Arch. Pharm. Chem. Life Sci. 2014, 347, 327–333
Novel Farnesylthiosalicylic Acid Derivatives for Cancer Treatment
331
internal standard. MS spectra were recorded on a Mariner Mass
Spectrum (ESI). Element analysis was performed on an Eager 300
instrument. All compounds were routinely checked by TLC and
1H NMR. TLCs and preparative thin-layer chromatography were
performed on silica gel GF/UV 254, and the chromatograms were
conducted on silica gel (200–300 mesh, Merck) and visualized
under UV light at 254 and 365 nm. All solvents were reagent grade
and, when necessary, were purified and dried by standard
methods. Solutions after reactions and extractions were concen-
trated using a rotary evaporator operating at a reduced pressure
of ca. 20 Torr. Organic solutions were dried over anhydrous
sodium sulfate.
with anhydrous Na2SO4, and concentrated in vacuo, affording 1 as
a pale yellow waxy solid (2.16 g, 90%). H NMR (CDCl3, 300 MHz,
1
d ppm): 8.15 (m, H, Ar-H), 7.47 (m, 1H, Ar-H), 7.42 (m, 1H, Ar-H),
7.26 (m, 1H, Ar-H), 5.31 (m, 1H, SCH2CH), 5.09 (m, 2H, 2 ꢃ
–
CH CH CCH ), 3.57 (d, 2H, J ¼ 4.5Hz, SCH ), 1.89–2.02 (m, 8H,
–
2
3
2
–
–
2 ꢃ CCH CH CH), 1.50–1.68 (m, 12H, 4 ꢃ CH CCH ); MS (ESI)
2
2
3
m/z ¼ 357 [Mꢀ1]þ; Anal. calcd. for C22H30O2S: C, 73.70; H, 8.43.
Found: C, 73.77; H, 8.84.
2-(((2E,6E)-3,7,11-Trimethyldodeca-2,6,10-trien-1-yl)thio)-
benzoyl chloride 7
The parent compound 1 (0.36 g, 1 mmol) was dissolved in
anhydrous CH2Cl2 (6 mL), then oxalyl chloride (4 mmol) was
dropwise added. The mixture was stirred for 4 h at room
temperature. The solvent and excess oxalyl chloride was
evaporated in vacuo to obtain the farnesylthiosalicyl chloride 7
with no need for further purification.
(2E,6E)-1-Bromo-3,7,11-trimethyldodeca-2,6,10-triene 3
To a solution of farnesol 2 (2.87 g, 12.9 mmol) in diethyl ether
(15 mL) and pyridine (0.1 mL) under nitrogen atmosphere, PBr3
(1.52 g, 5.6 mmol) dissolved with n-hexane (6 mL) was added at
0°C, and then the mixture was stirred for 0.5 h and following for
2 h at room temperature. The upper layer was poured into ice
water, and extracted with diethyl ether (20 mL ꢃ 3). The organic
layer was combined, washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo to afford 3 as a colorless liquid
(2.79 g, 76%).
General procedure for the preparation of 8a–h
To a mixture of different substituted diamines (0.33 mmol) and
TEA (0.45 mmol) in CH2Cl2 (10 mL) was dropwise added a CH2Cl2
solution (5 mL) of farnesylthiosalicyl chloride 7 (1.12 g, 0.3 mmol)
at 0°C. After stirred for another 0.5 h the mixture was added
20 mL water and extracted with CH2Cl2 (20 mL ꢃ 3). The organic
layer was combined, washed with brine, dried with anhydrous
Na2SO4 and concentrated in vacuo. The crude product was
separated by silica gel chromatography (CH2Cl2–MeOH ¼ 4:1 as
the eluent) to afford 8a–h as a yellowish oil.
Methyl 2-mercaptobenzoate 5
To a methanol solution (50 mL) of thiosalicylic acid 4 (5 g,
32.5 mmol), SOCl2 was added slowly and the mixture was stirred
for 1 h at 0°C, then warmed up to the room temperature and
refluxed for 6 h. The solvent was evaporated under reduced
pressure. The residue was dissolved in ethyl acetate (50 mL), and
then the solution was washed with saturated NaHCO3 (50 mL ꢃ 2)
and brine, dried with anhydrous Na2SO4. The crude product was
purified by silica gel chromatography (petroleum ether–ethyl
acetate ¼ 40:1 v/v as the eluent) to afford compound 5 as a
colorless liquid (4.62 g, 85%).
N-(2-(Diethylamino)ethyl)-2-(((2E,6E)-3,7,11-
trimethyldodeca-2,6,10-trien-1-yl)thio)benzamide 8a
Yellowish oil, 78% yield. IR (KBr, cmꢀ1): 3420, 3156, 1690, 1605,
1593, 1420; 1H NMR (DMSO-d6, 300 MHz, d ppm): 8.05 (m, 1H, Ar-
H), 7.83 (m, 1H, Ar-H), 7.30–7.38 (m, 2H, Ar-H), 5.23 (m, 1H,
–
SCH CH), 5.07–5.09 (m, 2H, 2 ꢃ CH CH CCH ), 3.56 (d, 2H,
–
2
2
3
J ¼ 9.0 Hz, SCH2), 2.99–3.05 (m, 8H, 4 ꢃ NCH2), 1.99 (m, 8H,
2 ꢃ CCH2CH2CH), 1.53–1.68 (m, 12H, 4 ꢃ CH3), 0.98 (m, 6H,
2 ꢃ CH2CH3); MS (ESI) m/z ¼ 457 [MþH]þ; Anal. calcd. for
C28H44N2OS: C, 73.63; H, 9.71; N, 6.13. Found: C, 73.52; H, 9.94;
N, 6.01.
Methyl 2-(((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-
yl)thio)benzoate 6
A mixture of 5 (1.8 g, 12 mmol), K2CO3 (2.6 g, 14 mmol), and 3
(3.4 g, 12 mmol) in acetonitrile (80 mL) was refluxed for 6 h. The
solvent was evaporated in vacuum and water was added. The
solution was neutralized with 2 N HCl solution to pH 6–7, and
then extracted with CH2Cl2 (20 mL ꢃ 3). The organic layer was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel (petroleum ether–ethyl acetate
¼ 30:1 v/v as the eluent), yield 6 as yellowish oil (3.66 g, 82%). 1H
NMR (CDCl3, 300 MHz, d ppm): 7.96 (m, 1H, Ar-H), 7.74 (m, 1H, Ar-
H), 7.30 (m, 1H, Ar-H), 7.14 (m, 1H, Ar-H), 5.34 (m, 1H, SCH2CH),
N-(3-(Dimethylamino)propyl)-2-(((2E,6E)-3,7,11-
trimethyldodeca-2,6,10-trien-1-yl)thio)benzamide 8b
Yellowish oil, 80% yield. IR (KBr, cmꢀ1): 3400, 3046, 1701, 1610,
1590, 1435; 1H NMR (DMSO-d6, 300 MHz, d ppm): 7.98 (m, 2H, Ar-
H), 7.31 (m, 2H, Ar-H), 5.33 (m, 1H, SCH2CH), 5.14 (m, 2H,
–
2 ꢃ CH CH CCH ), 3.38 (d, 2H, J ¼ 9.0 Hz, SCH ), 3.05 (m, 2H,
–
2
3
2
NCH2), 2.47 (m, 2H, NCH2), 2.24 (s, 6H, CH3NCH3), 1.90–1.99 (m,
8H, 2 ꢃ CCH2CH2CH), 1.54–1.69 (m, 14H, 4 ꢃ CH3, CH2CH2CH2);
MS (ESI) m/z ¼ 443 [MþH]þ; Anal. calcd. for C27H42N2OS: C, 73.25;
H, 9.56; N, 6.33. Found: C, 73.42; H, 9.31; N, 6.25.
–
5.09 (m, 2H, 2 ꢃ CH CH CCH ), 3.92 (s, 3H, OCH ), 3.58 (d, 2H,
–
2
3
3
J ¼ 7.8 Hz, SCH2), 1.89–2.02 (m, 8H, 2 ꢃ CCH2CH2CH), 1.50–1.68
–
(m, 12H, 4 ꢃ CH CCH ).
–
3
2-(((2E,6E)-3,7,11-Trimethyldodeca-2,6,10-trien-1-yl)thio)-
benzoic acid 1
N-(3-(Diethylamino)propyl)-2-(((2E,6E)-3,7,11-
trimethyldodeca-2,6,10-trien-1-yl)thio)benzamide 8c
Yellowish oil, 74% yield. IR (KBr, cmꢀ1): 3346, 3058, 1692, 1613,
1580, 1450; 1H NMR (DMSO-d6, 300 MHz, d ppm): 8.08 (m, 1H, Ar-
H), 7.89 (m, 1H, Ar-H), 7.30 (m, 2H, Ar-H), 5.23 (m, 1H, SCH2CH),
Compound 6 (2.50 g, 6.72 mmol) was dissolved in 60 mL of
methanol, then 1 N NaOH (10 mL) was added at room tempera-
ture. The mixture was stirred for 10 h at 60°C, and then cooled.
The solvent was evaporated and the residue was dissolved in 1 M
HCl solution and following extracted with ethyl acetate (30 mL
ꢃ 3). The organic layer was combined, washed with brine, dried
–
5.06 (m, 2H, 2 ꢃ CH CH CCH ), 3.48–3.42 (m, 4H, SCH , NCH ),
–
2
3
2
2
2.42 (m, 6H, 3 ꢃ NCH2), 1.90–1.99 (m, 8H, 2 ꢃ CCH2CH2CH), 1.54–
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