Synthesis of conjugate esters of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione and ursolic acid 3-O-acyl derivatives

Full text of DOI:10.1007/s10600-016-1588-5

DOI 10.1007/s10600-016-1588-5
Chemistry of Natural Compounds, Vol. 52, No. 1, January, 2016
SYNTHESIS OF CONJUGATE ESTERS OF
5-(4-HYDROXYPHENYL)-3H-1,2-DITHIOLE-3-THIONE
AND URSOLIC ACID 3-O-ACYL DERIVATIVES
*
S. A. Popov, L. M. Kornaukhova, A. V. Shpatov,
and I. A. Grigorꢀev
Chemical conjugates of H S-donors and non-steroidal anti-inflammatory drugs (NSAIDs) are being investigated as
2
anti-inflammatory and chemoprevention agents [1]. Dithiolethiones, in particular 5-(4-methoxyphenyl)-3H-1,2-dithiole-3-
thione (1a, ADT), are H S donors and exhibit marked antioxidant activity (free-radical binding, lipid peroxidation inhibition)
2
[2]. Desmethylanethol trithione (1b, ADTOH) is a known ADT metabolite and is used as a synthon to prepare new promising
NSAID conjugate derivatives [3]. Available triterpenoids such as ursolic acid (UA, 2a) and its synthetic derivatives were also
reported to have anti-inflammatory, antioxidant, and antitumor activity [4].
30
RO
20
29
19
S
H
H
12
26
S
18
17
1'
O
R
2
25
3'
7'
1
9
28
14
S
1b, Et N
3
O
O
S
2c
1a: R = Me;1b: R = H
H
H
3
5
5'
27
S
9'
CH COO
R O
1
3
8'
O
1b
H
H
O
2
3
24
S
23
a
HO
2a: R = H, R = OH
2b: R = CH CO, R = OH
2c: R = CH CO, R = Cl
1
1
1
2
O
3
3
2
2
b
S
O
S
S
O
S
O
Et N
3
H
S
OH
6
S
O
H
O
O
c
HO
H
O
O
4''
H
1''
O
O
H
4
5
O
a. Py, Ac O; b. SOCl ; c. 1b, DCC, DMAP
2
2
Triterpenoid conjugate derivatives were reported to have a higher level of chemoprotection and lower toxicity than
the precursor compounds [5]. Therefore, it seemed interesting to prepare molecules combining the natural compound 2a and
1b as the H S donor. For this, we synthesized conjugate esters of UA 3-O-acyl derivatives with 5-(4-hydroxyphenyl)-3H-1,2-
2
dithiole-3-thione (1b) with the S-containing substituent in different positions relative to the triterpenoid scaffold.
ADTOH was prepared from anethole as before [6]. 3-O-Acyl derivatives 2b and 4 were prepared by treating UAwith
Ac O and succinic anhydride in the presence of Et N, respectively. The triterpenoid C-28 ester was synthesized via the
2
3
reaction of 3-O-acetylursolyl chloride (2c) with ADTOH. A solution of 2b (0.45 g, 0.9 mmol) in thionylchloride (3.3 g,
27 mmol) was held for 6 h at 20–25°C and concentrated in vacuo at ꢁ40°C to afford 2c as a yellow glassy substance that was
used immediately without further purification to produce ester 3. A solution of 2c in CH Cl (5 mL) was treated over 15 min
2
2
Novosibirsk Institute of Organic Chemistry, Prosp. Akad. Lavrentꢀeva, 9, Novosibirsk, 630090, Russia,
fax: +7 383 330 97 52, e-mail: spopov@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1, January–February,
2016, pp. 157–158. Original article submitted July 1, 2015.
©
0009-3130/16/5201-0183 2016 Springer Science+Business Media New York
183

with a solution of 1b (0.20 g, 0.9 mmol), 4-dimethylaminopyridine (1 mg), and Et N (2 mL) in CH Cl (5 mL) at 15–25°C,
3
2
2
stirred for 4–6 h, and concentrated in vacuo. The residue was dissolved in MTBE, washed with HCl (2 N, 10 mL) and NaOH
(2 N, 10 mL), dried (Na SO ), and concentrated in vacuo. The residue was chromatographed (SiO , CH Cl ) to afford
2
4
2
2
2
28-[4-(3H-1,2-dithiole-3-thione-5-yl)phenyl]-3ꢂ-acetoxyurs-12-en-28-oate (3) as a red powder (0.52 g, 81%), mp 142°C.
+
Mass spectrum m/z (I , %): 706 (M , 1), 582 (4), 554 (5), 525 (2), 496 (1), 466 (4), 453 (18), 438 (4), 393 (6), 303 (6), 301 (4), 276
rel
(4), 262 (7), 248 (87), 216 (23), 203 (100), 189 (59), 133 (60), 119 (39), 107 (36), 81 (42), 69 (53), 55 (47), 43 (68). Found [M]
–1
706.3171, C H O S , calcd 706.3179. IR spectrum (KBr, ꢃ, cm ): 3435, 2968, 2947, 2926, 2872, 1734, 1659, 1639, 1601, 1526,
41 54 4 3
1493, 1456, 1412, 1389, 1369, 1308, 1248, 1211, 1180, 1167, 1144, 1130, 1109, 1090, 1074, 1028, 984, 966, 951, 941, 897, 856,
1
839, 808, 791, 733, 696, 677. UV spectrum (MeOH, ꢄ , nm) (log ꢅ): 433 (3.9), 321 (4.23), 275 (3.92), 229 (4.07). Í NMR
max
§
§
§
spectrum (300 MHz, CDCl , ꢆ, ppm, J/Hz): 0.83 (3H, s, H-26 ), 0.83 (3H, s, H-25 ), 0.84 (3H, s, H-24 ), 0.87 (3H, d, J
= 6.4,
3
29,19
= 11.3, H-18),
§
H-29), 0.92 (3H, s, H-23 ), 0.95 (3Í, d, J = 6.3, H-30), 1.10 (3H, s, H-27), 2.02 (3H, s, OCOCH ), 2.31 (1Í, br.d, J
A,B
3
18,19
4.47 (1Í, dd, J
= J
= 8.0, Í-3), 5.30 (1Í, dd, J
= J
= 3.5, Í-12), 7.12 (2Í, d, J = J = 8.7, Í-2ꢀ, 6ꢀ), 7.35 (1H,
3,2ax
3,2eq
12,11ax
12,11eq 2ꢀ,3ꢀ 6ꢀ,5ꢀ
13
§
s, Í-8ꢀ), 7.62 (2Í, d, J = J = 8.7, Í-3ꢀ, 5ꢀ). C NMR spectrum (75 MHz, CDCl , ꢆ, ppm): 15.4 (q, C-25), 16.6 (q, C-24 ), 16.8
3ꢀ,2ꢀ
5ꢀ,6ꢀ
3
§
#
#
‡
‡
(q, C-26 ), 17.4 (q, C-29), 18.0 (t, C-6), 21.0 (q, C-30 ), 21.1 (q, OCOCH ), 23.2 (t, C-11 ), 23.3 (q, C-27), 23.4 (t, C-2 ), 24.1 (t,
3
‡
¶
¶
C-16 ), 26.8 (q, C-23), 27.9 (t, C-15), 30.4 (t, C-21), 32.9 (t, C-7), 36.4 (t, C-22), 36.7 (s, C-10 ), 37.5 (s, C-4 ), 38.2 (t, C-1), 38.7 (d,
†
†
C-20 ), 38.9 (d, C-19 ), 39.6 (s, C-8), 42.0 (s, C-14), 47.3 (d, C-9), 48.6 (s, C-17), 52.8 (d, C-18), 55.1 (d, C-5), 80.7 (d, C-3), 122.8 (dd,
*
C-2ꢀ, 6ꢀ), 125.9 (d, Ñ-12), 127.9 (dd, C-3ꢀ, 5ꢀ), 128.7 (s, C-4ꢀ), 135.7 (d, C-8ꢀ), 137.5 (s, C-13), 154.0 (s, C-1ꢀ), 170.6 (s, OCOCH ),
3
*
*
13
171.7 (s, C-7ꢀ ), 175.3 (s, C-28 ), 215.2 (s, Ñ-9ꢀ) (assignments for atoms in PMR and C NMR spectra marked with the same
§,#,‡,¶,†,*
symbols
may be interchanged).
UA succinate (4) reacted regioselectively with ADTOH in the presence of dicyclohexylcarbodiimide (DCC) to form
a disubstituted succinic acid ester with a free C-28 carboxylic acid. A mixture of 4 (0.2 g, 0.36 mmol), 1b (0.081 g, 36 mmol),
and 4-dimethylaminopyridine (1 mg) in CH Cl (10 mL) at 0°C was treated with a solution of DCC (0.078 g, 0.38 mmol) in
2
2
CH Cl (2 mL), stirred for 6 h at 0–20°C, washed with HCl solution (1 N, 10 mL) and H O (10 mL), dried (Na SO ), and
2
2
2
2
4
concentrated in vacuo. The concentrate was chromatographed (SiO , CH Cl ) to afford 3ꢂ-O-{4-oxo-4-[4-(3H-1,2-dithiole-
2
2
2
3-thione-5-yl)phenoxy]butanoyl}ursolic acid (5, 0.21 g, 75%) as a red powder, mp 231–233°C. Mass spectrum m/z (I , %):
rel
+
764 (M , 0.1), 510 (1), 440 (1), 438 (6), 423 (3), 395 (1), 390 (2), 377 (1), 369 (1), 327 (1), 308 (1), 307 (4), 300 (4), 248 (100), 226
(82), 203 (79), 200 (55), 190 (49), 161 (90), 133 (82), 118 (36), 107 (23), 101 (43), 95 (23), 81 (23), 69 (31), 55 (24). Found [M]
–1
764.3259, C H O S , calcd 764.3234. IR spectrum (KBr, ꢃ, cm ): 3325, 2968, 2926, 2872, 2855, 1763, 1730, 1692, 1626, 1601,
43 56 6 3
1580, 1526, 1491, 1456, 1412, 1387, 1369, 1313, 1275, 1254, 1211, 1182, 1169, 1128, 1028, 986, 966, 949, 924, 910, 895, 833, 806,
789, 756, 694, 662, 629, 571, 538, 515. UV spectrum (MeOH, ꢄ , nm) (log ꢅ): 433 (3.73), 321 (4.0), 274 (3.69), 230 (3.85), 203
max
1
§
§
§
(4.09). Í NMR spectrum (400 MHz, CDCl , ꢆ, ppm, J/Hz): 0.73 (3H, s, H-26 ), 0.84 (3H, s, H-25 ), 0.84 (3H, s, H-24 ), 0.84 (3H, d,
3
§
J
= 6.5, H-29), 0.92 (3Í, d, J = 6.1, H-30), 0.93 (3H, s, H-23 ), 1.04 (3H, s, H-27), 2.15 (1Í, br.d, J
= 11.3, H-18), 2.73 (2H,
29,19
A,B
18,19
#
#
m, H-2ꢀꢀ ), 2.89 (2Í, m, Í-3ꢀꢀ ), 4.54 (1Í, dd, J
= J
= 7.6, Í-3), 5.20 (1Í, m, Í-12), 7.21 (2Í, d, J = J = 8.5, Í-2ꢀ, 6ꢀ),
3,2ax
3,2eq 2ꢀ,3ꢀ 6ꢀ,5ꢀ
13
7.37 (1H, s, Í-8ꢀ), 7.65 (2Í, d, J = J = 8.5, Í-3ꢀ, 5ꢀ), 11.67 (1H, br.s, ÑÎÎÍ). C NMR spectrum (100 MHz, CDCl , ꢆ,ppm):
15.4 (q, C-25), 16.6 (q, C-24 ), 16.9 (q, C-26 ), 16.9 (q, C-29 ), 18.0 (t, C-6), 21.0 (q, C-30), 23.1 (t, C-11 ), 23.4 (t, C-2 ), 23.4 (q, C-27),
3ꢀ,2ꢀ
5ꢀ,6ꢀ
3
§
§
§
#
#
#
23.8 (t, C-16 ), 27.8 (t, C-15), 28.0 (q, C-23), 29.2 (t, C-3ꢀꢀ), 29.3 (t, C-2ꢀꢀ), 30.4 (t, C-21), 32.6 (t, C-7), 36.5 (t, C-22), 36.7 (s,
‡
‡
¶
¶
C-10 ), 37.6 (s, C-4 ), 38.0 (t, C-1), 38.6 (d, C-20 ), 38.8 (d, C-19 ), 39.3 (s, C-8), 41.7 (s, C-14), 47.3 (d, C-9), 47.8 (s, C-17), 52.3
(d, C-18), 55.1 (d, C-5), 81.5 (d, C-3), 122.7 (dd, C-2ꢀ, 6ꢀ), 125.5 (d, Ñ-12), 128.1 (dd, C-3ꢀ, 5ꢀ), 129.1 (s, C-4ꢀ), 135.9 (d, C-8ꢀ), 137.8
†
†
†
(s, C-13), 153.4 (s, C-1ꢀꢀ), 170.4 (s, C-4ꢀꢀ ), 171.5 (s, C-7ꢀ ), 171.6 (s, C-1ꢀꢀ ), 184.0 (s, C-28), 215.3 (s, Ñ-9ꢀ) (assignments for
13
§,#,‡,¶,†
atoms in PMR and C NMR spectra marked with the same symbols
may be interchanged).
An attempt to prepare monosubstituted succinate 6 by acylation of 1b was unsuccessful. Compound 6 was exclusively
easily hydrolyzed and always gave quantitative yields of starting 1b. The acetyl protection was removed from 3 using
NaOH–MeOH–dioxane. However, several products from partial destruction of the S-containing heterocycle by the base were
apparently formed. Hydrolysis of succinate 5 in this system gave UAsuccinate (4),ADTOH (1b), and a small amount of UA (2a).
The synthesized ursolic acid conjugate derivatives with S-containing substituents in different positions relative to the
terpene scaffold are interesting as potential anti-inflammatory and chemoprevention agents.
184

ACKNOWLEDGMENT
Analytical and spectral studies used the Khimiya Service Center for Collective Use, SB, RAS. The work was performed
under the auspices of Project No. 12 of the NAS of Belarus and SB RAS Joint Basic Research.
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