G Model
CCLET 3055 1–5
Z.-Q. Wang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
5
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
[10] D. Laheru, P. Shah, N.V. Rajeshkumar, et al., Integrated preclinical and clinical
development of S-trans, trans-Farnesylthiosalicylic acid (FTS, Salirasib) in pan-
creatic cancer, Invest. New Drugs 30 (2012) 2391–2399.
[11] A.M. Tsimberidou, M.A. Rudek, D. Hong, et al., Phase 1 first-in-human clinical
study of S-trans,trans-farnesylthiosalicylic acid (salirasib) in patients with solid
tumors, Cancer Chemother. Pharmacol. 65 (2010) 235–241.
[12] L. Goldberg, A. Ocherashvilli, D. Daniels, et al., Salirasib (farnesyl thiosalicylic acid)
for brain tumor treatment: a convection-enhanced drug delivery study in rats,
Mol. Cancer Ther. 7 (2008) 3609–3616.
[13] R. Haklai, G. Elad-Sfadia, Y. Egozi, Y. Kloog, Orally administered FTS (salirasib)
inhibits human pancreatic tumor growth in nude mice, Cancer Chemother.
Pharmacol. 61 (2008) 89–96.
[14] Y. Ling, Z.Q. Wang, H.Y. Zhu, et al., Synthesis and biological evaluation of
farnesylthiosalicylamides as potential anti-tumor agents, Bioorg. Med. Chem.
22 (2014) 374–380.
[15] Y. Ling, X.L. Ye, Z.Z. Zhang, et al., Novel nitric oxide-releasing derivatives of
farnesylthiosalicylic acid: synthesis and evaluation of anti-hepatocellular carci-
noma activity, J. Med. Chem. 54 (2011) 3251–3259.
[16] Y. Ling, X.L. Ye, H. Ji, et al., Synthesis and evaluation of nitric oxide-releasing
derivatives of farnesylthiosalicylic acid as anti-tumor agents, Bioorg. Med. Chem.
18 (2010) 3448–3456.
[17] Y. Ling, Y.A. Xiao, G.T. Chen, et al., Synthesis and in vitro biological evaluation of
farnesylthiosalicylic acid derivatives as anti-tumor carcinoma agents, Chin.
Chem. Lett. 23 (2012) 1141–1144.
[18] J. Cuzick, F. Otto, J.A. Baron, et al., Aspirin and non-steroidal anti-inflammatory
drugs for cancer prevention: an international consensus statement, Lancet Oncol.
10 (2009) 501–507.
[19] M.Y. Lai, J.A. Huang, Z.H. Liang, et al., Mechanisms underlying aspirin-mediated
growth inhibition and apoptosis induction of cyclooxygenase-2 negative colon
cancer cell line SW480, World J. Gastroenterol. 14 (2008) 4227–4233.
[20] R.E. Langley, S. Burdett, J.F. Tierney, et al., Aspirin and cancer: has aspirin been
overlooked as an adjuvant therapy? Br. J. Cancer 105 (2011) 1107–1113.
[21] C. Bosetti, V. Rosato, S. Gallus, J. Cuzick, C. La Vecchia, Aspirin and cancer risk: a
quantitative review to 2011, Ann. Oncol. 23 (2012) 1403–1415.
[22] A.M. Algra, P.M. Rothwell, Effects of regular aspirin on long-term cancer incidence
and metastasis: a systematic comparison of evidence from observational studies
versus randomised trials, Lancet Oncol. 13 (2012) 518–527.
[23] D.J. Elder, A. Hague, D.J. Hicks, C. Paraskeva, Differential growth inhibition by the
aspirin metabolite salicylate in human colorectal tumor cell lines: enhanced
apoptosis in carcinoma and in vitro-transformed adenoma relative to adenoma
relative to adenoma cell lines, Cancer Res. 56 (1996) 2273–2276.
[24] H.G. Yu, J.A. Huang, Y.N. Yang, et al., The effects of acetylsalicylic acid on
proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer
cells, Eur. J. Clin. Invest. 32 (2002) 838–846.
[25] J.M. Garcı´a-Heredia, M. Herva´s, M.A. De la Rosa, J.A. Navarro, Acetylsalicylic acid 268
induces programmed cell death in Arabidopsis cell cultures, Planta 228 (2008)
269
270
89–97.
[26] The experimental procedures and data of selected compounds: 2-(2-(2-((2E,6E)- 271
3,7,11-Trimethyldodeca-2,6,10-trienylthio)benzamido)ethylcarbamoyl)-phenyl
272
acetate (9a): To the CH2Cl2 (5 mL) solution of compound 7a (0.5 g, 1 mmol) was 273
added TFA (5 mL), and the mixture was stirred at room temperature overnight. 274
The solvent was removed in vacuo, and the product was dissolved in dry CH2Cl2 275
(10 mmol) and triethylamine (0.21 mL, 1.5 mmol) was added, then p-acetoxy- 276
phenylpropenoic acid chloride (0.2 g, 1 mmol) dissolved in dry CH2Cl2 (10 mmol) 277
was dropwise added at 0 8C, and the reaction mixture was stirred at room 278
temperature. After the reaction completed (1 h later), the resulting mixture 279
was allowed to pour into ice-water (30 mL), and extracted with ethyl acetate 280
(30 mL Â 3). The organic phase was washed with brine, dried over anhydrous 281
sodium sulfate, filtered and evaporated to afford the crude product. Then it was 282
purified by column chromatography on silica gel (petroleum ether/ethyl ace- 283
tate = 2/1, v/v) to give compound 9a, pale yellow oil, and yield 81%. IR (KBr, cmÀ1): 284
n 3262, 3074, 2925, 1748, 1565, 1245, 1198; 1H NMR (300 MHz, CDCl3): d 7.62– 285
7.67 (m, 2H, Ar-H), 7.34–7.39 (m, 2H, Ar-H), 7.25–7.31 (m, 4H, Ar-H), 5.25 (m, 1H, 286
SCH2CH), 5.07 (m, 2H, 2 Â CH2CH5CCH3), 3.44–3.55 (m, 6H, SCH2, 2 Â NCH2), 2.28 287
(s, 3H, Ac), 1.97–2.02 (m, 8H, 2 Â CCH2CH2CH), 1.50–1.75 (m, 12H, 4 Â CH5CCH3); 288
MS (ESI) m/z = 563 [M+H]+; Anal. Calcd. for C33H42N2O4S: C, 70.43; H, 7.52; N, 289
4.98; Found: C, 70.28; H, 7.65; N, 5.84. 2-Hydroxy-N-(2-(2-((2E,6E)-3,7,11-tri- 290
methyldodeca-2,6,10-trienylthio)benzamido)ethyl)benzamide (10a): Compound 291
9a (0.28 g, 0.5 mmol) was dissolved in methanol (5 mL) and 1 mol/L NaOH (1 mL) 292
was added, and the mixture was stirred at room temperature for 2 h, then was 293
added water (20 mL), neutralized with 2 mol/L HCl to pH 5 and extracted with 294
ethyl acetate (20 mL Â 3). The organic layer was washed with brine, dried over 295
anhydrous Na2SO4, filtered and concentrated in vacuo to give 10a, pale yellow oil, 296
and yield 81%. IR (KBr, cmÀ1): n 3285, 3048, 2927, 1643, 1552, 1232, 1185; 1H 297
NMR (300 MHz, CDCl3): d 7.57–7.62 (m, 2H, Ar-H), 7.32–7.38 (m, 2H, Ar-H), 7.24– 298
7.31 (m, 4H, Ar-H), 5.26 (m, 1H, SCH2CH), 5.08 (m, 2H, 2 Â CH2CH5CCH3), 3.48– 299
3.60 (m, 6H, SCH2, 2 Â NCH2), 1.98–2.01 (m, 8H, 2 Â CCH2CH2CH), 1.50–1.79 (m, 300
12H, 4 Â CH5CCH3); MS (ESI): m/z 521 [M+H]+; Anal. Calcd. for C31H40N2O3S: C, 301
71.50; H, 7.74; N, 5.38; Found: C, 71.37; H, 7.82; N, 5.31. 2-Hydroxy-N-(3-(2- 302
((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)benzamido)propyl)benza-
303
mide (10b): Refer to the synthesis of 10a, compound 10b was obtained from 9b, 304
pale yellow oil, and yield 94%. IR (KBr, cmÀ1): n 3275, 3056, 2928, 1636, 1544, 305
1228, 1191; 1H NMR (300 MHz, CDCl3): d 7.61–7.65 (m, 2H, Ar-H), 7.36–7.42 (m, 306
2H, Ar-H), 7.26–7.34 (m, 4H, Ar-H), 5.26 (m, 1H, SCH2CH), 5.07 (m, 2H, 307
2 Â CH2CH5CCH3), 3.48–3.55 (m, 6H, SCH2, 2 Â NCH2), 3.32–3.36 (m, 2H, 308
NCH2CH2), 1.98–2.02 (m, 8H, 2 Â CCH2CH2CH), 1.54–1.71 (m, 12H, 309
4 Â CH5CCH3); MS (ESI): m/z 635 [M+H]+; Anal. Calcd. for C32H42N2O3S: C, 310
71.87; H, 7.92; N, 5.24; Found: C, 71.73; H, 8.01; N, 5.37.
311
Please cite this article in press as: Z.-Q. Wang, et al., Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid