Synthesis of α-aminoalkyl phosphonate derivatives of resveratrol as potential antitumour agents

Article abstract of DOI:10.1071/CH08029

Several ?-aminoalkyl phosphonate derivatives of resveratrol were first prepared by partial synthesis from resveratrol. Antitumour activities of the synthesized compounds were determined against a human nasopharyngeal epidermoid tumour cell line KB and a h

Full text of DOI:10.1071/CH08029

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 472–475
www.publish.csiro.au/journals/ajc
Synthesis of α-Aminoalkyl Phosphonate Derivatives
of Resveratrol as Potential Antitumour Agents
Lei Shi,A Xian-Feng Huang,A Zhen-Wei Zhu,A Huan-Qiu Li,A Jia-Yu Xue,A
Hai-Liang Zhu,A,B and Chang-Hong LiuA,B
AState Key Laboratory of Pharmaceutical Biotechnology, Nanjing University,
Nanjing 210093, China.
BCorresponding author. Email: zhuhl@nju.edu.cn
Several α-aminoalkyl phosphonate derivatives of resveratrol were first prepared by partial synthesis from resveratrol.
Antitumour activities of the synthesized compounds were determined against a human nasopharyngeal epidermoid tumour
cell line KB and a human normal cell line L02 in vitro. The results indicated that these compounds showed good cytotoxic
activity against KB but weak cytotoxic activity against L02. Compounds 5c and 5d showed significant cytotoxic activity
against KB, with median inhibition concentration (IC50) values of 0.4 µM and 0.9 µM, respectively. On the basis of the
biological results, the structure–activity relationship is discussed concisely. The potent antitumour activities shown by 5c
and 5d make these resveratrol phosphonate derivatives of great interest for further investigations.
Manuscript received: 25 January 2008.
Final version: 20 May 2008.
Introduction
line KB of eight new α-aminoalkyl phosphonate derivatives of
resveratrol and their SAR.
Resveratrol, a naturally occurring phytoalexin (trans-3,5,4ꢀ-
trihydroxy-trans-stilbene) present in grapes, berries, peanuts,
and red wine,[1,2] has been suggested as a potential cancer
chemopreventive agent based on its striking inhibitory effects
on cellular events associated with cancer initiation, promo-
tion, and progression.[3] Extensive data in human cell cultures
indicate that resveratrol exhibits activity against a wide vari-
ety of cancer cells such as hepatoma,[4,5] gastric cancer,[6]
leukemia,[7] lung cancer,[8] prostate cancer,[9] breast cancer,[10]
skin cancer,[11,12] and so on. The simplicity of resveratrol, asso-
ciated with its interesting anticancer activity, offers promise
for the rational design of new chemotherapeutic agents, and
efforts have recently been devoted regarding a detailed study
on the structure–activity relationships (SAR) of this type of sub-
stituted stilbene derivatives.[13,14] We have been exploring the
antitumour properties of a series of methoxylated resveratrol
derivatives modified by the introduction of lipophilic chains in
the C2 position of the molecule.[15] Among them, several com-
pounds exhibited similar activity to 5-fluorouracil (5-FU), an
anticancer drug.
Results and Discussion
Chemistry
In a previous study on resveratrol, we prepared a series
of methoxylated resveratrol derivatives modified in the C2
position.[15] To explore more potent antitumour agents, phos-
phonate was introduced into the structure of resveratrol.
The preparation of resveratrol analogues is outlined in
Scheme 1. Treatment of resveratrol with (CH3)2SO4 in 10%
NaOH solution under nitrogen afforded compound 2. Vilsmeier
formylation of compound 2 by treatment with a slight excess
of POCl3 in DMF at 0◦C yielded aldehyde compound 3. Then,
condensation reaction of compound 3 with a series of amines
afforded the Schiff bases, which were treated with diethyl phos-
phite and 4-methylbenzenesulfonic acid (TsOH) to afford the
targeted compounds (Scheme 1 and Fig. 1).
Biological Activity
Many α-aminophosphonate derivatives have been reported
to possess antitumour activities.[16,17] It is known that phos-
phorus substituents regulate important biological functions and
that molecular modifications involving the introduction of
organophosphorus functionalities could increase their biological
activity.[18–20]
Enlightened by these positive results and in continuation of
our work, we were encouraged to design and synthesize a series
of α-aminoalkyl phosphonate derivatives of resveratrol for anti-
tumour evaluation and SAR analysis. In the present work, we
describe the effective synthesis, and in vitro cytotoxic activi-
ties against a human nasopharyngeal epidermoid tumour cell
All of the compounds were tested for cytotoxic activity against
a human nasopharyngeal epidermoid tumour cell line KB and
a human normal cell line L02. The results are summarized in
Table1.Theresultsshowedthatmostofthecompoundsexhibited
good cytotoxic activity against KB but weak cytotoxic activity
against L02. In our previous study,[15] compound 3 showed the
most potent cytotoxic activity. In the present study, as expected,
most of the α-aminoalkyl phosphonate derivatives of resveratrol
exhibited better activity than compound 3. This result indicated
the introduction of the phosphonate group was able to signif-
icantly improve the activity of resveratrol derivatives. Among
these phosphonate compounds, compounds 5c, 5d, 5e, 5f, except
© CSIRO 2008
10.1071/CH08029
0004-9425/08/060472

Synthesis of α-Aminoalkyl Phosphonate Derivatives of Resveratrol
473
HO
CHO
H3CO
H3CO
H3CO
H3CO
(b)
(a)
OCH3
OH
OCH3
HO
1
3
2
(c)
R
R
P(OEt)2
O
H3CO
H3CO
H3CO
N
NH
(d)
OCH3
OCH3
4
H3CO
5
Scheme 1. Synthesis of the resveratrol analogues. Reagents and conditions: (a) (CH3)2SO4, 10% NaOH, 0–40◦C, 76% yield; (b) POCl3,
DMF, 0◦C, 69% yield; (c) RNH2, ethanol, reflux; (d) diethyl phosphite, 4-methylbenzenesulfonic acid (TsOH), ethanol, 80◦C, 65–78% yield.
P(OEt)2
R
O
Table 1. Cytotoxic activity of synthesized compounds against a human
nasopharyngeal epidermoid tumour cell line KB and a human normal
cell line L02
H3CO
NH
IC50 = 50% inhibitory concentration represents the mean s.d. from dose–
response curves of at least three experiments
OCH3
H3CO
N
5
Compound
KB (IC50 [µM])
L02 (IC50 [µM])
1
2
3
5a
5b
5c
5d
5e
>80
>80
O
10.2 0.5
8.9 0.3
3.2 0.1
11.5 0.2
0.4 0.1
0.9 0.1
5.2 0.1
6.5 0.1
12.1 0.8
28.2 2.2
13.4 0.2
46.5 1.5
43.7 0.3
25.6 2.1
63.4 3.6
15.4 0.5
26.9 1.2
35.4 2.3
39.5 2.0
70.6 3.2
>80
5a R ϭ
5c R ϭ
5e R ϭ
5b R ϭ
5d R ϭ
N
N
5f R ϭ
5hR ϭ
5f
5g
5h
OH
5g R ϭ
5-fluorouracil
16.7 0.4
Fig. 1. Structures of 5a–5h.
strategies to synthesize more potent antitumour agents derived
from resveratrol.
for 5h, containing straight side chains showed better activities
against KB than compounds 5b and 5g containing ringed side
chains. Compound 5a containing a morpholine ring side chain
also exhibited higher activity against KB than compounds 5b
and 5g. Of all the compounds, 5c and 5d, bearing two nitro-
gen atoms in their side chains, showed activity 30- and 15-fold
(median inhibition concentration (IC50) = 0.4 µM and 0.9 µM,
respectively) higher than 5-FU, an anticancer drug. In contrast,
introduction of an OH group in the side chain decreased the
inhibitory activity (IC50 value of compound 5h = 28.2 µM); this
may be due to the hydrophilicity of the OH group hindering the
compound from permeating the cell membrane.
Experimental
General
Resveratrol was bought from Xi’an Mingzhu Co., Xi’an, China.
1H NMR spectra were recorded on a Bruker DRX 500 or DPX
300 model spectrometer in [D6]DMSO. Chemical shifts (δ)
for 1H NMR spectra are reported in parts per million rela-
tive to residual solvent protons. Electrospray ionization-mass
spectrometry spectra were recorded on a Mariner System 5304
Mass spectrometer. Melting points were obtained by using
a Boetius micromelting point apparatus. Elemental analyses
were performed on a CHN-O-Rapid instrument. Flash-column
chromatography was performed on silica gel Merck Kieselgel 60
Conclusions
In summary, we synthesized a series of α-aminoalkyl phos-
phonate derivatives of resveratrol and examined their cytotoxic
activity against a human nasopharyngeal epidermoid tumour
cell line KB. According to the above results, introduction of
phosphonate was able to significantly improve the activity of
resveratrol derivatives, probably because the phosphonate group
makes the compounds transport through the cell membrane
easily. Altogether, our findings might provide novel promising
(230–400 mesh).TLC was performed on silica gel plates (GF254
,
Merk); spots were detected visually by ultraviolet irradiation
(254 nm).
Synthesis of trans-3,4ꢀ,5-Trimethoxystilbene 2
Dimethyl sulfate (4.9 mL) was dropped into a solution of
456 mg (2 mmol) of compound 1 in 5 mL of aq. NaOH (10%)

474
L. Shi et al.
under an atmosphere of nitrogen while cooling with an ice/water
bath, keeping the rate such that the temperature of the reac-
tion solution was under 40◦C. The mixture was stirred for
2 h, and extracted with 10 mL of EtOAc twice. The organic
layer was washed with water, dried over Na2SO4, and evap-
orated under vacuum. Purification by silica gel (petroleum
ether/dichloromethane, 1:1, Rf = 0.25) afforded compound 2
(colourless crystalline solid, 410 mg, 1.52 mmol, yield 76%),
mp 54–56◦C. ESI MS 271.3 [M + H]+. δH ([D6]DMSO) 3.77
(s, 9H), 6.39 (s, 1H), 6.74 (s, 2H), 6.94 (d, 2H, J 8.4), 7.02 (d,
1H, J 16.4), 7.21 (d, 1H, J 16.4), 7.53 (d, 2H, J 8.4). Calc. for
C17H18O3: C 75.53, H 6.71. Found: C 75.61, H 6.74%.
(s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 4.98 (d, 1H, J 26.8), 5.12 (q,
2H, J 7.0), 6.52 (s, 1H), 6.73 (s, 1H), 6.92–6.96 (m, 3H), 7.57
(d, 2H, J 8.4), 8.48 (d, 1H, J 16.4). Calc. for C28H40NO6P: C
64.97, H 7.99, N 2.71. Found: C 65.04, H 8.08, N 2.66%.
(E)-Diethyl 1-[N-3-(Dimethylamino)propylamino]-
1-[2-(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5c
White powder, yield 73%, mp 77–79◦C. ESI MS 521.2
[M + H]+. δH ([D6]DMSO) 0.91 (t, 3H, J 7.0), 1.12–1.15 (m,
2H), 1.22 (t, 3H, J 7.0), 2.38–2.43 (m, 6H), 2.57–2.80 (m, 4H),
3.39–3.42 (m, 2H), 3.72–3.80 (m, 11H), 4.57 (d, 1H, J 26.8),
6.50 (s, 1H), 6.73 (s, 1H), 6.85–6.96 (m, 3H), 7.55 (d, 2H, J
8.4), 8.39 (d, 1H, J 16.4). Calc. for C27H41N2O6P: C 62.29, H
7.94, N 5.38. Found: C 62.18, H 7.81, N 5.26%.
Synthesis of trans-2-Formyl-3,4ꢀ,5-trimethoxystilbene 3
To a solution of 270 mg (1 mmol) of compound 2 in 5 mL of
DMF was added dropwise 200 µL (0.21 g, 1.0 mmol) of POCl3
while cooling with an ice/water bath. The reaction mixture was
stirred for 30 min at room temperature. The solution was added
to a mixture of ice and water, and the yellow solution was
extracted with three 10-mL portions of dichloromethane. The
combined organic layers were washed with water, dried over
anhydrous sodium sulfate, filtered, evaporated, and recrystal-
lized from dichloromethane, and afforded compound 3 (yellow
solid, 206 mg, 0.69 mmol, yield 69%), mp 108–109◦C. ESI MS
299.3 [M + H]+. δH ([D6]DMSO) 3.78 (s, 3H), 3.90 (s, 3H),
3.92 (s, 3H), 6.63 (s, 1H), 6.91 (s, 1H), 6.97 (d, 2H, J 7.9), 7.21
(d, 1H, J 16.2), 7.50 (d, 2H, J 7.9), 7.95 (d, 1H, J 16.2), 10.41
(s, 1H). Calc. for C18H18O4: C 72.74, H 6.08. Found: C 72.56,
H 6.11%.
