G Model
CCLET-2599; No. of Pages 4
Chinese Chemical Letters
Original article
Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone
derivatives as anti-tumor agents§
b
a,
You-An Xiao a,b, Zhi-Qiang Wang b,c, Xue-Min Wang b, Yi Hui b, Yong Ling b, , Xin-Yang Wang , Li-Qin He
*
*
a Anhui University of Traditional Chinese Medicine, Anhui Key Laboratory of Modernized Chinese Material Medical, Hefei 230031, China
b Medical College, Nantong University, Nantong 226001, China
c Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Novel 2-aminoimidazolone derivatives were synthesized. Most compounds displayed strong anticancer
Received 13 March 2013
Received in revised form 15 April 2013
Accepted 26 April 2013
Available online xxx
activities against human carcinoma cells in vitro. Compounds 8a, 8b and 8j exhibited optimal activity
superior to 5-FU in most cancer cells tested. Especially, the IC50s of 8b (12.6–21.5
mmol/L) against five
tumor cells were 1–4 fold less than those of 5-FU (18.4–56.1 mol/L) in vitro. Furthermore, compound 8b
m
could induce SMMC-7721 cell apoptosis in a dose-dependent manner. Therefore, our novel findings may
provide a new framework for the design of new 2-aminoimidazolone derivatives for the treatment of
Keywords:
cancer.
Synthesis
ß 2013 Li-Qin He and Yong Ling. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
2-Aminoimidazolone
Anti-tumor agents
Cytotoxic activities
Cell apoptosis
rights reserved.
1. Introduction
It is reported that the small size and high electronegativity of
the fluorine atom often result in improved therapeutic drugs [11],
Cancer became the leading cause of mortality worldwide in
2010, and cancer cases are expected to double by 2020 [1]. Natural
products are a rich source for current clinical antitumor drugs and
further discovery of new drugs related to cancer [2]. Clinically
useful, novel and structurally diverse metabolites from marine
organisms display a wide variety of significant biological activity
[3,4]. For example, polyandrocarpamines A and B, extracted from a
Fijian ascidian [5], have been assessed for inhibition of human
tumor cells [6]. Dispacamide, separated from varieties of Carribean
Agelas sponges, shows potent antihistamine activity [7], and
Leucettamine B, isolated from the sponge Leucetta microraphis
Haeckel (alcarea class) of the Argulpelu Reef in Palau, mediates
inflammation (see Fig. 1) [8].
and introducing fluorine atoms into drugs can alter the rate and
route of drug metabolism [12]. Further, we found that some
compounds with a difluoromethoxy phenyl group show better
antitumor activity [13]. Meanwhile, for further improvement of
anticancer activity, different substituted alkane amines and
alcohol amines were selected to make further modifications on
the 2-aminoimidazolone core by ammonification. Therefore, 11
novel 2-aminoimidazolone derivatives containing difluoro-
methoxy phenyl group and different substituted amines were
synthesized, and their cytotoxicity and apoptosis effect were
evaluated in vitro with expectation to find better antitumor agents.
Herein, we report the synthesis and biological evaluation of these
compounds.
Interestingly, these natural, marine products share a common
skeletal structure, a 2-aminoimidazolone core. Meanwhile, many
synthetic compounds, which contain the 2-aminoimidazolone
core, were identified to possess anticancer activities [9,10].
Unfortunately, their antitumor activity is limited. Therefore,
development of new 2-aminoimidazolone derivatives with potent
anticancer activity should be of great significance.
2. Experimental
The synthesis of 8a–k is described in Scheme 1. The starting
material, vanillin 1, was etherified with CHClF2 to get 4-
(difluoromethoxy)-3-methoxybenzaldehyde 2 in 84.4% yields.
Then, compound 2 was transformed to 4-(difluoromethoxy)-3-
hydroxylbenzaldehyde 3 by demethylation with N-methyl-2-
pyrrolidone (NMP) with a yield of 88.3%. The glycine 4 was
treated with NH4SCN in the presence of acetic anhydride to give 1-
acetyl-2-thioxoimidazolidin-4-one 5 by cyclization under micro-
wave condition in 84.7% yield. The intermediate 3 was reacted
with 5 to form 5-(4-(difluoromethoxy)-3-hydroxybenzylidene)-2-
§
Comment: Compounds with potent anti-tumor activities were discovered,
which may induce cancer cell apoptosis in a dose-dependent manner.
* Corresponding authors.
1001-8417/$ – see front matter ß 2013 Li-Qin He and Yong Ling. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: Y.-A. Xiao, et al., Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives