Does Ortho-Substitution Enhance Cytotoxic Potencies in a Series of 3,5-Bis(benzylidene)-4-piperidones?

<b>Background:</b> A series of 3,5-benzylidene-4-piperidones, <b>1a</b>-<b>n</b>, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. <b>Methods:</b> The bioevaluation of <b>1a</b>-<b>n</b> was undertaken using human Molt/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles θ_A and θ_B and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, <b>1a</b>-<b>n</b> were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. <b>Results:</b> A positive correlation was noted between the interplanar angle θ_A of one of the aryl rings and the adjacent olefinic linkage with IC₅₀ values in the Molt4/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (π) value of the aryl substituents and the IC₅₀ values of the compounds towards the Molt4/C8 and CEM cells. The dienones in series <b>1</b> demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. <b>Conclusions:</b> The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents.