Fluorine-containing isosteres enable a structure-activity relationship study of gingerol derivatives

• Trifluoromethyl isosteres can be synthetically introduced into gingerol derivatives. • Introduction of these fluorinated isosteres maintained antiproliferative potency. • Analogs containing enones and free phenols had the highest antiproliferative activity. A series of fluorinated and non-fluorinated [6]-gingerol, [6]-paradol, [6]-shogaol and ferulate derivatives were synthesized. Testing these analogs in anti-proliferation assays with MCF-7, A549, HCT-116 and HEK-293 cell lines provided insight into the structural features that contribute to the anti-proliferative activity of naturally occurring ginger constituents. In particular, the use of both vinyl and alkyl trifluoromethyl isosteres allowed us to evaluate the structure-activity impact of the enone motif found in shogaols. Our results indicate that enone-containing derivatives have a higher potency, suggesting the conjugated enone motif characteristic of shogaols may be primarily responsible for the anti-cancer activity of the broader natural product family.