Bioorganic & Medicinal Chemistry Letters
Synthesis and cytotoxic activity of novel tetrahydrobenzodifuran–
imidazolium salt derivatives
b,
Chao-Bo Zhang a, Yang Liu a, Zheng-Fen Liu a, Sheng-Zu Duan a, Min-Yan Li c, Wen Chen a, , Yan Li
⇑
⇑
,
Hong-Bin Zhang a, Xiao-Dong Yang a,
⇑
a Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650091, PR China
b State Key Laboratory for Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming 650204, PR China
c Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, United States
a r t i c l e i n f o
a b s t r a c t
The synthesis of a series of novel 4-substituted 2,3,6,7-tetrahydrobenzo [1,2-b;4,5-b0]difuran–1H-imida-
zolium salts is presented. The biological properties of the compounds were evaluated in vitro against a
panel of human tumor cell lines. Results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-ben-
zimidazole ring, and substitution of the imidazolyl-3-position with a 2-naphthylmethyl substituent or
2-naphthylacyl substituent, were important to the cytotoxic activity. Notably, 3-(2-Naphthylmethyl)-
1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b0]difuran-4-yl)methyl)-1H-5,6-dimethyl-benzimidazol-3-ium
bromide (42) was found to be the most potent derivative against five human tumor cell lines with IC50
Article history:
Received 25 October 2016
Revised 10 February 2017
Accepted 22 February 2017
Available online xxxx
Keywords:
Tetrahydrobenzodifurans
Imidazolium salts
Cytotoxic activity
Cell cycle
values of 1.06–4.34 lM and more selective towards SMMC-7721, A549 and SW480 cell lines. 3-(2-
Naphthylacyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b0]difuran-4-yl)methyl)-1H-2-methyl-benzimidazol-
3-ium bromide (37) showed higher selectivity to SMMC-7721 and MCF-7 cell lines with IC50 values
2.7-fold and 8.4-fold lower than DDP. Study regarding to the antitumor mechanism of action showed that
compound 37 could induce cell cycle G1 phase arrest and apoptosis in SMMC-7721 cells.
Ó 2017 Elsevier Ltd. All rights reserved.
Apoptosis
Tetrahydrobenzodifurans and dihydrobenzofurans represent as
important classes of biologically active oxygen-containing hetero-
cycles. Naturally occurring compounds and biologically active
agents with dihydrobenzofuran and tetrahydrobenzodifuran
moieties exhibit a wide range of remarkable biological activities,
especially antitumor activity.1 As exemplified in Fig. 1, Megapodiol
with dihydrobenzofuran moiety is an anti-leukaemic agent,2
while Mesocyperusphenol A with tetrahydrobenzodifuran moiety
showed powerful cytotoxic activity against human T-cell leukemia
cells.3 Further study showed that Mesocyperusphenol A was a
potent 5-lipoxygenase inhibitor.4 On the other hand, imidazole
and their derivatives have attracted wide attention due to their
pharmaceutical potential resulting from their significant biological
activities,5 especially antitumor activity.6 For instance, natural imi-
dazolium chlorides Lepidiline A and B (Fig. 1) showed potent cyto-
toxic activity against four human cancer cell lines.7 However, to
the best of our knowledge, no scientific study on the exactly molec-
ular targets of Lepidilines was reported. Considering the value of
imidazolium salts, we have previously reported the synthesis of a
series of novel imidazolium salts, such as NMIB (Fig. 1), and their
potential antitumor activity.8 Further study of molecular mecha-
nisms showed that the imidazolium salt hybrids can induce the
cell cycle arrest and apoptosis in tumor cells.8c,g Studies on
molecular targets demonstrated that the imidazolium salt
hybrids may be the inhibitors of mTOR (mammalian target of
rapamycin) signaling.8i And the docking calculations also
supported this conclusion.8f,i
Molecular hybridization is a useful strategy in new drug design
and development during the past two decades.9 Considering the
anticancer activities of tetrahydrobenzodifuran, as well as the
potent cytotoxic activities of imidazole derivatives, we are inter-
ested in the preparation of the hybridizing compounds of 4-substi-
tuted 2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b0]difuran with imidazole
moieties. During the past several years, some anticancer agents
based on imidazolium salts were reported.8,10 To the best of
our knowledge, no reports concerning antitumor activity of
4-substituted 2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b0]difuran–imida-
zole hybrids could be found in the literature.
⇑
Corresponding authors.
Herein, a series of novel 4-substituted 2,3,6,7-tetrahydrobenzo
[1,2-b;4,5-b0] difuran imidazolium salts were synthesized to
0960-894X/Ó 2017 Elsevier Ltd. All rights reserved.