Structure-activity relationships of novel dithiocarbamates containing α,β-unsaturated ketone fragment as potent anticancer agents

Based on the structure of novel lead compound 8 discovered by our group, systematic structural modification was carried out. A series of compound 8’s derivatives were synthesized and evaluated for their activities against human non-small cell lung cancer cell line H460. Among them, twelve compounds showed significant proliferation inhibition activities with IC50 values <1 μM and compound 12r was the most potent one. Further study on compound 12r revealed that it has significant inhibitory effect on the growth of eight kinds of cancer cell lines with IC50 values <1 μM. Especially for cell lines A375 and HCT116, the IC50 values of 12r achieved 63 nM and 66 nM, respectively. Meanwhile, our research results also revealed the following structure-activity relationships: (a) different substitutions on the benzene ring or heteroaromatic rings greatly effect on the activity; (b) the presence of α,β-unsaturated ketone fragment is favorable for the activity; (c) the receptor cavity binding with amine moiety might be a relatively small hydrophobic cavity. These results will be valuable for the further development of this novel kind of dithiocarbamates.