that can be used as electrolytes or green solvents because of their
low vapor pressure and wide chemical stability.1 Imidazolium salts
are also used as precursors for stable carbenes with many applica-
tions in organic synthesis.2,3
edge, however, no reports concerning antitumor activity for phena-
cylimidazolium salt was reported.
The present investigation was stimulated by the discovery of
two new imidazolium halides (Fig. 1), 1,3-dibenzyl-4,5-dimethy-
limidazolium chloride (2) and 1,3-dibenzyl-2,4,5-trimethylimi-
dazolium chloride (3), isolated from the roots of Lepidium
meyenii, which showed potent cytotoxic activity against the hu-
man cancer cell lines (UMUC3, PACA2, MDA231, and FDIGROV).14
In our efforts to discover effective ligands for catalytic organic
transformation and active agents toward antitumor activity, we
were particularly interested in the imidazole ring. Our long stand-
ing interest in imidazole has resulted in the synthesis of a number
of imidazolium salts.15 In the present research, we have designed
and synthesized a series of novel imidazolium bromides, bearing
an aryl or alkyl substituent at position-1 and a phenacyl substitu-
ent at position-3 of imidazole ring. The purpose of this study was
to investigate effect of phenacylimidazolium bromides on the anti-
tumor activity, with the ultimate aim of developing novel potent
antitumor agents.
Based on the synthetic method described in our previous
reports,16,17 a number of 1-aryl and 1-alkyl substituted imidazoles
4a–4u were prepared, including a few N-arylimidazoles and
N-alkylimidazoles with highly electron-rich and highly sterically
hindered substituted groups (method A and B, Scheme 1).18
Twenty-one phenacylimidazolium salts were prepared as shown
in Scheme 1. 1-Aryl/alkyl and 3-phenacyl substituted imidazolium
bromides (compounds 5a–5u) were prepared with highly yields by
reaction of 1-aryl or 1-alkyl substituted imidazoles with the
A number of biological activities of imidazolium salts have been
reported including antimicrobial and antifungal (l,3-dialky imidazo-
lium chlorides),4 antitumor (l,3-dialky imidazolium iodides),5
antimuscarinic (1,3-disubstituted imidazolium halides),6 throm-
boxane synthetase inhibition (1,3-disubstituted imidazolium ha-
lides),7 anti-inflammatory (enol betaines of phenacyl halides),8
antiarrhythmic (1,3-disubstituted imidazolium halides),9 and plas-
mid DNA cleavage (monometallic cyclen complexes containing
1,3-disubstituted imidazolium bromides group)10 activity. In 1989,
aseriesofphenacylimidazoliumhalidesweresynthesizedandfound
to possess effective hypoglycemic activity by Dominianni.11 Progly-
cosyn (LY177507, 1, Fig. 1), a representative of these compounds,
stimulates glycogen synthesis and inhibits glucose production from
various substrates in rat hepatocytes.12 Additionally, phenacylimi-
dazolium salts have been used as intermediates in a regiospecific
synthesis of 3-substituted L
-histidines.13 To the best of our knowl-
* Corresponding authors. Tel.: +86 871 5031119; fax: +86 871 5035538 (H.-B.Z.).
E-mail addresses: zhanghbyd@gmail.com, zhanghb@yun.edu.cn (H.-B. Zhang).
These authors contributed equally to this paper.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.065

X.-D. Yang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1892–1895
1893
O
N
N
H3CO
N
N
Cl
2 R = H
3 R = CH3
R
Br
1
Figure 1. Chemical structure of proglycosyn and natural imidazolium chlorides.
corresponding phenacyl bromides in refluxing toluene.19 The
structures and yields of imidazolium halides derivatives were
shown in Scheme 1.
As shown in Table 1, compounds 5a–5c with a tert-butyl substi-
tuent at position-1 or a tert-butylacyl substituent at position-3 of
imidazole ring were almost inactive to all tumor cell lines investi-
The cytotoxic potential of all newly synthesized phenacylimi-
dazolium bromides was evaluated in vitro against a panel of hu-
man tumor cell lines according to procedures described in the
literature.20 The tumor cell line panel consisted of myeloid leukae-
mia (HL-60 and K562), epidermoid carcinoma (A431), ovarian car-
cinoma (Skov-3), gastric carcinoma (MKN-28), liver carcinoma
(SMMC-7721), laryngeal carcinoma (Hep-2), and lung carcinoma
(GLC-15). Cisplatin (DDP) was used as the reference drug. The re-
sults of the cytotoxicity studies were summarized in Table 1
(IC50 value, defined as the concentrations corresponding to 50%
growth inhibition).
gated at the concentration of 200 lM. However, compounds 5d–5h
with other alkyl substituents (adamantyl and phenethyl) at posi-
tion-1 of imidazole ring exhibited moderate cytotoxic activities.
Among them, compound 5f, bearing a naphthylacyl substituent
at position-3 of imidazole, was the most active.
Compared with above alkyl substituted derivatives, 1- and
3-aromatic substituted imidazolium bromides 5e–5u exhibited
higher cytotoxic activities. Most of this kind of derivatives showed
remarkable activities. Compounds 5j, 5n, 5o, and 5s, bearing a
highly sterically hindered alkyl substituted benzene (2,4,6-trim-
ethylbenzene or 2,6-diisopropylbenzene) at position-1 and an elec-
Synthesis of 1-substituted imidazoles
R2
R2
R2
O
R2
R2
R2
O
MeOH
35% Formaldehyde
R1 NH2
+
N
N
NH4Cl, 85% H3PO4
4-8 h
N
R1
O
rt, 16 h
R1
4a~u
Method A
Method B
24-82%
78-85%
R2
R2
R2
NH
CuI (5-20%), K2CO3, Si(OEt)4 ,
200o, 40 min
R2
R1 Br
+
N
N
N
(Microwave irradiation)
R1
4a~u
Synthesis of phenacylimidazolium bromides
R2
R2
O
R2
R2
O
toluene
R1
+
R3
N
N
R3
Br
N
reflux
8-16 h
N
R1
Br
4a~u
5a~u
75-99%
5a
5b
5c
5d
5e
5f
5g
5h
5i
R1=t-C4H9
R1=t-C4H9
R2=H
R2=H
R2=H
R2=H
R2=H
R2=H
R3=C6H5
R3=C6H4(OCH3)-4
R1=C6H2(CH3)3-2,4,6
R1=adamantyl
R3=t-C4H9
R3=C6H5
R1=adamantyl
R3=C6H4(OCH3)-4
R3=2-naphthyl
R3=C6H4(OCH3)-4
R3=2-naphthyl
R3=C6H5
R1=adamantyl
R1=CH2CH2C6H2(OCH3)2-3,4 R2=H
R1=CH2CH2C6H3(OCH3)2-3,4 R2=H
R1=C6H2(CH3)3-2,4,6
R1=C6H2(CH3)3-2,4,6
R1=C6H4(CH2COCH3)-4
R1=C6H4(CH2COCH3)-4
R1=C6H4(NO2)-4
R2=H
R2=H
R2=H
R2=H
R2=H
5j
5k
5l
R3=C6H4(OCH3)-4
R3=C6H5
R3=C6H4(OCH3)-4
5m
R3=C6H4(OCH3)-4
5n
R1=C6H2(CH3)3-2,4,6
R2=H
R3=2-naphthyl
R3=C6H4(OCH3)-4
R3=2-naphthyl
5o
5p
5q
5r
5s
5t
R1=C6H3(i-C3H7)2-2,6
R1=C6H3(i-C3H7)2-2,6
R1=C6H2(CH3)3-2,4,6
R2=H
R2=H
R2=H
R3=C6H3(3-CH2OCH2-4)
R3=C6H3(3-CH2OCH2-4)
R1=C6H3(i-C3H7)2-2,6
R1=C6H2(CH3)3-2,4,6
R1=C6H2(CH3)3-2,4,6
R1=C6H3(i-C3H7)2-2,6
R2=H
R2=CH3 R3=2-naphthyl
R2=H
R2=H
R3=C6H4(Br)-4
R3=C6H4(Br)-4
5u
Scheme 1. Synthesis of phenacylimidazolium bromides 5a–5u.

