Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells

Sixty-nine
novel α,β-unsaturated carbonyl based compounds,
including cyclohexanone, tetralone, oxime, and oxime ether analogs,
were synthesized. The antiproliferative activity determined by using
seven different human cancer cell lines provided a structure–activity
relationship. Compound 8ag exhibited high antiproliferative
activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with
IC50 value of 0.02 μM, comparable to the positive
control Erlotinib. The ten most active antiproliferative compounds
were assessed for mechanistic effects on BRAFV600E, EGFR
TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed
by cancer cells. Compound 8af exhibited the most potent
BRAFV600E inhibitory activity with an IC50 value
of 0.9 μM. Oxime analog 7o displayed the most potent
EGFR TK inhibitory activity with an IC50 of 0.07 μM,
which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role
as anticancer and MDR reversal agents.