Synthesis and in vitro cytotoxicity of novel ursolic acid derivatives

Article abstract of DOI:10.3390/molecules15064033

In an effort to improve potential hepatoprotective and anti-tumor activities, eight novel ursolic acid (UA) derivatives were designed and synthesized with substitution at positions of C-3, C-11and C-28 of UA. Their structures were confirmed using IR, MS and 1H-NMR and elemental analysis. Their in vitro cytotoxicity against various cancer cell lines (HeLa, SKOV3 and BGC-823) was evaluated by the standard MTT assay. Among them, compound 13 exhibited more potent cytotoxicity than ursolic acid.

Full text of DOI:10.3390/molecules15064033

Molecules 2010, 15, 4033-4040; doi:10.3390/molecules15064033
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and in vitro Cytotoxicity of Novel Ursolic Acid
Derivatives
Yanqiu Meng *, Yanling Song *, Zhaokai Yan and Yan Xia
Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, liaoning
110042, China; E-Mails: yanzhaokai110926@163.com (Z.Y.); xiayan1@126.com (Y.X.)
* Author to whom correspondence should be addressed; E-Mail: mengyanqiu@hotmail.com (Y.M.);
yanlingsong521@126.com (Y.S.); Tel.: +86-13840387750; Fax: +86-24-89383622.
Received: 21 April 2010; in revised form: 13 May 2010 / Accepted: 26 May 2010 /
Published: 4 June 2010
Abstract: In an effort to improve potential hepatoprotective and anti-tumor activities, eight
novel ursolic acid (UA) derivatives were designed and synthesized with substitution at
positions of C-3, C-11and C-28 of UA. Their structures were confirmed using IR, MS and
1H-NMR and elemental analysis. Their in vitro cytotoxicity against various cancer cell
lines (HeLa, SKOV3 and BGC-823) was evaluated by the standard MTT assay. Among
them, compound 13 exhibited more potent cytotoxicity than ursolic acid.
Keywords: ursolic acid derivatives; structure modification; anti-tumor activity
1. Introduction
Ursolic acid (1, UA) is a pentacyclic triterpene compound isolated from many types of medicinal
plants [1]. It has been reported to possess a wide range of pharmacological properties, including
antiinflammatory, antiallergic, antibacterial, antiviral and antitumor activities. Among these interesting
biological activities, the most intriguing property is the high cytotoxic activity. In 1990, it has been
ranked as one of the most promising tumor preventive medications by Japanese authors [2].
UA and their derivatives have been reported to inhibit interferon-induced NO production capacity,
and the activities would be significantly enhanced by introduced methoxycarbonyl, carbonyl, or cyano-
functional groups [3–7]. Based on the reports that the ester functionality at C-3 is essential for the
pharmacological activities of pentacyclic triterpenes [8], and a hydrogen donor group at either C-3

Molecules 2010, 15
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position and/or C-28 position of ursolic acid is essential for the cytotoxic activity [9], a series of UA
derivatives have been synthesized and their cytotoxic activities have been evaluated in vitro against
three cancer cell lines (HeLa, SKOV3 and BGC-823). The results showed that acetylation of the C-3
alcohol together with coupling of a substitued amino group at C-28 results in derivatives having
stronger cell growth inhibitory than ursolic acid. In addition, introduction of a carbonyl group on C-11
of UA can also inhibit tumor cell growth.
2. Results and Discussion
2.1. Synthesis of UA derivatives
Ursolic acid was used as the lead compound and the structure modification was done at the
positions C-3, C-11 and C-28. The synthetic pathways are shown in Scheme 1.
Scheme 1. Synthesis of Ursolic acid derivatives.
COOH
HO
1
j
a
e
COOH
COOH
k
COOH
7
O
h
14
H3CH2CH2CCOO
H3CCOO
2
f
b
O
COCl
COCl
COCl
COOH
H3CH2CH2CCOO
O
H3CCOO
8
15
11
H3CCOO
l
3
c
g
i
O
CONHR3
CONHR2
CONHR4
COCl
H3CCOO
H3CH2CH2CCOO
O
H3CCOO
4
d
9: R2= CH2CH2CH2OH
OCH3
F
16: R4= CH2COOCH3
17: R4= CH2C6H5
H2C
12: R3=
F
10: R2=
13: R3=
N
(CH2)2CH2
O
O
CONHR1
5: R1=
H3CCOO
C6H5
CH(CH3)CH2OH
R1=
6:
Reagents and conditions: (a) Ac2O, DMAP, THF, r.t.; (b) CrO3, Ac2O, AcOH, r.t.; (c) CH2Cl2,
(COCl)2, r.t.; (d) Et3N, NH2R1, r.t.; (e) Jones’ reagent, acetone, 0 ºC; (f) (COCl)2, CH2Cl2, r.t.;
(g) NH2R2 ,Et3N, r.t.; (h) CH2Cl2, (COCl)2, r.t.; (i) NH2R3, r.t.; (j) (CH3CH2CH2)2O, DMAP, THF,
r.t.; (k) CH2Cl2, (COCl)2, r.t.; (l) Et3N, NH2R4, r.t.

