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Synthesis and Anti-proliferative in-vitro Activity of Two Natural Dihydrostilbenes and their Analogues.

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244
Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
Full Paper
Synthesis and Anti-proliferative in-vitro Activity of Two Natural
Dihydrostilbenes and their Analogues
Wei-Ge Zhang1,3, Rui Zhao1, Jian Ren1, Li-Xiang Ren2, Jin-Guang Lin1, Dai-Lin Liu3,
Ying-Liang Wu2, and Xin-Sheng Yao3
1
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, P. R. China
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, P. R. China
3
Shenzhen Keylab for Research and Development of New Drugs, Shenzhen, P. R. China
2
A total synthetic route for two natural dihydrostilbenes with significant cytotoxicity toward
human cancer cell lines, (3-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)phenol 1a and 6-(3-hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol 1b), which were isolated from Bulbophyllum odoratissimum
Lindl, was developed via Wittig–Horner reaction. The natural products 1a and 1b were obtained
in 28% and 20% overall yield, respectively. Additionally, nine analogues, 1c-1k, of the two natural dihydrostilbenes were synthesized and evaluated for their anti-proliferative activity against
human SGC-7901, KB and HT-1080 cell lines by MTT assay. The activities of 1c and 1d were in the
same range as those of the natural products 1a and 1b.
Keywords: Anti-proliferative activity / Natural dihydrostilbene / Total synthesis /
Received: September 12, 2006; accepted: November 7, 2006
DOI 10.1002/ardp.200600146
Introduction
Stilbenoids, such as dihydrostilbenes, stilbenes, phenanthrenes, and their oligomers, constitute an important
class of natural products, which attract increasing interest chiefly due to their various pharmacological effects,
for instance, anti-oxidant activity [1], cancer chemopreventive effect [2], anti-tumor activity [3], inhibition of
cyclooxygenase [4], inhibition of platelet aggregation [5].
In addition, some synthetic dihydrostilbenes, known as
the analogues of combretastatin A-4, were found to be
tubulin polymerization inhibitors and display strong
anti-mitotic activity to a broad spectrum of human cancer lines [6].
In our effort to search for naturally-occurring cytotoxic
agents present in traditional Chinese medicines using
the Pyricularia oryzae bioassay [7], a set of dihydrostilbenes, including 3-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-
Correspondence: Wei-Ge Zhang, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe
District Shenyang 110016, P. R. China
E-mail: zhangweige2000@sina.com
Fax: +86 24 23986393
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 1. Structures of two natural dihydrostilbenes and their
analogues.
ethyl)phenol 1a and 6-(3-hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol 1b (Fig. 1), were obtained from Bulbophyllum
odoratissimum Lindl, a folk herb for the treatment of
phthisis and rheumatism in the southern part of China
Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
Natural Dihydrostilbenes and Their Analogues
245
Reagents and conditions: a) CH3OH, H2SO4, reflux, 12 h; b) PhCH2Cl, K2CO3, DMF, 608C, 16 h; c) NaBH4, I2, THF, 08C,
2 h, then 708C, 6 h; d) KMnO4, ZrOCl268 H2O, THF, rt, ultrasound irradiation, 10 h; e) (CH3O)2SO2 or PhCH2Cl,
Na2B4O7610 H2O, rt, overnight; f) CH2Cl2, K2CO3, DMF, reflux, 4 h; g) NaBH4, I2, THF, 08C, 2 h, then 708C, 8 h; h) SOCl2,
N(C2H5)3, ClCH2CH2Cl, rt, 6 h; i) P(OC2H5)3, 1408C, 8 h; j) aldehyde 5, NaH, DMF, 08C, 1 h, rt, 6 h; k) H2, Pd-C, EtOAc, rt,
48 h.
Scheme 1. Synthesis route of natural dihydrostilbene compounds 1a, b.
[8]. Compound 1a is a new natural product firstly found
in our laboratory, which demonstrates significant cytotoxic activity [9]. Although compound 1b had also been
isolated from the orchid Cirrhopetalum andersonii [10], the
total synthesis and bioactivity of 1b, to our knowledge,
have not been reported yet.
For the purpose of searching for new antitumor agents
and understanding their structure-activity relationships,
we developed a general synthetic route to the two natural dihydrostilbenes 1a, 1b and their analogues 1c – 1k
(Fig. 1) and preliminarily evaluated in vitro the anti-proliferative activity of all synthesized compounds.
Results and discussion
The first aim of our present work was the total synthesis
of the natural dihydrostilbenes 1a and 1b. Retro-synthetic analysis of 1a and 1b led to 3-hydroxybenzoic acid
and methyl 3,4,5-trihydroxybenzoate, while our general
approach to the total synthesis of these compounds is
described in Scheme 1.
Aldehyde 5 was viewed as the requisite intermediate
for the total synthesis of the natural dihydrostilbenes 1a
and 1b. The commercially available and cheap 3-hydroxy-
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
benzoic acid was used as starting material, which was
treated with CH3OH/H2SO4 to give benzoic ester 2. The mOH group of 2 was protected with benzyl chloride to yield
3. Employing NaBH4/I2 as a safe and inexpensive reducing
agent [11] to replace LiAlH4, we got 4 in 88.9% yield. Since
KMnO4/ZrOCl268 H2O had been proven to be efficient for
the highly selective oxidation of primary benzylic alcohols to the corresponding aldehyde [12], we obtained
aldehyde 5 in 96.3% yield by treatment of 4 with this new
oxidant in diethyl ether at room temperature for 36 h. As
this oxidation is a liquid-solid biphasic process, we considered that ultrasound should promote this reaction,
and this assumption was readily proven valid by experiment. Thus, when we carried out this reaction for 8 h
under ultrasound irradiation, the desired aldehyde 5 was
obtained in 98.5% yield.
Following the reported methodologies [13] with slight
modifications, compound 7a and 7b were prepared in
73.3 and 49.1%, respectively, via mono-alkylation of mOH of methyl 3,4,5-trihydroxybenzoate and cyclization
by treatment with CH2Cl2 and K2CO3 in DMF. The resultant esters were subjected to reduction with NaBH4/I2 to
provide benzyl alcohol 8a and 8b in 89.3 and 86.7% yield,
which were treated with SOCl2 and Et3N to form benzyl
chloride 9a and 9b in 96.7 and 95.5% yield, respectively.
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W.-G. Zhang et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
Reagents and conditions: l) NaH, DMF, 08C, 1 h, rt, 6 h; m) H2, Pd-C, EtOAc, rt, 48 h.
Scheme 2. Synthesis of dihydrostilbene analogues 1c – 1k.
Further, Michaelis-Arbuzov reaction of 9a and 9b with
P(OEt)3 provided 10a and 10b, both of which could be
used directly in the next step. Phosphite 10a and 10b
were treated with NaH in DMF, followed by addition of
aldehyde 5 to afford the trans-stilbenes 10a and 10b by
Wittig-Horner reaction in 47.3 and 51.1% yield, respectively. Catalytic hydrogenation of 10a and 10b over palladium on carbon provided the natural dihydrostilbenes
1a and 1b in 94.5 and 98.3% yield, resulting from reduction of the double bond and removal of the benzyl protecting group. The synthetic materials 1a and 1b were
identical in 1H-NMR and MS with the samples of the natural products.
Having accomplished the total synthesis of the natural
dihydrostilbenes 1a and 1b, our attention was focused on
the synthesis of their analogues 1c – 1k. This task was
achieved in a two-step reaction sequence similar to the
method described above, which is outlined in Scheme 2.
Wittig-Horner reaction of phosphite 10a or 10b with
diverse aldehydes 12a – 12f provided corresponding transstilbenes 13a – 13i in 46.5 to 55.8% yield, which were converted into dihydrostilbenes 1c – 1k by catalytic hydrogenation in 94.7 to 99.1% yield. The structures of those
dihydrostilbenes 1c – 1k were characterized by the application of MS and 1H-NMR.
The anti-proliferative activity of all obtained compounds was assessed in vitro against three human cancer
cell lines, SGC-7901 gastric carcinoma, KB nasopharyngeal carcinoma, and HT-1080 fibrosarcoma, by colorimetric MTT assay using cisplatin as positive control and
expressed as IC50 values. IC50 is the concentration (lM)
required to inhibit tumor cell proliferation by 50% after
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Table 1. Anti-proliferative activity in vitro of the natural dihydrostilbenes 1a, 1b, and their analogs 1c – 1k against three human
cancer cell lines.
Compounds
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
Cisplatin
IC50 (lM)
SGC-7901
KB
HT-1080
8.30
9.20
7.30
9.90
A 100
60.5
A 100
A 100
A 100
A 100
A 100
9.48
5.50
8.70
4.20
8.50
A 100
A 100
A 100
>100
87.5
A 100
49.4
1.46
25.5
40.0
37.9
43.3
89.3
87.7
A 100
A 100
A 100
A 100
54.7
21.3
24 h of exposure of the cells to a tested compound. The
measured IC50 values for the natural dihydrostilbenes 1a,
1b, and their analogues 1c – 1k are summarized in
Table 1.
