Synthesis and Activity of Fluorinated Derivatives of Sulindac Sulphide and Sulindac Sulphone

The synthesis of fluorinated derivatives of the sulphide and sulphone metabolites of sulindac, a non-steroidal anti-inflammatory agent with chemopreventative activity, is reported. The key step in the synthesis is a Pummerer-rearrangement of the parent sulindac sulphoxide using (diethylamino)sulphur trifluoride as an activating agent and as a source of the fluoride nucleophile. The reaction leads to the formation of the 4-fluoromethylthio and 4-fluoromethylsulphonyl derivatives of sulindac (4a and 4b, respectively). Sulindac sulphide is 2.5 times more potent as a COX-1 inhibitor compared with its fluorinated counterpart 4a. The sulphones were inactive as COX-1 inhibitors, and none of the compounds inhibited COX-2 concentrations up to 0.1 mM. Cytotoxicity assays showed that 4a and 4b were as cytotoxic as sulindac sulphide and sulindac sulphone on 3719 colorectal carcinoma cell lines. Compound 4b was the most potent compound on RCA cells with an IC50 of 95 μM (sulindac sulphide 140μM, sulindac sulphone 175 μM). Fluorinated sulindac derivatives warrant further investigation since we have shown that cytotoxic activity can be retained or even increased independently from COX-inhibitory properties. This could help minimize the undesired side-effects associated with chronic sulindac administration.