Molecules 2010, 15
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Compound 2 was prepared by reaction of UA with acetic anhydride in THF in the presence of
DMAP, then reacted with chromium trioxide in acetic acid solution containing 5% acetic anhydride to
obtain compound 3, which was treated with oxalyl chloride to yield compound 4. The crude
intermediate 4 was condensed with appropriate amino compounds in the presence of triethylamine to
give compounds 5, 6. The oxidation of the hydroxyl group of UA afforded the target product 2 in 91%
yield. The 3-oxo-ursolic acid 7 was treated with oxalyl chloride to give the 3-oxoursolyl chloride 8.
This intermediate was then condensed with the appropriate amino compound in the presence of
triethylamine to give compounds 9, 10. Compound 2 was treated with oxalyl chloride to give the 3-O-
acetylursolyl chloride 11. This intermediate was then condensed with the appropriate amino compound
in the presence of triethylamine to give the compounds 12, 13. Compound 14 was prepared by UA
reacted with butyric anhydride in the presence of DMAP in THF. Compounds 16, 17 were obtained
from 14 according to the same method used for synthesizing compound 12. The target compounds
were purified on a silica gel column with petroleum ether/ethyl acetate (or acetone) as eluents and their
structures confirmed by mp, IR, MS, 1H-NMR and elemental analysis.
2.2. Bioactivity
Antitumor activities of compounds 5, 6, 9, 10, 12, 13, 16, 17 were evaluated in vitro using the MTT
method against HeLa, BGC-823 and SKOV3 cell lines with UA as the positive control. Tumor cells
(200 μL per well) were cultured in 96-well culture plates in RPMI 1640 containing 10% FCS under
5% CO2 and 37 ºC. After 24 h, the appropriate test compound was added with different indicated
concentrations of 10-5, 10-6, 10-7, and 10-8 mol/L, respectively, for another 72 h incubation. Then MTT
was added, and absorbance was measured on an ELISA reader at a wavelength of 490 nm. Each test
was performed three times. The concentration of compounds which gives 50% growth inhibition
corresponds to the IC50. The results are summarized in Table 1.
Table 1. Inhibitory activity of ursolic acid and its analogues on different cancer cell proliferation.
Comp.
Inhibition rate for different cell (%)a
IC50(μmol·L-1)b
HeLa
12.36
SKOV3
9.06
BGC-823
10.20
HeLa
>10
SKOV3
>10
BGC-823
>10
1
5
6
32.39
29.69
1.93
31.59
5.04
>10
>10
>10
>10
>10
>10
22.57
9
39.98
0.15
8.01
0.08
NT
34.84
0.18
>10
>10
>10
2.71
>10
>10
>10
>10
>10
7.40
NT
>10
>10
>10
4.46
5.63
>10
10
12
13
16
17
17.82
92.97
41.87
5.15
12.89
85.03
65.12
13.17
62.28
NT
4.66
>10
a
b
Inhibitory percentage of cells treated with 10 μmol/L of each compound for 96 h; The agent
concentration (uM) that inhibited HeLa cells growth by 50%. NT: not test.

Molecules 2010, 15
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As shown, most of the evaluated compounds esterified at the 3-OH and coupled at C-28 with
selected amino acid methyl esters displayed stronger inhibitory activity than UA against the three
cancer cell lines. Among them, compound 13 (inhibition rates for HeLa, SKOV3, BGC-823 cells (%),
92.97, 62.28, 85.03, IC50 values of 13, 2.71 μM, 7.40 μM, 4.46 μM) displayed the most potent
antitumor activity. Compounds 5, 6, 9 (inhibition rates (%), 32.39, 29.69, 39.98) presented strong
inhibition in the HeLa cell line model. Compound 6 (inhibition rate for SKOV3 cell (%), 22.57)
presented strong inhibition in this cell line model. Compounds 5, 9 (inhibition rates for BGC-823 cell
(%) 31.59, 34.84) presented strong inhibition in the BGC-823 cell line model. By comparison of
compounds acetylated or butylated at C-3, we can conclude that acetylated compounds exhibit more
activity than the butylated ones. Some compounds such as the 3-carbonyl group or 11-carbonyl group
UA derivatives might also be important for improving the tumor cell growth inhibitory activity
3. Experimental
3.1. General
UA with over 98% purity was purchased from China Chengdu Scholar Bio-Tech.Co., Ltd. Other
reagents (analytical grade) were bought from commercial suppliers and used without further
purification unless otherwise noted. The melting points were determined on an electrically heated X-4
digital visual melting point apparatus and are uncorrected. IR spectra were recorded on a
1
ThermoNicolet 470FT spectrometer. H-NMR spectra were measured on a Bruker ARX-300 MHz
spectrometer at room temperature, with TMS as the internal standard. ESI-MS were determined with
Thermo-Finnigan LCQ equipment. Elemental analyses were performed on a Carlo-Erba 1106
Elemental Analysis instrument.
3.2. General procedure for the synthesis of N-[3β-acetoxyurs-11-oxo-12-en -28-acyl]-amine
compounds 5,6
A solution of UA (300 mg, 0.658 mmol) in THF (10 mL), pyridine (1 mL), acetic anhydride (1 mL)
and a small amount of DMAP was stirred for 4 h at room temperature. When the reaction was
complete, the solvent was cncentrated in vacuo and the solids were dispersed in water, then acidified to
pH 3–4 with HCl, filtered, washed with water to neutrality, and dried at room temperature to give
white solid compound 2. A mixture of compound 2 (50 mg, 0.1 mmol) with acetic anhydride
(0.75 mL), acetic acid (14.25 mL) and CrO3 (99.6 mg, 0.1 mmol) was stirred for 4–6 h at room
temperature. Water (20 mL) and CH2Cl2 (20 mL) were added. When stratified, the water layer was
extracted twice with CH2Cl2, combined organic phase, washed with saturated NaHCO3, then washed
with water to neutrality. Dried over Na2SO4, filtered, and concentrated in vacuo. Compound 3 was
obtained as a light green oil, which was dissolved in CH2Cl2 (10 mL), oxalyl chloride (0.2 mmol) was
added and the mixture stirred 20 h to give compound 4. Reaction solvent and unreacted oxalyl chloride
were eliminated by vacuum. Then the residue was dissolved in cyclonexane (5 mL). This was done
twice. Acyl chloride was mixed with CH2Cl2 (5 mL) and Et3N to adjust the pH to 9–10. The solution
was stirred for 5 min and amine (0.3 mmol) was added in at room temperature. The reaction
completion was detected by TLC. The dichloromethane was eliminated by vacuum, brine (5 mL) was

