Synthesis of novel benzo[ b ]furans and benzo[ b ]thiophenes: Analogs of combretastatin and resveratrol

Article abstract of DOI:10.1515/HC.2010.003

A rapid and efficient synthesis of fused polyphenolic/polymethoxy benzofurans and benzothiophenes that have potential as antitumor agents and components of anti-HIV combination therapy has been achieved.

Full text of DOI:10.1515/HC.2010.003

Heterocycl. Commun., Vol. 16(4-6), pp. 241–244, 2010 • Copyright © by Walter de Gruyter • Berlin • New York. DOI 10.1515/HC.2010.003
Synthesis of novel benzo[b]furans and benzo[b]thiophenes:
analogs of combretastatin and resveratrol
There is also much interest in the hydroxylated trans-
stilbenes, such as resveratrol, which have a wide range of
potential therapeutic uses in experimental systems such
as anti-aging, anti-HIV and cancer chemoprevention.
Resveratrol produces a cascade of events resulting from a
broad range of cellular targets including oxidative pathways
(Xia et al., 2010), ribonucleotide reductase (Fontecave et
al., 1998), SIRT1 (Baur and Sinclair, 2006), glycosylation
(Zhang et al., 2010), and cholesterol synthesis (Macarulla
et al., 2009). We recently reported that combination of the
ribonucleotide reductase inhibitor gemcitabine with decit-
abine results in potent inhibition of HIV replication in
cell culture (Clouser et al., 2010) and have recently dem-
onstrated that combination of resveratrol and decitabine
also has anti-HIV activity (Chauhan and Patterson, unpub-
lished). Here, we report the synthesis of benzo[b]furan and
benzo[b]thiophene hydroxylated stilbene derivatives that
could serve as either anticancer agents or components of
HIV combination therapy with decitabine.
Jay Chauhan, Alexandre R. Monteil and Steven
E. Patterson*
Center for Drug Design, Academic Health Center,
University of Minnesota, 516 Delaware St SE,
Minneapolis, MS 55455, USA
*Corresponding author
e-mail: Patte219@umn.edu
Abstract
A rapid and efficient synthesis of fused polyphenolic/
polymethoxy benzofurans and benzothiophenes that have po-
tential as antitumor agents and components of anti-HIV com-
bination therapy has been achieved.
Keywords: benzofuran; benzothiophene; cancer;
combretastatin; HIV; polyphenol; resveratrol.
Introduction
Results and discussion
The potent antineoplastic drug combretastatin A4 and its
phosphate prodrug have generated much recent interest
owing, at least in part, to their dual function as anti-angiogen-
esis and antimitotic agents (Cirla and Mann, 2003; Siemann
et al., 2009). Combretastatin A4 has therefore recently served
as a lead molecule for generation of a large number of ana-
logs as potential anticancer agents (Odlo et al., 2008, 2010;
Ducki et al., 2009a,b; Liu et al., 2009; Schobert et al., 2009,
2010; Biersack et al., 2010a,b; Brachet et al., 2010; Chen et
al., 2010; Lee et al., 2010; Lorion et al., 2010; Ty et al., 2010;
Zoldakova et al., 2010). SAR studies have demonstrated that
the cisoid conformation and the 3,4,5-trimethoxyphenyl moi-
ety (ring A) are required for potent activity (Cirla and Mann,
2003; Hsieh et al., 2005; Hu et al., 2006).
Synthesis of the target molecules was performed by treatment
of commercially available benzofuran (1) and benzothio-
phene (2) with bromine to yield 2,3-dibromoheteraromatics
3 and 4, respectively (Hussain et al., 2009a,b) (Scheme 1).
Monocoupling under Suzuki-Miyaura conditions with 3,5-
dimethoxyphenylboronic acid was highly selective for the
2-position (Heynderickx et al., 2002; Hung et al., 2010),
providing 5a and 6a, followed by a second coupling of the
remaining aryl bromide with 4-methoxyphenylboronic acid
to give oxygen and sulfur derivatives 7a and 8a. Finally,
global deprotection of the methoxy groups was achieved by
treatment with boron tribromide (Roberti et al., 2006) to give
2,3-diphenylheteroaryl analogs 9a and 10a, accordingly. In a
similar manner, regioisomers 9b and 10b of compounds 9a
and 10a were also synthesized by inverting the order of the
boronic acid coupling partner in the established route. Thus,
coupling with 4-methoxyphenylboronic acid followed by a
second coupling with 3,5-dimethoxyphenylboronic acid and
standard deprotection (Roberti et al., 2006) gave regioiso-
meric resveratrol analogs 9b and 10b, respectively.
OH
MeO
MeO
A
B
OH
OMe
OH
OMe
HO
Combretastatin A4
Resveratrol
SAR studies have shown that a 3,5-dimethoxy motif in
resveratrol derivatives (Fulda, 2010) and a 3,4,5-trimethoxy
