Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents
- Bioorg Med Chem. 2014 Jan 1;22(1):374-80. doi: 10.1016/j.bmc.2013.11.013.
- 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Medical College, Nantong University, Nantong 226001, PR China.
- 2. Medical College, Nantong University, Nantong 226001, PR China.
- 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
- 4. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
- 5. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
Fourteen hybrids of farnesylthiosalicylic acid (FTS) with various diamines were synthesized and biologically evaluated. It was found that FTS-monoamide molecules (10a-g) displayed strong anti-proliferative activity against seven human Cancer cell lines, superior to FTS and FTS-bisamide compounds (11a-g). The mono-amide 10f was the most active, with IC₅₀s of 3.78-7.63 μM against all tested Cancer cells, even more potent than sorafenib (9.12-22.9 μM). In addition, 10f induced SMMC-7721 cell Apoptosis, down-regulated the expression of Bcl-2 and up-regulated Bax and Caspase-3. Furthermore, 10f had the improved aqueous solubility relative to FTS. Finally, treatment with 10f dose-dependently inhibited the Ras-related signaling pathways in SMMC-7721 cells. Collectively, 10f could be a promising candidate for the intervention of human cancers.