Synthesis and cytotoxicity of substituted aromatic curcuminoids against human oral epidermal carcinoma-KB cell line

Introduction: The survival rate of oral cancer, like other types of cancers, has not been improved regardless of the early diagnosis and the introduction of advanced therapies. Treatment for oral cancer includes surgery, radiation therapy, and chemotherapy. However, the effectiveness has been limited due to recurrence and undesirable side effects. Metabolites from plant sources have been shown to be relatively less toxic and thus are considered as potential anti-cancer agents. Interestingly, curcumin isolated from the rhizome of Curcuma longa L. possesses broad-spectrum bioactivities. We focused on the synthesis of curcumin-based analogs bearing -OH/-OCH3/-F groups on the phenyl rings in our continuous efforts to search for curcumin-based anti-cancer agents. The synthesized compounds were subsequently evaluated for the cytotoxic activities against KB cancer cell line (an epidermal carcinoma of the mouth). Methods: The desired curcuminoids were synthesized via aldol reactions between benzaldehyde derivatives and pentane-2,4-dione using n-butylamine as a catalyst. Structures were distinguished by NMR and MS spectra. The cytotoxic activity against KB was determined through the half-maximal inhibitory concentration (IC50, mM). Results: Six curcumin analogs (1-6) were successfully synthesized in a yield of 48-76%. The 3- hydroxy/fluoro curcumin analogs (3, IC50 = 15.61 0.13 mM; 6, IC50 = 22.65 1.76 mM) exhibited better anti-cancer activities when compared to curcumin (1, IC50 = 33.35 2.66 mM), whereas the para-fluoro substitution patterns displayed lower inhibitory activities (4, 5) against KB cancer cell line. Conclusions: The synthetic yields are dependent on the position and nature of substituents in aromatic rings. The presence of electron-donating groups gives products (1-3) in lower yields when compared to those (4-6) prepared from fluorinated benzaldehydes as starting materials. The curcuminoids bearing -OH groups at para-positions in aromatic rings (1, 2) can be responsible for better inhibition of cell growth, whereas the fluoro-substituted compounds (4, 5) make a negative contribution to inhibitory activity. Furthermore, the contributions -OH/-F groups at meta-position in aromatic rings of (3, 6) on the cytotoxicity against KB are remarkable and firstly reported in our findings.