Synthesis and biological evaluation of farnesylthiosalicylamides as potential anti-tumor agents

Yong Ling; Zhiqiang Wang; Hongyan Zhu; Xuemin Wang; Wei Zhang; Xinyang Wang; Li Chen; Zhangjian Huang; Yihua Zhang

doi:10.1016/j.bmc.2013.11.013

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. Epub 2013 Nov 15.

Authors

Yong Ling¹, Zhiqiang Wang¹, Hongyan Zhu², Xuemin Wang², Wei Zhang², Xinyang Wang², Li Chen³, Zhangjian Huang⁴, Yihua Zhang⁵

Affiliations

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: zyhtgd@hotmail.com.

PMID: 24300920
DOI: 10.1016/j.bmc.2013.11.013

Abstract

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.

Keywords: Anti-cancer agents; Cell apoptosis; Diamines; Farnesylthiosalicylic acid; Ras-related signaling pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis
Farnesol / analogs & derivatives*
Farnesol / chemical synthesis
Farnesol / chemistry
Humans
Neoplasms / drug therapy*
Salicylates / chemical synthesis*
Salicylates / chemistry
Signal Transduction

Substances

Antineoplastic Agents
Salicylates
farnesylthiosalicylic acid
Farnesol