Molecules 2010, 15
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added and the mixture was acidified with concentrated HCl to pH 3–4. A white solid was precipitated,
filtered, the filter cake was washed to neutrality with water and dried to give a white solid.
3.2.1. N-[3β-Acetoxy-urs-11-oxo-12-en-28-acyl]aniline (5)
Compound 4 was reacted with aniline (0.3 mmol) using the general procedure to give compound 5
(27.5 mg, yield: 43%); m.p. 215–217 ºC; IR (KBr): 3389, 2930, 1712, 1658, 1610, 1599, 1534, 1499,
1439, 1373, 1260, 754, 691 cm-1; 1H-NMR (CDCl3): 7.10–7.45 (m, 5H, Ar-H), 5.75 (s, 1H, NH), 5.65
(s, 1H, H-12), 4.50 (m, 1H, H-3), 2.06 (s, 3H, CH3CO), 0.86, 0.90, 0.95, 0.97, 1.03 (s, each 3H), 0.81
(d, 3H, CH3), 0.87 (d, 3H, CH3); MS m/z: 605.0 [M+18]+; Elemental analysis (%, found) C, 77.68
(77.64); H,8.98 (9.09); N, 2.29 (2.38).
3.2.2. N-[3-Acetoxy-urs-11-oxo-12-en-28-acyl]-4-methylpiperazine (6)
Compound 4 was reacted 2-amino-1-propanol (0.3 mmol) using the general procedure to afford
compound 6 (28mg, yield: 50.3%); m.p. 203–204 ºC; IR (KBr): 3441, 2929, 1732, 1657, 1630, 1457,
1
1366, 1246 cm-1; H-NMR (CDCl3): 5.636 (s, 1H, H-12), 5.845–5.861 (d, 1H, NH), 4.537 (m, 1H,
H-3), 3.502–3.615 (m, 2H, CH2OH), 3.982 (m, H, NCH), 2.063 (s, 3H, CH3CO), 1.102 (s, 3H, CH3),
1.089 (s, 3H, CH3), 0.953 (s, 3H, CH3), 0.938 (s, 3H, CH3), 0.900 (d, 3H, CH3) ,0.882 (s, 3H, CH3),
0.798–0.820 (d, 3H, CH3), 0.813 (d, 3H, CH3); MS m/z: 570.5 [M+1]+; Elemental analysis (%, found)
C,73.71 (73.77); H, 9.73 (9.61); N, 2.46 (2.52).
3.3. General procedure for the synthesis of N-[3-oxo-urs-12-en-28-oyl]-amine compounds 9,10
To a solution of compound 1 (100 mg, 0.22 mmol) in acetone (1.5 mL) Jones’ reagent (0.4 mL) was
added dropwise in an ice-salt bath. The reaction mixture was allowed to warm up to room temperature
and stirred for 1 hour. After cooling to 0 ºC, 2-propanol (5 mL) was added and the solution stirred at
room temperature for 30 minutes. The green precipitate was collected and washed well with acetone.
The acetone solution from the combined filtrates were concentrated and dried. By purification on a
silica gel column compound 7 was obtained as a white solid. A mixture of compound 7 (50 mg,
0.11 mmol) and oxalyl chloride (0.04 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 20 h.
The mixture was concentrated to dryness under reduced pressure. Cyclohexane (3 × 1 mL) was added
to the residue, then concentrated to dryness to yield crude 3-oxoursolyl chloride 8. To a CH2Cl2 (4 mL)
solution of 8 was added an amine compound (0.44 mmol). The reaction mixture was stirred in
presence of Et3N at room temperature. The resultant residue was partitioned with 3 mL water, then
treated with 2N HCl to pH 3, CH2Cl2 was removed under vacuum to precipitate a white solid which
was filtered and the filter cake was washed with water to pH 7, and dried. The crude was purified on a
silica gel column with petroleum ether/ethyl acetate to yield a white powder.
3.3.1. N-[3-Oxo-urs-12-en-28-oyl]-3-amino-1-propanol (9)
Compound 8 was reacted by using general procedure with 3-amino-1-propanol to give compound 9.
The reaction mixture was stirred at room temperature for 5 h. Elution with petroleum ether/ethyl
acetate (v/v) = 3:1; Yield: 45.1%; m.p. 112–114 ºC; IR (KBr): 3398, 2927, 1704, 1634, 1527, 1456,

