New sulfurated cinnamic acid derivatives as multitarget anticancer agents

It is well known that inflammatory conditions in selected organs increase the risk of cancer. Compounds of the inflammatory tumor microenvironment include leukocytes, cytokines, complement components and are orchestrated by transcription factors, such as STAT-3 (Signal Transducer and Activator of Transcription 3) and NF-kB.1,2 Therefore drugs able to inhibit one or both transcription factors could be useful tools to treat cancer disease. Since natural sulfurated compounds (such as dithiolethiones, allicin, diallylpolysulfides and S-methylmethanethiosulfonate) and some cinnamic acid derivatives (in particular ferulic acid and caffeic acid) are endowed with cancer chemopreventive properties, through multiple mechanisms (including STAT3 and/or NF-kB inhibition), we decided to synthesize a set of novel drug hybrids (Fig.1) where the two components of the molecule can act in a synergistic way, thus obtaining new more potent multitarget antiproliferative agents. The new synthesized compounds were submitted to the AlphaScreen-based assay, to investigate their ability to bind STAT-3 SH2 domain and to Luciferase promoter activities assay, to measure their ability to inhibit NF-kB promoter activity. Results showed that most of the new hybrid compounds inhibited HCT-116 cell proliferation in vitro with IC50 in micromolar range. In addition, they were able to strongly and selectively bind STAT-3 SH2 domain (whereas the parent drugs were completely devoid of this ability at the tested concentrations) and were also able to inhibit the NF-kB transcriptional activity in HCT-116 cell line. Studies are ongoing to better define the profile of our new hybrids as potential dual STAT-3/NF-kB inhibitors.