3,5-Bis-benzylidene-4-piperidones and related compounds with high activity towards P388 leukemia cells

3,5-Bis(benzylidene)-4-piperidones and related compounds were prepared and found to have between 100 and 9700 times the activity of N,N'-bis(2-chloroethyl)-N-nitrosourea towards P388 leukemia cells. The shapes of six of these molecules--determined by X-ray crystallography--were compared, but no correlation between the stereochemistry of the molecules or their electronic properties and cytotoxicity was apparent. Molecular modification of the compounds by forming two mono-benzylidene compounds, a related acyclic derivative and an N-acyl compound resulted in diminished but retained high cytotoxicity. Two representative compounds lowered glutathione levels of liver following their intraperitoneal injection into mice. Two quaternary ammonium compounds were shown to bind in the minor groove of DNA, while four related non-quaternary ammonium derivatives did not demonstrate this property. We conclude that the modes of action of these highly cytotoxic compounds include alkylation of cellular thiols and DNA binding, but interference with other biochemical processes is also probably involved.