motif in combretastatin (Cirla and Mann, 2003; Hsieh et al.,
2005; Hu et al., 2006) was found to be essential for potent pro-
apoptotic activity. Thus, compounds 7c, 8c and their regio-
isomers 7d, 8d were synthesized employing a similar strategy
to that shown above. In conclusion, we have synthesized 12
R2
X
R1
X=O, Benzo[b]furans
X=S, Benzo[b]thiophenes
R1=R2=OMe, OH
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242 J. Chauhan et al.
R1
R3
(HO)2B
R2
Br
Br
Br
Br2
R1
R2
X
X
X
Pd(PPh3)4
2M Na2CO3
1, X=O
2, X=S
3, X=O
4, X=S
5a-c, X=O
6a-c, X=S
R3
R4
toluene, reflux
R4
R6
R4
R5
R5
(HO)2B
R5
R6
R6
1M BBr3
DCM
R1
R1
R2
X
X
Pd(PPh3)4
7a-d, X=O
8a-d, X=S
R2
9a,b, X=O
10a,b, X=S
2M Na2CO3
toluene, reflux
R3
R3
R1
R2
R3
R4
R5
R6
-
-
-
-
-
-
5a/6a
OMe
H
OMe
H
5b/6b
5c/6c
7a/8a
7b/8b
7c/8c
7d/8d
9a/10a
9b/10b
H
OMe
OMe OMe OMe
OMe
H
H
OMe
H
H
OMe
H
H
OMe
OMe
OMe
OMe
OMe
OMe OMe OMe
H
OMe
OH
H
H
H
OMe
OH
H
OMe OMe OMe
H
OH
H
H
OH
OH
OH
Scheme 1 Synthesis of the title compounds.
column chromatography (hexane/EtOAc) to produce the desired
compounds.
resveratrol/combretastatin analogs (compounds 7–10) that
feature either a benzo[b]furan or benzo[b]thiophene back-
bone. The biological activity of these individual compounds
and their combination with decitabine will be reported in due
course.
General procedure for methoxy group deprotection
Protected aryl (1.0 mmol) was dissolved in anhydrous CH2Cl2
(10 ml). Boron tribromide (1 m in CH2Cl2, 3.2 mmol) was added to
the solution at -78°C and the resulting mixture was allowed to warm
to room temperature and stirred for 20 h. The solution was poured
into H2O (20 ml) and the two phases were separated. The aqueous
layer was extracted with CH2Cl2 (2×10 ml), and the organic portions
combined and washed with 1 m sodium thiosulfate (10 ml), followed
by H2O (10 ml). The organic portion was dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (hexane/EtOAc) to produce the desired compound.
Experimental
1H NMR and 13C NMR spectra were recorded using a Varian
Unity Plus 600 MHz NMR (Varian, Inc., Santa Clara, CA, USA).
High resolution mass spectra were acquired on an Agilent
G1969-TOF system (Agilent Technologies, Inc., Palo Alto, CA,
USA).
General procedure for Suzuki-Miyaura coupling
Representative data for the synthesis of
compound 10b
Aryl halide (2.00 mmol) and boronic acid (1.2 equiv., 2.40 mmol)
were dissolved in toluene/ethanol (10: 3/20 ml). Aqueous Na2CO3
(2 m, 3 equiv.) was added and the resulting mixture was deoxygen-
ated with a stream of argon. After 10 min, Pd(PPh3)4 (5 mol%) was
added and the reaction mixture was heated to reflux for 6 h. After
cooling, the reaction mixture was quenched with sat. NH4Cl (3 ml)
and partitioned between EtOAc (50 ml) and H2O (20 ml). The aque-
ous phase was extracted with EtOAc (3×20 ml) and the organic
portions combined, washed with H2O (20 ml), sat. NaCl (20 ml),
dried (Na2SO4) and reduced in vacuo. The residue was purified by
6b; 1H NMR (CDCl3) δ 7.81 (1 H, d, J=8.0, Ar), 7.73 (1 H, d, J=8.0,
Ar), 7.67 (2 H, d, J=8.5, Ar), 7.42 (1 H, t, J=7.6, Ar), 7.33 (1 H, t,
J=7.6, Ar), 6.96 (2 H, d, J=8.5, Ar), 3.80 (3 H, s, OMe). 13C NMR
(CDCl3) δ 160.3, 139.5, 138.4, 137.7, 131.2, 125.6, 125.5, 125.4,
123.3, 122.4, 114.3, 104.5, 55.6.
8b; 1H NMR (CDCl3) δ 7.83 (1 H, d, J=9.1, Ar), 7.62 (1 H, d, J=9.1,
Ar), 7.41–7.26 (4 H, m, Ar), 6.79 (2 H, d, J=8.6, Ar), 6.49 (2 H, d,
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Synthesis of novel benzo[b]furans and benzo[b]thiophenes 243
J=1.7, Ar), 6.47 (1 H, t, J=1.7, Ar), 3.77 (3 H, s, OMe), 3.71 (6 H,
s, 2×OMe). 13C NMR (CDCl3) δ 161.2, 159.5, 141.1, 139.7, 138.7,
137.9, 132.4, 130.9, 126.8, 124.7, 124.5, 123.4, 122.2, 114.1, 108.6,
105.8, 100.0, 55.6.
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1
10b; H NMR (acetone-d6) δ 8.62 (1 H, s, OH), 8.34 (2 H, s, OH),
7.91 (1 H, d, J=9.1, Ar), 7.57 (1 H, d, J=9.1, Ar), 7.37–7.32 (2 H, m,
Ar), 7.26 (2 H, d, J=8.4, Ar), 6.79 (2 H, d, J=8.4, Ar), 6.39 (1 H, d,
J=2.1, Ar), 6.31 (2 H, d, J=2.1, Ar). 13C NMR (acetone-d6) δ 159.1,
157.7, 141.4, 139.3, 138.4, 137.8, 132.3, 130.7, 125.6, 124.6, 124.5,
123.2, 122.1, 115.6, 108.9, 102.2; m/z (ESI): 333 (100%, M-H+), 667
(70%, 2M-H+); HRMS: m/z [M-H]+ calc. for C20H13O3S: 333.0591,
found: 333.0586.
Acknowledgements
This research was funded by the Center for Drug Design, the
Academic Health Center, University of Minnesota, MS, USA.
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