1894
X.-D. Yang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1892–1895
Table 1
Cytotoxic activities of phenacylimidazolium bromides in vitrob (IC50 Ma)
, l
Compound
HL-60
A431
Skov-3
MKN-28
K562
SMMC-7721
Hep-2
GLC-15
5a
5b
5c
5d
5e
5f
5g
5h
5i
>200
>200
112.6
39.0
14.7
4.2
50.4
54.2
31.3
3.1
>200
66.2
>200
13.3
6.3
>200
>200
191.8
59.3
5.6
>200
>200
>200
197.5
158.1
12.8
>200
85.4
>200
5.0
>200
>200
>200
>200
1.5
>200
>200
154.4
107.9
27.9
7.7
62.3
34.4
16.8
4.7
>200
116.8
132.0
93.4
7.1
>200
178.8
>200
108.0
59.3
0.8
33.4
50.2
>200
2.2
6.4
4.0
3.4
0.8
187.6
75.0
15.6
1.7
37.4
11.0
29.9
1.6
>200
168.8
>200
2.4
62.3
77.2
97.6
1.5
5j
5k
5l
25.8
44.4
8.6
2.8
1.1
1.5
6.1
4.5
4.1
7.0
>200
61.1
26.6
2.1
5.0
1.9
31.5
25.5
3.7
>200
140.1
112.7
8.7
10.0
9.6
85.3
59.6
1.7
>200
16.7
112.6
2.7
2.6
0.4
70.1
12.1
0.2
53.4
91.6
>200
6.8
>200
84.8
41.6
0.7
2.8
3.5
12.3
11.6
1.9
53.5
26.5
97.6
0.4
5.1
6.2
23.5
36.9
4.3
14.5
75.5
4.4
5m
5n
5o
5p
5q
5r
4.2
9.9
14.7
18.2
5.1
10.5
33.5
44.3
9.8
5s
3.9
5t
5u
DDP
13.4
3.8
4.7
5.4
4.6
2.0
33.1
11.3
1.7
76.6
35.3
4.3
21.4
2.8
4.7
23.8
10.9
9.2
22.1
9.2
1.5
36.9
18.4
5.7
a
Cytotoxicity as IC50 for each cell line, is the concentration of compound which reduced by 50% the optical density of treated cells with respect to untreated cells using the
MTT assay.
b
Data represent the mean values of three independent determinations.
R2
R2
O
R3
N
N
R1
Br
R1
=
Alkyl
R2
=
H
>
R3
=
>
CH3
Alkyl
>
>
H3CO
Best
5j
Best
O
N
N
Best Potent Compound
H3CO
Br
Scheme 2. Structure–activity relationship of phenacylimidazolium bromides.
tron-rich phenacyl or naphthylacyl substituent at position-3 of
imidazole ring, displayed potent or similar cytotoxic activity
in vitro compared with DDP. The IC50 values of these compounds
bromides 5j, 5n, 5o, and 5s can be considered promising leads for
further structural modifications guided by the valuable informa-
tion derivable from our detailed SARs.
were lower than 10.0 lM against all of human tumor cell lines
investigated. Interestingly, compound 5j, with a 2,4,6-trimethyl-
benzene at position-1 and a 4-mehtoxyphenacyl substituent at po-
sition-3 of imidazole ring, was found to be the most potent
Acknowledgments
This work was supported by a Grant (706052) from the Founda-
tion of the Chinese Ministry of Education for Fostering Important Sci-
entific Program and a Grant (2007B0006Z) from the Natural Science
Foundation of Yunnan Province, which are gratefully acknowledged.
derivative with IC50 values lower than 5.0 lM against 8 strains hu-
man tumor cell lines and more active than DDP (except against
MKN-28 cell). These results suggested that substitution of the po-
sition-1 with a highly sterically hindered alkyl substituted benzene
and substitution of the position-3 with an electron-rich phenacyl
substituent played a vital role in the modulation of the cytotoxic
activities (Scheme 2).
In conclusion, a number of novel phenacylimidazolium halides
derivatives prepared in this paper proved to be remarkably potent
antitumor activities. Phenacylimidazolium bromides 5j, 5n, 5o,
and 5s, bearing a highly sterically hindered alkyl substituted ben-
zene at position-1 and an electron-rich phenacyl or naphthylacyl
substituent at position-3 of imidazole ring, were found to be the
References and notes
1. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Visser, A. E.; Swatloski, R. P.;
Rogers, R. D. Green Chem. 2002, 2, 1.
2. (a) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46,
2988; (b)N-Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-VCH:
Weinheim, Germany, 2006.
3. (a) Crudden, C. M.; Allen, D. P. Coord. Chem. Rev. 2004, 248, 2247; (b) Peris, E.;
Crabtree, R. H. Coord. Chem. Rev. 2004, 248, 2247; (c) Cesar, V.; Bellemin-
Laponnaz, S.; Gade, L. H. Chem. Soc. Rev. 2004, 33, 619; (d) Hahn, F. E. Angew.
