Citation: Zhi-Qiang Wang, Ren-An Chang, Hai-Ying Huang, Xue-Min Wang, Xin-Yang Wang, Li Chen, Yong Ling. Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents[J]. Chinese Chemical Letters, ;2014, 25(12): 1545-1549. doi: 10.1016/j.cclet.2014.06.021 shu

Synthesis and biological evaluation of novel farnesylthiosalicylic acid/salicylic acid hybrids as potential anti-tumor agents

Zhi-Qiang Wang ^a,b,c ,
Ren-An Chang ^c,d ,
Hai-Ying Huang ^c,d ,
Xue-Min Wang ^c ,
Xin-Yang Wang ^c ,
Li Chen ^a,b,, ,
Yong Ling ^b,c,,

a.
a. Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;
b.
b. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;
c.
c. School of Pharmacy, Nantong University, Nantong 226001, China;
d.
d. Department of Hepatobiliary Surgery, Affiliated Hospital, Nantong University, Nantong 226001, China

Corresponding author: Li Chen, Yong Ling,
Received Date: 5 May 2014
Available Online: 13 June 2014
Fund Project: We gratefully acknowledge the Natural Science Foundation of China (No. 81302628) (No. 81302628)Jiangsu Province (No. BK2011389) (No. BK2011389) China Pharmaceutical University for the Open Project Program of State Key Laboratory of Natural Medicines (No. SKLNMKF201415) for the financial support, and also thank a project funded by the Priority Academic Programs Development (PAPD) of Jiangsu Higher Education Institutions. (No. SKLNMKF201415)

A series of FTS/salicylic acid hybrids was designed and synthesized and their in vitro antitumor activities were evaluated. It was found that the anti-proliferation activities of hybrids were better than that of FTS. Compound 10a displayed the strongest antitumor activities with IC₅₀ values of 5.72-9.76 mmol/L and selectively inhibited tumor cell proliferation. In addition, 10a induced tumor cell apoptosis in a dosedependent manner by up-regulating the expression of Bax and caspase-3 and down-regulating Bcl-2. Our findings suggest that these novel hybrids may hold a great promise as therapeutic agents for the intervention of human cancers.
- Farnesylthiosalicylic acid,
- Salicylic acid,
- Antitumor activities,
- Cell apoptosis
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  [26] The experimental procedures and data of selected compounds: 2-(2-(2-((2E,6E)-3,7,11-Trimethyldodeca-2,6,10-trienylthio)benzamido)ethylcarbamoyl)-phenyl acetate (9a): To the CH₂Cl₂ (5 mL) solution of compound 7a (0.5 g, 1 mmol) was added TFA (5 mL), and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the product was dissolved in dry CH₂Cl₂ (10 mmol) and triethylamine (0.21 mL, 1.5 mmol) was added, then p-acetoxyphenylpropenoic acid chloride (0.2 g, 1 mmol) dissolved in dry CH₂Cl₂ (10 mmol) was dropwise added at 0 ℃, and the reaction mixture was stirred at room temperature. After the reaction completed (1 h later), the resulting mixture was allowed to pour into ice-water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford the crude product. Then it was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 2/1, v/v) to give compound 9a, pale yellow oil, and yield 81%. IR (KBr, cm^-1): ν 3262, 3074, 2925, 1748, 1565, 1245, 1198; ¹H NMR (300 MHz, CDCl₃): δ 7.62-7.67 (m, 2H, Ar-H), 7.34-7.39 (m, 2H, Ar-H), 7.25-7.31 (m, 4H, Ar-H), 5.25 (m, 1H, SCH₂CH), 5.07 (m, 2H, 2 × CH₂CH=CCH₃), 3.44-3.55 (m, 6H, SCH₂, 2 × NCH₂), 2.28 (s, 3H, Ac), 1.97-2.02 (m, 8H, 2 × CCH₂CH₂CH), 1.50-1.75 (m, 12H, 4 × CH=CCH₃); MS (ESI): m/z 563 [M+H]⁺; Anal. Calcd. for C₃₃H₄₂N₂O₄S: C, 70.43; H, 7.52; N, 4.98; Found: C, 70.28; H, 7.65; N, 5.84. 2-Hydroxy-N-(2-(2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)benzamido)ethyl)benzamide (10a): Compound 9a (0.28 g, 0.5 mmol) was dissolved in methanol (5 mL) and 1 mol/L NaOH (1 mL) was added, and the mixture was stirred at room temperature for 2 h, then was added water (20 mL), neutralized with 2 mol/L HCl to pH 5 and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give 10a, pale yellow oil, and yield 81%. IR (KBr, cm^-1): ν 3285, 3048, 2927, 1643, 1552, 1232, 1185; 1H NMR (300 MHz, CDCl₃): δ 7.57-7.62 (m, 2H, Ar-H), 7.32-7.38 (m, 2H, Ar-H), 7.24-7.31 (m, 4H, Ar-H), 5.26 (m, 1H, SCH₂CH), 5.08 (m, 2H, 2 × CH₂CH=CCH₃), 3.48-3.60 (m, 6H, SCH₂, 2 × NCH₂), 1.98-2.01 (m, 8H, 2 × CCH₂CH₂CH), 1.50-1.79 (m, 12H, 4 × CH=CCH₃); MS (ESI): m/z 521 [M+H]⁺; Anal. Calcd. for C₃₁H₄0N₂O₃S: C, 71.50; H, 7.74; N, 5.38; Found: C, 71.37; H, 7.82; N, 5.31. 2-Hydroxy-N-(3-(2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)benzamido)-propyl)benzamide (10b): Refer to the synthesis of 10a, compound 10b was obtained from 9b, pale yellow oil, and yield 94%. IR (KBr, cm^-1): ν 3275, 3056, 2928, 1636, 1544, 1228, 1191; ¹H NMR (300 MHz, CDCl₃): δ 7.61-7.65 (m, 2H, Ar-H), 7.36-7.42 (m, 2H, Ar-H), 7.26-7.34 (m, 4H, Ar-H), 5.26 (m, 1H, SCH₂CH), 5.07 (m, 2H, 2 × CH₂CH=CCH₃), 3.48-3.55 (m, 6H, SCH₂, 2× NCH₂), 3.32-3.36 (m, 2H, NCH₂CH2₂), 1.98-2.02 (m, 8H, 2 × CCH₂CH₂CH), 1.54-1.71 (m, 12H, 4 × CH=CCH₃); CCH₃); MS (ESI): m/z 635 [M+H]⁺; Anal. Calcd. for C₃₂H₄₂N₂O₃S: C, 71.87; H, 7.92; N, 5.24; Found: C, 71.73; H, 8.01; N, 5.37.
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