Molecules 2010, 15
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1
1382, 1077cm-1; H-NMR (CDCl3): δ6.23 (s, 1H, NH), 5.33(s, 1H, H-12), 3.60(m, 2H, CH2OH),
3.59(br, 1H, NHCHa), 3.17(br, 1H, NHCHb), 2.52 (m, 1H, H-2b), 2.42 (m, 1H, H-2a), 1.12 (s, 3H,
CH3), 1.10(s, 3H, CH3), 0.97 (s, 3H, CH3), 0.90 (d, 3H, CH3), 0.84 (s, 3H, CH3); ESI-MS: 512.5
(M+H)+; Elemental analysis (%, found) C, 77.38 (77.45); H,10.41 (10.44); N, 2.81 (2.74).
3.3.2. N-[3-Oxo-urs-12-en-28-oyl]-4-methoxyaniline (10)
Compound 8 was reacted with p-methoxyaniline using the general procedure to give compound 10.
The reaction mixture was stirred at room temperature for 5 h. Eluted with petroleum ether/ethyl acetate
(v/v) = 3:1; Yield: 45.1%; m.p. 112–114 ºC; IR (KBr): 3420, 2897, 1650, 1600, 1589, 1490, 1298,
977cm-1; 1H-NMR (CDCl3): δ6.23 (s, 1H, NH), 5.33(s, 1H, H-12), 3.60(m, 2H, CH2OH), 3.59(br, 1H,
NHCHa), 3.17(br, 1H, NHCHb), 2.52 (m, 1H, H-2b), 2.42 (m, 1H, H-2a), 1.12 (s, 3H, CH3), 1.10(s,
3H, CH3), 0.97 (s, 3H, CH3), 0.90 (d, 3H, CH3), 0.84 (s, 3H, CH3); ESI-MS: 560.5 (M+H)+; Elemental
analysis (%, found) C, 78.99 (79.10); H, 9.79 (9.87); N, 2.54 (2.49).
3.4. General procedure for the synthesis of N-[3β-acetoxyurs-12-en-28-oyl]-amines 12,13
A mixture of compound 2 (50 mg, 0.11 mmol) and oxalyl chloride (0.04 mL) in CH2Cl2 (2 mL) was
stirred at room temperature for 20 hours. The mixture was concentrated to dryness under reduced
pressure. Cyclohexane (3 × 1 mL) was added to the residue, then concentrated to dryness to yield
crude 3-O-acetylursolyl chloride 11. To a CH2Cl2 (4 mL) solution of 11 was added the appropriate
amine compound (0.44 mmol). The reaction mixture was stirred in the presence of Et3N at room
temperature. The resultant residue was partitioned in 3 mL water, then treated with 2N HCl to pH 3,
CH2Cl2 was removed under vacuum to precipitate a white solid, that was filtered and the filter cake
was washed with water to pH 7, and dried. The crude was purified on a silica gel column with
petroleum ether/ ethyl acetate to yield a white powder.
3.4.1. N-[3β-Acetoxyurs-12-en-28-oyl]-3’,4’-difluorobenzylamine (12)
Compound 11 was reacted with 3’,4’-difluorobenzylamine using the general procedure to give
compound 12. Eluted by petroleum ether/ethyl acetate (v/v) = 8:1; Yield: 50.1%; m.p. 110–112 ºC; IR
(KBr): 3538, 3002, 1694, 1594, 1497, 1410, 1352, 1035 cm-1; 1H-NMR (CDCl3): δ 6.965–7.108 (m,
3H, Ph-H) 6.194 (d, 1H, NH), 5.251–5.262 (m, 1H, H-12), 4.471–4.504 (br, 1H, NHCH2),
4.099–4.132 (m, 1H, H-3), 2.052 (s, 3H, CH3CO), 1.089 (s, 3H, CH3), 0.925 (s, 6H, CH3×2), 0.867 (m,
9H, CH3×3), 0.676 (s, 3H, CH3); ESI-MS: 624.4 (M+H)+; Elemental analysis (%, found) C, 74.71
(74.60); H, 9.00 (9.06); N, 2.34 (2.29).
3.4.2. N-[3β-Acetoxyurs-12-en-28-oyl]-3-morpholin-4-yl-1-propylamine (13)
Compound 11 was reacted with 3-morpholin-4-yl-propylamine using the general procedure to give
compound 13. Eluted by petroleum ether/ethyl acetate (v/v) = 1:6; Yield: 42.4%; m.p. 98–100 ºC; IR
(KBr): 3468, 2998, 1694, 1593, 1497, 1421, 1311, 977cm-1;1H-NMR (CDCl3): δ6.369 (d, 1H, NH),
5.286 (s, 1H, H-12), 4.500 (t, 1H, H-3), 3.431 (m, 1H, NCH), 2.051 (s, 3H, CH3CO), 1.089 (s, 3H,

Molecules 2010, 15
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CH3), 0.942 (s, 6H, CH3×2), 0.856–0.889 (m, 6H, CH3×2), 0.772 (s, 3H, CH3); ESI-MS:
626.1(M+H)+; Elemental analysis (%, found) C, 74.85 (74.71); H, 10.69 (10.61); N, 4.38 (4.47).
3.5. General procedure for the synthesis of N-[3β- butyryloxyloxy-urs-12-ene-28-oyl] amines 16,17
Compound 14 was obtained from ursolic acid 1 (100 mg, 0.22 mmol) and butyric anhydride by
using the same method described for the preparation of compound 2. A mixture of compound 14
(50 mg, 0.11 mmol) and oxalyl chloride (0.04 mL) in CH2Cl2 (2 mL) was stirred at room temperature
for 20 h. The mixture was concentrated to dryness under reduced pressure. Cyclohexane (3 × 1 mL)
was added to the residue, which was then concentrated to dryness to yield crude 3-O-butyryloxyl
chloride 15. To a CH2Cl2 (4 mL) solution of 15 was added an amine compound (0.44 mmol). The
reaction mixture was stirred in the presence of Et3N at room temperature (TLC control). The resulting
residue was partitioned in 3 mL water, then treated with 2N HCl to pH 3, CH2Cl2 was removed under
vacuum to precipitate white solid that was filtered and the filter cake was washed with water to pH 7,
and dried. The crude was purified on a silica gel column with petroleum ether/ethyl acetate as eluents
to yield a white powder.
3.5.1. Methyl N-[3β-butyryloxyl-urs-12-en-28-oyl]-2-amine acetate (16)
Compound 14 was reacted with glycine methyl ester hydrochloride using the general procedure to
give compound 16. Eluted by petroleum ether/ethyl acetate (v/v) = 5:1; Yield: 69.5%; m.p. 79–84 ºC;
1
IR (KBr): 3388, 2897, 1724, 1664, 1532, 1467, 1311, 1025cm-1; H-NMR (CDCl3):δ 6.517 (m, 1H,
NH), 5.397 (t-like, 1H, H-12), 4.488 (m, 1H, H-3), 4.075–4.115 (br, 1H, NHCHa), 3.809–3.846 (br,
1H, NHCHb), 3.753 (s, 3H, O CH3), 2.273 (s, 3H, CH3CO), 1.090 (s, 3H, CH3), 0.943 (s, 9H, CH3×3),
0.852 (m, 12H, CH3×4), 0.701 (s,3H, CH3); ESI-MS m/z: 598.6 (M+H)+; Elemental analysis (%,
found) C, 73.96 (74.08); H, 10.15 (10.25); N, 2.45 (2.33).
3.5.2. N-[3β- butyryloxyl-urs-12-en-28-oyl]-benzyl amine (17)
Compound 14 was reacted with benzylamine using the general procedure to give compound 17.
Eluted by petroleum ether/ acetone (v/v) = 7:1; 61.8%. m.p. 92–94 ºC; IR (KBr): 3498, 2826, 1684,
1
1612, 1487, 1398, 1108cm-1; H-NMR (CDCl3), δ 7.233–7.337 (m, 5H, Ar-H), 6.151 (t, 1H, NH),
5.208 (t, 1H, H-12), 4.552 (d, 1H, Ar-CHa), 4.482 (m, 1H, H-3), 4.155(d, 1H, Ar-CHb), 2.288 (m, 2H,
CH2CO), 1.078 (s, 3H, CH3), 0.945 (m, 9H, CH3×3), 0.853 (m, 9H, CH3×3), 0.701 (s, 3H, CH3); ESI-
MS: 616.8 (M+H)+; Elemental analysis (%, found) C, 79.73(79.69); H, 10.33(10.28); N, 2.21(2.27).
4. Conclusions
We have described the synthesis and basic structure-activity relationship of a series of novel
derivatives of ursolic acid as potential lead compounds for the development of new anticancer drugs.
Our data suggest that: (1) most UA conjugates with an amino acid methyl ester, amino alcohol, amino
alcohols acetate or benzylamine at C-28 and with an acetoxy group at C-3 have greater
antiproliferative ability on HeLa cells; (2) compound 13 showed significant anti-tumor activity against
HeLa, BGC-823 and SKOV3 cells.

Molecules 2010, 15
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Acknowledgements
The authors thank Scientific Found of Ministry of Education for Returned Chinese Scholars,
Natural Science Found of Liaoning Province of China (No20042009), Science and Technology Found
of Shenyang City of China (No20050785) for financial support.
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Sample Availability: Samples of the compounds are available from the authors.
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