Chem., Int. Ed. 2006, 45, 1384; (e) Diez-Gonzalez, S.; Nolan, S. P. Coord. Chem.
Rev. 2007, 251, 874; (f) Wong, F. T.; Patra, P. K.; Seayad, J.; Zhang, Y.; Ying, J. Y.
Org. Lett. 2008, 10, 2333.
most potent compounds with IC50 values lower than 10.0
lM
against a panel of human tumor cell lines. Therefore, imidazolium

X.-D. Yang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1892–1895
1895
4. (a) Vik, A.; Hedner, E.; Charnock, C.; Tangen, L. W.; Samuelsen, Ø.; Larsson, R.;
Bohlinb, L.; Gundersen, L. L. Bioorg. Med. Chem. 2007, 15, 4016; (b)
Demberelnyamba, D.; Kim, K. S.; Choi, S.; Park, S. Y.; Lee, H.; Kim, C. J.; Yoo, I.
D. Bioorg. Med. Chem. 2004, 12, 853; (c) Pernak, J.; Skrzypzzak, A.; Kucharski, S.;
Krysinski, J. Arch. Pharm. 1984, 317, 430.
5. (a) Fortuna, C. G.; Barresi, V.; Berellini, G.; Musumarra, G. Bioorg. Med. Chem.
2008, 16, 4150; (b) Ballistreri, F. P.; Barresi, V.; Benedetti, P.; Caltabiano, G.;
Fortuna, C. G.; Longo, M. L.; Musumarraa, G. Bioorg. Med. Chem. 2004, 12,
1689.
6. Miyachi, H.; Kiyota, H.; Segawa, M. Bioorg. Med. Chem. Lett. 1999, 9, 3003.
7. Iizuka, K.; Kamijo, T.; Yamamoto, R.; Harada, H. U.S. Patent 4,461,905, 1984.
8. Haugwitz; R. D.; Narayanan; V. L. U.S. Patent 3,852,301, 1974.
9. Lis, R.; Morgan, T. K., Jr.; DeVita, R. J.; Davey, D. D.; Lumman, W. C., Jr.; Wohl, R.
A.; Diamond, J.; Wong, S. S.; Sullivan, M. E. J. Med. Chem. 1987, 30, 696.
10. Li, Q. L.; Huang, J.; Wang, Q.; Jiang, N.; Xia, C. Q.; Lin, H. H.; Wua, J.; Yu, X. Q.
Bioorg. Med. Chem. 2006, 14, 4151.
11. (a) Dominianni, S. J.; Yen, T. T. J. Med. Chem. 1989, 32, 2301; (b) Yen, T. T.;
Dominianni, S. J.; Harris, R. A.; Stephens, T. W. In New Antidiabetic Drugs; Bailey,
C. J., Flatt, P. R., Eds.; Smith-Gordon: London, 1990; pp 245–247.
12. (a) Harris, R. A.; Yamanouchi, K.; Roach, P. J.; Yen, T. T.; Dominianni, S. J.;
Stephens, T. W. J. Biol. Chem. 1989, 264, 14674; (b) Guo, Z.; Wals, P. A.; Katz, J. J.
Biol. Chem. 1991, 266, 22323; (c) Agius, L. Biochem. J. 1997, 325, 667.
13. Chivikas, C. J.; Hodges, J. C. J. Org. Chem. 1987, 52, 3591.
18. General procedure for the preparation of N-arylimidazoles 4a–4u. Method A: see
Ref. 16, yield 4g 80%, 4i 85% and 4n 78%. Method B: see Ref. 17, yield 4a 82%, 4c
60%, 4e 43% and 4m 24%.
19. General procedure for the preparation of phenacylimidazolium bromides 5a–5u. A
mixture of N-arylimidazoles 4a–4u (1 mmol) and phenacyl bromides
(1.2 mmol) was stirred in toluene (10 ml) at reflux for 8–16 h. A white solid
was formed. After completion of the reaction as indicated by TLC, the
precipitate was filtered through
a small pad of Celite, and washed with
toluene (3 Â 10 ml), then dried to afford 5a–5u in 75–99% yields. Pure samples
were obtained after recrystallization from appropriate solvent (acetone or
methanol). Compound 5j: white powder, yield 90%, mp 312–314 °C. ESI-MS m/e
336 [M+1ÀBr]+ (69), 335 [MÀBr]+ (100). IR (KBr) 3423, 3156, 3119, 2954, 2916,
2838, 1693, 1600, 1571, 1512, 1462, 1422, 1244, 1214, 1177, 1113, 1065, 1015,
983, 839, 813, 745, 670 cmÀ1 1H NMR (300 MHz, DMSO-d6) d 9.36 (s, 1H,
.
