Curcumin derivatives with 1,5-diaryl-3-oxo-1,4-pentadiene: novel dual-function lead compounds showing anticancer and...

1,5-Diaryl-3-oxo-1,4-pentadiene is an excellent pharmacophore derived from Curcumin. Synthesis of six focused 1,5-diaryl-3-oxo-1,4-pentadiene libraries (1a-1e, 2a-2e, 3a-3e, 4a-4e, 5a-5e and intermediates A-E) and cytotoxicity screening identified compounds 1d-5d with N-3-F-PhCH₂, which are generally more active than the corresponding molecules possessing the unsubstituted benzylidene moiety. The IC₅₀ values of 14 out of 35 compounds are lower than 5 µM, particularly 5d and 4d, which have IC₅₀ values of 0.17 µM (A549) and 0.68 µM (HeLa), respectively. Most compounds exhibited a preferential and selective toxicity to cancer cells versus normal liver cells (LO2), except for 3c, 4c, 4e and 5e, which exhibited slightly poor activity. In total, 7 human cancer cell lines were analyzed, with all derivatives showing broad-spectrum activity. Simultaneously, multidrug resistance (MDR) reversal activity and cellular uptake were determined. Analysis of data revealed that most compounds with simple 2 F, 4 F or 3-Br at benzylidene possessed potent MDR-reversing properties, reducing the expression level of the drug-resistance gene MDR1 to below 50% versus control, in particular, 4a and 4e, with reductions to less than 10% and 15%, respectively. Importantly, the intermediates (C, D and E), 3a, 3b, 4a, 4d, 4e, 5d and 5e displayed both potent MDR-reverting properties and strong cytotoxicity, which may serve as a guideline for future molecular modification strategies to develop dual-function agents in cancer therapy.