As can be seen from the presented data, natural dihydrostilbenes 1a, 1b and their analogues 1c, 1d were found
to have significant anti-proliferative activity, which IC50
values against SGC-7901 and KB cell lines were smaller
than 10.0 lM. Conversion of the m-OMe (1a and 1c) to a
hydrophilic m-OH group on the ring A (1b and 1d) caused
a 1.6 to 2.0-fold decrease in inhibition of the growth of KB
cell, and there was only a slight reduction in inhibitory
activity against SGC-7901 and HT-1080 cell lines. Removal
of the hydroxyl group at the m-position on the ring A of
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Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
1a or 1b and replacement with an amino group, to afford
its derivative 1c or 1d, resulted in a slight increase in the
activity against all three cell lines. The introduction of
–OH, –F, –OCH3, or –N(CH3)2 at the p-position on the ring
B, along with the removal of the hydroxyl or amino
group at the m-position on the ring B, almost eliminated
growth inhibition activity. Furthermore, it is clear that
activity of the natural dihydrostilbenes and their analogues against SGC-7901 and KB cell lines is generally
higher than that against the HT-1080 cell line.
In summary, the first total synthesis of two natural
dihydrostilbenes, 3-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)phenol 1a and 6-(3-hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol 1b, had thus been achieved in 28.3 and 20.4%
overall yield, respectively. In addition, nine analogues of
1a and 1b were prepared and tested for their anti-proliferative activity against SGC-7901, KB, and HT-1080 cell
lines using MTT assay. Among the analogues synthesized,
1c and 1d bearing an amino moiety in place of the phenolic OH of the natural products 1a and 1b showed significant anti-proliferative activity against SGC-7901 and KB
cell lines (IC50 a 10.0 lM), while the cytotoxicity of other
analogues was markedly reduced with respect to all three
cell lines.
Natural Dihydrostilbenes and Their Analogues
247
was poured into ice water (500 mL). After filtration and washing
with water, the crude product was purified by column chromatography (n-hexane : EtOAc = 3 : 1) to give 3 (39.1 g, 89.6% from mhydroxybenzoic acid) as a white solid: mp 74 – 768C; 1H-NMR
(400 MHz, CDCl3) d: 3.95 (3H, s), 5.12 (2H, s), 7.19 (1H, m), 7.34 –
7.48 (6H, m), 7.67 (2H, m) [14].
(3-(Benzyloxy)phenyl)methanol 4
To a suspension of compound 3 (24.2 g, 0.100 mol) and NaBH4
(9.0 g, 0.235 mol) in dry THF (300 mL) was added a solution of I2
(25.4 g, 0.100 mol) in dry THF (200 mL) over 2 h at 08C under
nitrogen atmosphere. The mixture was stirred at 708C for 6 h,
and then concentrated in vacuo. The residue was dissolved in
EtOAc (500 mL), and the resulting solution was washed with
water, dried over anhydrous Na2SO4, and evaporated. The crude
product was purified by column chromatography (n-hexane :
EtOAc = 3 : 1) to give 4 (19.0 g, 88.9%) as a white solid: mp 46 –
488C; 1H-NMR (300 MHz, CDCl3) d: 4.65 (2H, s), 5.06 (2H, s), 6.89 –
7.01 (3H, m), 7.24 – 7.41 (6H, m) [15].
3-(Benzyloxy)benzaldehyde 5
A mixture of 4 (15.2 g, 0.071 mol), KMnO4 (33.7 g, 0.213 mol) and
ZrOCl268 H2O (6.75 g, 0.021 mol) in THF (300 mL) was treated
under ultrasound irradiation for 8 h at room temperature. After
filtration, the filter cake was washed with EtOAc. The filtrate
was concentrated in vacuo and purified by column chromatography (n-hexane : EtOAc = 3 : 1) to give 5 (14.8 g, 98.5%) as a white
solid: mp 57 – 588C (56 – 588C) [16].
Methyl-3,4-dihydroxy-5-methoxybenzoate 6a
Experimental
Melting points for the compounds were determined using a hotstage microscope and are uncorrected. 1H- and 13C-NMR spectra
were taken in CDCl3 or DMSO-d6 solution on Bruker AVANCE400, Bruker ARX-300 or Bruker ARX-600 spectrometers with TMS
as the internal reference (Bruker BioSciences, USA). MS spectra
were obtained using Bruker Esqure 2000 or Shimadzu GCMSQP5050A spectrometers (Shimadzu, Japan). Elemental analyses
(C, H, and N) were performed by Jilin University (Changchun,
China). Column chromatography was run on silica gel (200 – 300
mesh) from Qingdao Ocean Chemicals (Qingdao, Shandong,
China). Unless otherwise noted, all the materials were obtained
from commercially available sources and were used without
further purification.
Chemistry
Methyl-3-hydroxybenzoate 2 and Methyl-3(benzyloxy)benzoate 3
To a solution of 3-hydroxybenzoic acid (25.0 g, 0.180 mol) in
CH3OH (250 mL) conc. H2SO4 (37.5 mL) was added dropwise. The
resulting mixture was refluxed for 12 h. After cooling at room
temperature, the mixture was diluted with water, extracted
with EtOAc, and the organic layer was washed with saturated
brine, dried over Na2SO4, filtered, and concentrated to give a
crude product 2 which was used directly for the next step. Benzyl chloride (23.0 mL, 0.20 mol) was added to the suspension of 2
and K2CO3 (37.3 g, 0.27 mol) in DMF (150 mL), then the reaction
mixture was stirred at 608C for 16 h. After cooling, the mixture
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
A solution of NaOH (19.5 g, 0.488 mol) in H2O (75 mL) and
(CH3O)2SO2 (45 mL) were added to a stirred solution of methyl
gallate (15 g, 0.083 mol) and Na2B4O7610 H2O (37.5 g, 0.098 mol)
in H2O (750 mL), and the mixture was stirred overnight at room
temperature. The resulting mixture was then acidified to pH 3 –
4 with 10% H2SO4. The solid was filtered, and the filtrate was
extract with EtOAc. The extract was washed with saturated
brine, dried over anhydrous Na2SO4, and concentrated to give
crude 6a (14.4 g).
Methyl-3-(benzyloxy)-4,5-dihydroxybenzoate 6b
A solution of Na2B4O7610 H2O (160 g, 0.42 mol) in H2O (480 mL)
was added to a stirred suspension of methyl gallate (40 g,
0.22 mol) and K2CO3 (160 g, 1.16 mol) in DMF (320 mL), and the
mixture was stirred for 30 min at room temperature. Then
PhCH2Cl (27.2 mL, 0.22 mol) was added, and the mixture was
stirred overnight at the same temperature. The reaction mixture
was then acidified to pH 3 – 4 with 10% H2SO4, the resulting solid
was filtered, and the filtrate was extracted with EtOAc. The
extract was washed with saturated brine, dried over anhydrous
Na2SO4, and concentrated to give crude 6b (42.3 g).
Methyl-7-methoxybenzo[d][1,3]dioxole-5-carboxylate 7a
To a suspension of CH2Cl2 (6.95 mL, 0.108 mol) and K2CO3 (19.9 g,
0.144 mol) in DMF (300 mL) was added dropwise a solution of 6a
(14.4 g, 0.0727 mol) in DMF (250 mL) and the mixture was stirred
and heated to reflux for 4 h. The mixture was cooled, then filtered and the filter cake was washed with EtOAc. The filtrate was
washed with water, dried over anhydrous Na2SO4, and evaporated. The crude product was purified by column chromatograwww.archpharm.com
248
W.-G. Zhang et al.
phy (n-hexane : EtOAc = 3 : 1) to give 7a (10.4 g, 59.8% from methyl
gallate) as a white solid: mp 89 – 908C; 1H-NMR (400 MHz, CDCl3)
d: 3.86 (3H, s), 3.88 (3H, s), 6.06 (2H, s), 7.21 (1H, d, J = 1.5Hz), 7.33
(1H, d, J = 1.5 Hz) [17].
Methyl 7-(benzyloxy)benzo[d][1,3]dioxole-5-carboxylate
7b
Compound 7b was prepared from 6b following the procedure
described for 7a and obtained in 49.1% yield (from methyl gallate) as a white solid: mp 78 – 798C; 1H-NMR (400 MHz, CDCl3) d:
3.87 (3H, s), 5.19 (2H, s), 6.04 (2H, s), 7.20 – 7.45 (7H, m); 13C-NMR
(100 MHz, CDCl3) d: 52.1, 71.5, 102.2, 104.3, 112.2, 124.4, 127.7,
128.2, 128.6, 136.2, 139.9, 142.2, 148.9,166.3; MS (ESI) m/z 594.6
[2M + Na+]+, 303.8 [M + NH4+]+, 287.0 [M]+ [17].
(7-Methoxybenzo[d][1,3]dioxol-5-yl)methanol 8a
To a suspension of compound 7a (5.00 g, 23.8 mmol) and NaBH4
(2.16 g, 57.1 mmol) in dry THF (150 mL) was added a solution of
I2 (6.04 g, 23.8 mmol) in dry THF (100 mL) dropwise over 2 h at
08C under nitrogen atmosphere. The mixture was refluxed for
8 h, and then concentrated in vacuo to give the residue which
was dissolved in EtOAc (300 mL), then washed with water, dried
over anhydrous Na2SO4, and evaporated. The crude product was
purified by column chromatography (n-hexane : EtOAc = 3 : 1) to
give 8a (3.87 g, 89.3%) as a white solid: mp 66 – 678C; 1H-NMR
(400 MHz, CDCl3) d: 3.87 (3H, s), 4.52 (2H, brs), 5.93 (2H, s), 6.50
(1H, s), 6.51 (1H, s) [18].