Himidazole-2), 8.08 (d, 2H, J = 8.7 Hz, PhH), 7.99 (d, 2H, J = 6.5 Hz, Himidazole-4,5),
7.18–7.16 (m, 4H, PhH), 6.09 (s, 2H, PhCOCH2), 3.89 (s, 3H, OCH3), 2.35 (s, 3H,
CH3), 2.08 (s, 6H, 2 Â CH3). 13C NMR (75 MHz, DMSO-d6) d 189.27, 164.17,
140.30, 138.92, 134.27, 131.13, 130.65, 129.26, 126.40, 124.68, 123.38, 114.40,
55.78, 55.41, 20.57, 16.82. HR-ESI-MS m/z Calcd for C21H23BrN2O2 414.0943,
found 414.0912. Compound 5n: white powder, yield 99%, mp 294–296 °C. ESI-
MS m/e 356 [M+1ÀBr]+ (85), 355 [MÀBr]+ (100). IR (KBr) 3418, 3156, 3119,
2954, 2916, 2838, 1693, 1600, 1571, 1512, 1462, 1422, 1364, 1244, 1214, 1177,
1113, 1065, 1015, 983, 861, 839, 812, 745, 670 cmÀ1 1H NMR (300 MHz,
.
14. Cui, B.; Zheng, B. L.; He, K.; Zheng, Q. Y. J. Nat. Prod. 2003, 66, 1101.
15. (a) Zhao, Y. H.; Zhou, Y. Y.; Ma, D. D.; Liu, J. P.; Li, L.; Zhang, T. Y.; Zhang, H. B.
Org. Biomol. Chem. 2003, 1, 1643; (b) Liu, J. P.; Zhao, Y. H.; Zhou, Y. Y.; Li, L.;
Zhang, T. Y.; Zhang, H. B. Org. Biomol. Chem. 2003, 1, 3227; (c) Zhang, T. Y.;
Zhang, H. B. Tetrahedron Lett. 2002, 43, 193; (d) Zhang, H. B.; Yang, X. D.; Qing,
C.; Liu, Y. L.; Li, L.; Liu, J. P. Chin. Patent ZL200610011025.7, 2008.
16. Yang, X. D.; Li, L.; Zhang, H. B. Helv. Chim. Acta 2008, 91, 1435.
17. (a) Liu, J. P.; Chen, J. B.; Zhou, Y. Y.; Li, L.; Zhang, H. B. Synthesis 2003,
2661; (b) Liu, J. P.; Ren, Z. Y.; Zhou, Y. Y.; Zhang, H. B. Chin. J. Org. Chem.
2004, 24, 1091.
DMSO-d6) d 9.42 (s, 1H, Himidazole-2), 8.86 (s, 1H, Himidazole-5), 8.23–8.03 (m, 6H,
PhH and Himidazole-4), 7.79–7.69 (m, 2H, PhH), 7.19 (s, 2H, PhH), 6.29 (s, 2H,
PhCOCH2), 2.36 (s, 3H, CH3), 2.11 (s, 6H, 2 Â CH3). 13C NMR (75 MHz, DMSO-d6)
d
191.44, 140.71, 139.40, 135.95, 134.68, 132.43, 131.54, 131.28, 131.07,
129.68, 129.21, 128.26, 127.77, 125.12, 123.87, 123.59, 56.29, 20.99, 17.27. HR-
ESI-MS m/z Calcd for C24H23BrN2O 434.0994, found 434.0992.
20. (a) Kim, D.-K.; Ryu, D. H.; Lee, J. Y.; Lee, N.; Kim, Y.-W.; Kim, J.-S.; Chang, K.; Im,
G.-J.; Kim, T.-K.; Choi, W.-S. J. Med. Chem. 2001, 44, 1594; (b) Cao, R.; Chen, Q.;
Hou, X.; Chen, H.; Guan, H.; Ma, Y.; Peng, W.; Xu, A. Bioorg. Med. Chem. 2004, 12,
4613.