(E)-Diethyl 1-[N-3-(Diethylamino)propylamino]-
1-[2-(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5d
White powder, yield 68%, mp 84–86◦C. ESI MS 549.3
[M + H]+. δH ([D6]DMSO) 0.90–0.94 (m, 6H), 1.11–1.14 (m,
2H), 1.20–1.24 (m, 6H), 2.30–2.34 (m, 2H), 2.40–2.43 (m, 4H),
2.57–2.61 (m, 2H), 3.22–3.26 (m, 2H), 3.71 (s, 3H), 3.82 (s, 3H),
3.88 (s, 3H), 4.02–4.04 (m, 2H), 4.63 (d, 1H, J 26.8), 6.51 (s,
1H), 6.72 (s, 1H), 6.86–6.97 (m, 3H), 7.46 (d, 2H, J 8.4), 8.12 (d,
1H, J 16.4). Calc. for C29H45N2O6P: C 63.48, H 8.27, N 5.11.
Found: C 63.44, H 8.12, N 5.23%.
(E)-Diethyl 1-(N-Butylamino)-1-[2-
(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5e
General Procedure for the Synthesis of 5a–5h
Compound 3 (1 mmol) was dissolved in 5 mL of ethanol,
and amine was added to the solution. The reaction mixture
was refluxed for 30 min. Then, 2 mmol of diethyl phosphite
and 0.1 mmol of TsOH were added to the reaction solution,
and stirred at 80◦C for 4 h. The mixture was evaporated under
vacuum, and added to 10 mL of water, and the solution was
extracted with 5-mL portions of EtOAc twice. The combined
organic layers were washed with water, dried over anhydrous
sodium sulfate, filtered, and evaporated. Purification by silica
gel (petroleum spirits/ethyl acetate 3:1, Rf values ranged from
0.2 to 0.3) afforded pure products.
White powder, yield 65%, mp 63–65◦C. ESI MS 492.3
[M + H]+. δH ([D6]DMSO) 0.79 (t, 3H, J 7.0), 0.93–0.98 (m,
3H), 1.18–1.36 (m, 7H), 2.25–2.30 (m, 2H), 3.63–3.68 (m, 2H),
3.77 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 4.07–4.10 (m, 2H), 4.82
(d, 1H, J 26.8), 6.50 (s, 1H), 6.76 (s, 1H), 6.93–6.99 (m, 3H),
7.51 (d, 2H, J 8.4), 8.15 (d, 1H, J 16.4). Calc. for C26H38NO6P:
C 63.53, H 7.79, N 2.85. Found: C 63.62, H 7.85, N 2.93%.
(E)-Diethyl 1-(N-Propylamino)-1-[2-
(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5f
(E)-Diethyl 1-(N-Morpholinoethylamino)-1-
[2-(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5a
White powder, yield 76%, mp 59–61◦C. ESI MS 478.3
[M + H]+. δH ([D6]DMSO) 0.68 (t, 3H, J 7.3), 0.97 (t, 3H, J
6.9), 1.15–1.30 (m, 5H), 2.22 (t, 2H, J 6.7), 3.70–3.71 (m, 2H),
3.75 (s, 3H), 3.77 (s, 3H), 3.80 (s, 3H), 4.03–4.10 (m, 2H), 4.86
(d, 1H, J 26.8), 6.53 (s, 1H), 6.77 (s, 1H), 6.95–7.01 (m, 3H),
7.53 (d, 2H, J 8.4), 8.18 (d, 1H, J 16.4). Calc. for C25H36NO6P:
C 62.88, H 7.60, N 2.93. Found: C 62.72, H 7.55, N 2.87%.
White powder, yield 70%, mp 72–74◦C. ESI MS 549.3
[M + H]+. δH ([D6]DMSO) 0.99 (t, 3H, J 7.0), 1.32 (t, 3H, J
7.0), 2.09–2.12 (m, 2H), 2.26–2.29 (m, 2H), 2.40–2.43 (m, 2H),
2.49–2.53 (m, 2H), 3.28–3.33 (m, 4H), 3.73 (q, 2H, J 7.0), 3.81
(s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 4.20 (q, 2H, J 7.0), 4.98 (d,
1H, J 26.8), 6.51 (s, 1H), 6.84 (s, 1H), 6.94 (d, 2H, J 8.4), 7.00
(d, 1H, J 16.4), 7.62 (d, 2H, J 8.4), 8.40 (d, 1H, J 16.4). Calc.
for C28H41N2O7P: C 61.30, H 7.53, N 5.11. Found: C 61.38, H
7.58, N 5.06%.
(E)-Diethyl 1-(N-Benzylamino)-1-[2-
(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5g
White powder, yield 68%, mp 92–94◦C. ESI MS 526.4
[M + H]+. δH ([D6]DMSO) 0.94 (t, 3H, J 7.0), 1.23 (t, 3H, J
7.0), 3.64–3.68 (m, 4H), 3.77 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H),
4.04–4.06 (m, 2H), 4.84 (d, 1H, J 26.8), 6.50 (s, 1H), 6.56 (s,
1H), 6.80–6.81 (m, 1H), 6.82–6.88 (m, 2H), 6.90–6.92 (m, 2H),
7.19–7.21 (m, 2H), 7.35–7.37 (m, 2H), 7.51–7.52 (m, 1H), 8.24
(d, 1H, J 16.4). Calc. for C29H36NO6P: C 66.27, H 6.90, N 2.67.
Found: C 66.24, H 6.82, N 2.59%.
(E)-Diethyl 1-(N-Cyclohexylamino)-1-[2-
(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5b
White powder, yield 78%, mp 65–67◦C. ESI MS 518.3
[M + H]+. δH ([D6]DMSO) 0.99 (t, 3H, J 7.0), 1.01–1.15 (m,
4H), 1.17–1.20 (m, 2H), 1.32 (t, 3H, J 7.0), 1.47–1.51 (m, 2H),
1.60–1.63 (m, 2H), 1.72–1.76 (m, 1H), 3.72 (q, 2H, J 7.0), 3.81

Synthesis of α-Aminoalkyl Phosphonate Derivatives of Resveratrol
475
(E)-Diethyl 1-(N-2-Hydroxyethylamino)-1-[2-
(4-methoxystyryl)-4,6-dimethoxyphenyl]
methanephosphonate 5h
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White powder, yield 72%, mp 115–117◦C. ESI MS 480.3
[M + H]+. δH ([D6]DMSO) 0.73 (t, 3H, J 7.3), 0.98 (t, 3H, J
6.9), 2.72–2.76 (m, 2H), 3.61–3.63 (m, 2H), 3.71–3.75 (m, 2H),
3.79 (s, 3H), 3.82 (s, 3H), 3.93 (s, 3H), 4.05–4.08 (m, 2H), 4.86
(d, 1H, J 26.8), 6.53 (s, 1H), 6.77 (s, 1H), 6.95–7.01 (m, 3H),
7.53 (d, 2H, J 8.4), 8.18 (d, 1H, J 16.4). Calc. for C24H34NO7P:
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Cytotoxicity Assay Against KB Cells
The cytotoxicity was evaluated as described elsewhere[21] with
some modifications. Briefly, target tumour cells were grown
to log phase in RPMI 1640 medium supplemented with 10%
fetal bovine serum. After diluting to 2 × 104 cells mL−1 with
the complete medium, 100 mL of the cell suspension obtained
was added to each well of 96-well culture plates. The subse-
quent incubation was carried out at 37◦C, 5% CO2 atmosphere
for 24 h before the cytotoxicity assessments. Tested samples at
preset concentrations were added to six wells with 5-FU co-
assayed as a positive reference. After a 48-h exposure period,
40 mL of phosphate buffered saline containing 2.5 mg mL−1
of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) was added to each well. Four hours later, the medium
was replaced by 150 mL DMSO to solubilize the purple for-
mazan crystals produced. The absorbance at 570 nm of each
well was measured on an ELISA plate reader. The IC50 value
was defined as the concentration at which 50% survival of cells
occurred.
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Acknowledgements
The work was co-financed by a grant (Project 30772627) from National
Natural Science Foundation of China, and by High Technique Research
(BG2007330): Development of Agricultural Biofungicide, Baoman agent.
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