A series of 3,5-bis(arylidene)-4-piperidone (DAP) compounds are considered as synthetic analogues of
curcumin for anticancer properties. We performed structure-activity relationship studies by synthesizing a number of
DAPs N-alkylated or acylated with nitroxides or their
amine precursors as potent
antioxidant moieties. Both subtituents on arylidene rings and on
piperidone nitrogen (five- or six-membered, 2- or 3-substituted or 3,4-disubstituted isoindoline nitroxides) were varied. The anticancer efficacy of the new DAP compounds was tested by measuring their cytotoxicity to
cancer cell lines A2780 and MCF-7 and to the H9c2 cell line. The results showed that all DAP compounds induced a significant loss of cell viability in the human
cancer cell lines tested; however, only
pyrroline appended nitroxides (5c (Selvendiran, K.; Tong, L.; Bratasz, A.; Kuppusamy, L. M.; Ahmed, S.; Ravi, Y.; Trigg, N. J.; Rivera, B. K.; Kálai, T.; Hideg, K.; Kuppusamy, P. Mol.
Cancer Ther. 2010, 9, 1169-1179), 5e, 7, 9) showed limited toxicity toward noncancerous cell lines. Computer docking simulations support the
biological activity tested. These results suggest that
antioxidant-conjugated
DAPs will be useful as a safe and effective
anticancer agent for
cancer therapy.