(7-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)methanol 8b
Compound 8b was prepared from 7b as described above for the
preparation of 8a and obtained in 86.7% yield as a white solid:
mp 62 – 648C; 1H-NMR (400 MHz, CDCl3) d: 1.83 (1H, s), 4.51 (2H,
s), 5.16 (2H, s), 5.93 (2H, s), 6.53 (1H, s), 6.58 (1H, s), 7.28 – 7.43 (5H,
m) [19].
6-(Chloromethyl)-4-methoxybenzo[d][1,3]dioxole 9a
To a solution of compound 8a (3.00 g, 16.5 mmol) and Et3N
(2.43 mL, 17.5 mmol) in 1,2-dichloroethane (80 mL) was added
dropwise SOCl2 (1.80 mL, 24.7 mmol) and the mixture was stirred for 6 h at room temperature. The reaction mixture was
washed with 5% Na2CO3, dried over anhydrous Na2SO4, and evaporated. The crude product was purified by column chromatography (n-hexane : EtOAc = 3 : 1) to give 9a (3.21 g, 96.7%) as a
white powder: mp 94 – 968C; 1H-NMR (400 MHz, CDCl3) d: 3.90
(3H, s), 4.43 (2H, s), 5.97 (2H, s), 6.56 (1H, s), 6.58 (1H, s) [20].
4-(Benzyloxy)-6-(chloromethyl)benzo[d][1,3]dioxole 9b
Compound 9b was prepared from 8b in a manner similar to that
described above for 9a and obtained in 95.5% yield as a white
powder: mp 85 – 878C; 1H-NMR (400 MHz, CDCl3) d: 4.44 (2H, s),
5.16 (2H, s), 5.97 (2H, s), 6.57 (1H, s), 6.61 (1H, s), 7.32 – 7.45 (5H,
m).
Diethyl(7-methoxybenzo[d][1,3]dioxol-5yl)methylphosphonate 10a and 6-(3-(Benzyloxy) styryl)-4methoxybenzo[d][1,3]dioxole 11a
A mixture of 9a (0.300 g, 1.50 mmol) and triethyl phosphite
(0.499 g, 3.00 mmol) was refluxed at 1408C for 8 h, then residual
triethyl phosphite was removed in vacuo to give compound 10a.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
To a suspension of NaH (0.240 g, 6.00 mmol) in dry DMF (5 mL)
was added 10a in dry DMF (10 mL) dropwise at 08C under nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h, to which aldehyde 5 (0.318 g, 1.50 mmol) in dry
DMF (5 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 6 h, and then
was poured into ice water (100 mL). After filtration and washing
with water, the crude product was purified by column chromatography (n-hexane : EtOAc = 3 : 1) to give 11a (0.256 g, 47.3%) as a
viscous oil: 1H-NMR (300 MHz, CDCl3) d: 3.97 (3H, s), 5.12 (2H, brs),
6.01 (2H, s), 6.67 (1H, d, J = 1.2Hz), 6.77 (1H, d, J = 1.2Hz), 6.88 –
7.49 (11H, m); MS (EI) m/z 360 [M]+ (34), 91 (100).
Compounds 13a – 13i were prepared as described as described
above for 10a and 11a.
Yields and spectroscopic date of compounds 10b, 11b,
and 13a – 13i
Diethyl(7-(benzyloxy)benzo[d][1,3]dioxol-5yl)methylphosphonate 10b and 4-(Benzyloxy)-6-3(benzyloxy)styryl)benzo[d][1,3]dioxole 11b
Yield 51.1%; mp 105 – 1078C; 1H-NMR (300 MHz, CDCl3) d: 5.10
(2H, s), 5.21 (2H, s), 5.99 (2H, s), 6.69 (1H, d, J = 1.2Hz), 6.75 (1H, d, J
= 1.2Hz), 6.89 – 7.47 (16H, m); MS (EI) m/z 436 [M]+ (25), 91 (100).
4-Methoxy-6-(3-nitrostyryl)benzo[d][1,3]dioxole 13a
Yield 48.5%, oil; 1H-NMR (300 MHz, CDCl3) d: 3.88 (3H, s), 6.01 (2H,
s), 6.74 (1H, d, J = 1.2 Hz), 6.77 (1H, d, J = 1.2Hz), 6.94 (1H, d, J =
16.2 Hz), 7.10 (1H, d, J = 16.2 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.73 (1H,
d, J = 7.8 Hz), 8.11 (1H, s), 8.35 (1H, s); MS (EI) m/z 299 [M]+.
4-(Benzyloxy)-6-(3-nitrostyryl)benzo[d][1,3]dioxole 13b
Yield 50.2%; mp 109 – 1118C; 1H-NMR (300 MHz, CDCl3) d: 5.23
(2H, s),6.01 (2H, s), 6.73 (1H, d, J = 1.2 Hz), 6.75 (1H, d, J = 1.2 Hz),
6.93 (1H, d, J = 16.2 Hz), 7.08 (1H, d, J = 16.2 Hz), 7.51 (1H, d, J =
7.8Hz), 7.74 (1H, d, J = 7.8 Hz), 7.31 – 7.47 (5H, m), 8.07 (1H, s), 8.31
(1H, s); MS (EI) m/z 375 [M]+ (15), 91 (100).
6-(4-(Benzyloxy)styryl)-4-methoxybenzo[d][1,3]dioxole
3c
Yield 46.5%, oil; 1H-NMR (300 MHz, CDCl3) d: 3.82 (3H, s), 5.12
(2H, s), 5.98 (2H, s), 6.72 (1H, d, J = 1.2 Hz), 6.74 (2H, d, J = 8.7 Hz),
6.77 (1H, d, J = 1.2 Hz), 6.90 (2H, s), 7.32 – 7.47 (5H, m), 7.80 (2H, d,
J = 8.7 Hz). MS (EI) m/z: 360 [M]+ (12), 91 (100).
4-(Benzyloxy)-6-(4(benzyloxy)styryl)benzo[d][1,3]dioxole 13d
Yield 50.2%; mp 127 – 1298C; 1H-NMR (300 MHz, CDCl3) d: 5.08
(2H, s), 5.21 (2H, s), 5.98 (2H, s), 6.67 (1H, d, J = 1.2 Hz), 6.73 (1H, d,
J = 1.2 Hz), 6.85 (2H, s), 6.96 (2H, d, J = 8.7 Hz), 7.32 – 7.47 (10H, m),
7.84 (2H, d, J = 8.7 Hz). MS (EI) m/z: 436 [M]+ (21), 91 (100).
6-(4-Fluorostyryl)-4-methoxybenzo[d][1,3]dioxole 13e
Yield 48.5%; mp 80 – 828C; 1H-NMR (300 MHz, CDCl3) d: 3.94 (3H,
s), 5.99 (2H, s), 6.64 (1H, d, J = 1.2 Hz), 6.74 (1H, d, J = 1.2 Hz), 6.90
(2H, s), 7.03 (2H, m), 7.43 (2H, m); MS (EI) m/z 272 [M]+.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
4-(Benzyloxy)-6-(4-fluorostyryl)benzo[d][1,3]dioxole 13f
Yield 48.9%; mp 97 – 998C; 1H-NMR (300 MHz, CDCl3) d: 5.21 (2H,
s), 5.99 (2H, s), 6.68 (1H, d, J = 1.2 Hz), 6.74 (1H, d, J = 1. 2Hz), 6.86
(2H, s), 7.03 (2H, t), 7.35 (2H, m), 7.39 – 7.46 (5H, m); MS (EI) m/z
348 [M+] (32), 91 (100).
Natural Dihydrostilbenes and Their Analogues
249
(1H, s), 6.53 (1H, d, J = 7.8 Hz), 6.58 (1H, d, J = 7.8 Hz), 7.00 (1H, t, J
= 7.8 Hz); MS (EI) m/z 271 [M]+ (35), 165 (100), 106 (24), 77 (16);
Anal. Calcd. for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.96; H, 6.53; N, 5.01.
6-(3-Aminophenethyl)benzo[d][1,3]dioxol-4-ol 1d
4-(Benzyloxy)-6-(4-methoxystyryl)benzo[d][1,3]dioxole
13g
Yield 55.8%; mp 98 – 1008C; 1H-NMR (600 MHz, CDCl3) d: 3.82 (3H,
s), 5.21 (2H, s), 5.98 (2H, s), 6.68 (1H, d, J = 1.2 Hz), 6.74 (1H, d, J =
1.2 Hz), 6.82 (1H, d, J = 16.2 Hz), 6.86 (1H, d, J = 16.2 Hz), 6.88 (2H,
d, J = 8.4 Hz), 7.31 – 7.40 (5H, m), 7.46 (2H, d, J = 8.4 Hz); MS (EI) m/z
360 [M]+ (9), 91 (100).
4-(2-(7-(Benzyloxy)benzo[d][1,3]dioxol-5-yl)vinyl)-N,Ndimethylbenzenamine 13h
Yield 52.9%; mp 154 – 1568C; 1H-NMR (300 MHz, CDCl3) d: 2.99 (6H,
s), 5.21 (2H, s), 5.97 (2H, s), 6.70 (1H, d, J = 16.2 Hz), 6.80 (1H, d, J =
1.2Hz), 6.85 (1H, d, J = 16.2 Hz), 6.85 (1H, s), 6.86 (1H, d, J = 1.2 Hz),
6.89 (1H, s), 7.32-7.47 (7H, m); MS (EI) m/z 373 [M]+ (13), 91 (100).
6-(4-(Benzyloxy)-3-methoxystyryl)-4methoxybenzo[d][1,3]dioxole 13i
Yield 50.3%; mp 108 – 1108C; 1H-NMR (600 MHz, CDCl3) d: 3.94
(3H, s), 3.95 (3H, s), 5.18 (2H, s), 5.98 (2H, s), 6.63 (1H, s), 6.73 (1H,
s), 6.85 (1H, d, J = 16.2 Hz), 6.86 (1H, d, J = 16.2 Hz), 6.87 (1H, d, J =
7.8 Hz), 6.95 (1H, d, J = 7.8 Hz), 7.05 (1H, s), 7.29 – 7.45 (5H, m); MS
(EI) m/z 390 [M]+ (20), 91 (100).
Yield 97.3%; mp 135 – 1388C; 1H-NMR (300 MHz, DMSO) d: 2.64
(4H, s), 4.90 (2H, brs), 5.88 (2H, s), 6.26 (1H, s), 6.30 (1H, s), 6.36
(1H, d, J = 7.8 Hz), 6.38 (1H, d, J = 7.8 Hz), 6.41 (1H, s), 6.90 (1H, t, J
= 7.8 Hz), 9.49 (1H, s); MS (EI) m/z 257 [M]+ (40), 151 (100), 106 (11),
77 (8); Anal. Calcd. for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.
Found: C, 70.36; H, 5.91; N, 5.23.
4-(2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)ethyl)phenol 1e
Yield 96.4%, oil; 1H-NMR (300 MHz, CDCl3) d: 2.79 (4H, brs), 3.85
(3H, s), 5.92 (2H, s), 6.27 (1H, d, J = 1.2 Hz), 6.36 (1H, d, J = 1.2 Hz),
6.74 (2H, d, J = 7.8 Hz), 7.02 (2H, d, J = 7.8 Hz); MS (EI) m/z 272 [M]+
(16), 165 (100), 107 (42), 77 (22); Anal. Calcd. for C16H16O4: C,
70.57; H, 5.92. Found: C, 70.85; H, 6.09.
6-(4-Hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol 1f
Yield 97.4%; mp 129 – 1308C; 1H-NMR (300 MHz, CDCl3) d: 2.77
(4H, brs), 5.92 (2H, s), 6.29 (1H, s), 6.31 (1H, s), 6.74 (2H, d, J = 7.8
Hz), 7.02 (2H, d, J = 7.8 Hz); MS (EI) m/z 258 [M]+ (12), 151 (86), 107
(100), 77 (37); Anal. Calcd. for C15H14O4: C, 69.76; H, 5.46. Found:
C, 69.62; H, 5.32.
6-(4-Fluorophenethyl)-4-methoxybenzo[d][1,3]dioxole 1g
Synthesis, yields and spectroscopic date of compounds
1a – 1k
Yield 95.5%; mp 39 – 418C; 1H-NMR (300 MHz, CDCl3) d: 2.81 (4H,
m), 3.84 (3H, s), 5.93 (2H, s), 6.25 (1H, d, J = 1.0 Hz), 6.35 (1H, d, J =
1.0 Hz), 6.95 (2H, m), 7.08 (2H, m); MS (EI) m/z 274 [M]+ (11), 165
(100), 109 (22), 77 (22); Anal. Calcd. for C16H15FO3: C, 70.06; H,
5.51. Found: C, 70.22; H, 5.37.
3-(2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)ethyl)phenol 1a
6-(4-Fluorophenethyl)benzo[d][1,3]dioxol-4-ol 1h
A solution of 11a (0.120 g, 0.333 mmol) in EtOAc (10.0 mL) was
stirred in the presence of 10% Pd-C (0.006 g) under a hydrogen
atmosphere at room temperature for 48 h. The catalyst was
removed by filtration and washed with EtOAc. The filtrate was
concentrated in vacuo and purified by column chromatography
(n-hexane : EtOAc = 3 : 1) to give dihydrostilbene 1a (0.0857 g,
94.5%) as a white powder: mp 55 – 578C; 1H-NMR (300 MHz,
CDCl3) d: 2.81 (4H, brs), 3.85 (3H, brs), 4.82 (1H, brs), 5.93 (2H, s),
6.29 (1H, d, J = 1.5 Hz), 6.38 (1H, d, J = 1.5Hz), 6.65 (1H, s), 6.67 (1H,
d, J = 7.5 Hz), 6.74 (1H, d, J = 7.5Hz), 7.14 (1H, t, J = 7.5 Hz); MS (EI)
m/z 272 [M]+ (13), 165 (100), 77 (36); Anal. Calcd. for C16H16O4: C,
70.57; H, 5.92. Found: C, 70.80; H, 5.69.
Compounds 1b – k were prepared using the same method.
Yield 94.7%; mp 91 – 938C; 1H-NMR (300 MHz, CDCl3) d: 2.78 (4H,
m), 4.70 (1H, brs), 5.93 (2H, s), 6.28 (1H, s), 6.29 (1H, s), 6.95 (2H,
m), 7.09 (2H, m); MS (EI) m/z 260 [M]+ (12), 151 (100), 109 (69), 95
(5); Anal. Calcd. for C15H13FO3: C, 69.22; H, 5.03. Found: C, 69.46;
H, 5.09.
6-(3-Hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol 1b
Yield 98.3%; mp 125 – 1288C; 1H-NMR (300 MHz, DMSO) d: 2.50
(2H, brs), 2.68 (2H, brs), 5.88 (2H, s), 6.25 (1H, s), 6.31 (1H, s), 6.56
(1H, s), 6.57 (1H, d, J = 7.5 Hz), 6.59 (1H, d, J = 7.5 Hz), 7.04 (1H, t, J
= 7.5 Hz), 9.24 (1H, s), 9.53 (1H, s); MS (EI) m/z 258 [M]+ (19), 151
(100), 77 (13); Anal. Calcd. for C15H14O4: C, 69.76; H, 5.46. Found:
C, 69.99; H, 5.24.
3-(2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)ethyl)benzenamine 1c
1
Yield 97.8%, oil; H-NMR (300 MHz, CDCl3) d 2.78 (4H, s), 3.85 (3H,
s), 5.91 (2H, s), 6.30 (1H, d, J = 1.2 Hz), 6.38 (1H, d, J = 1.2 Hz), 6.50
i
2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
3.3.9 6-(4-Methoxyphenethyl)benzo[d][1,3]dioxol-4-ol 1i
Yield 96.8%; mp 96 – 978C; 1H-NMR (300 MHz, CDCl3) d: 2.78 (4H,
brs), 3.78 (3H, s), 5.90 (2H, s), 6.29 (1H, s), 6.31 (1H, s), 6.80 (2H, d, J
= 7.8 Hz), 7.05 (2H, d, J = 7.8 Hz); MS (EI) m/z 272 [M]+ (7), 151 (21),
121 (100), 77 (11); Anal. Calcd. for C16H16O4: C, 70.57; H, 5.92.
Found: C, 70.64; H, 5.88.
6-(4-(Dimethylamino)phenethyl)benzo[d][1,3]-dioxol-4-ol
1j
Yield 99.1%; mp 189 – 1918C; 1H-NMR (300 MHz, CDCl3) d: 2.64
(4H, brs), 2.82 (6H, s), 5.86 (2H, s), 6.24 (1H, d, J = 1.2Hz), 6.29 (1H,
d, J = 1.2Hz), 6.62 (2H, d, J = 7.8 Hz), 7.00 (2H, d, J = 7.8 Hz); MS (EI)
m/z 285 [M]+ (5), 134 (100); Anal. Calcd. for C17H19NO3: C, 71.56; H,
6.71; N, 4.91. Found: C, 71.20; H, 6.53.
2-Methoxy-4-(2-(7-methoxybenzo[d][1,3]dioxol-5yl)ethyl)phenol 1k
Yield 97.2%; mp 59 – 618C; 1H-NMR (300 MHz, CDCl3) d: 2.79 (4H,
s), 3.85 (6H, s), 5.45 (1H, brs), 5.93 (2H, s), 6.28 (1H, d, J = 1.2 Hz),
6.37 (1H, d, J = 1.2 Hz), 6.64 (1H, dd, J = 7.9 Hz, J = 1.2 Hz), 6.68 (1H,
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W.-G. Zhang et al.
d, J = 1.2 Hz), 6.83 (1H, d, J = 7.9 Hz); MS (EI) m/z 302 [M]+ (11), 165
(100), 137 (98), 77 (32); Anal. Calcd. for C17H18O5: C, 67.54; H, 6.00.
Found: C, 67.79; H, 6.16.
Cytotoxicity assays
An MTT colorimetric assay was employed according to the established procedure [21]. Since compounds 1a – 1k had very low
aqueous solubility, all dilutions involving these compounds
were performed in DMSO prior to the addition of 0.5 lL aliquots
to each well. After the addition of the samples to the cell cultures, the cells were incubated for 24 h before the MTT reagent
was added. The assays were performed in the Cell Culture
Laboratory. All of the compounds were initially tested once in
each of the cell lines. The active compounds (IC50 a 100 lM) were
tested again, and the values shown for these cytotoxic substance
are the averages of two determinations.
Arch. Pharm. Chem. Life Sci. 2007, 340, 244 – 250
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