Novel hybrid molecules of 3,5-bis(benzylidene)-4-piperidones and dichloroacetic acid which demonstrate potent tumour-selective cytotoxicity

• Novel hybrid molecules displaying high potency towards human colon cancer HCT116 cells. • Most compounds are far less toxic to non-malignant CRL1790 cells leading to high selectivity index values. • Lead molecules demonstrated >100 times higher potency than a reference drug 5-FU. • The mode of action of representative compounds includes lowering of the mitochondrial membrane potential and increase in ROS generation. A novel class of hybrid molecules 2a - o was designed as candidate antineoplastic agents from dichloroacetic acid which is a known inhibitor of pyruvate dehydrogenase kinase and a number of cytotoxic 3,5-bis(benzylidene)-4-piperidones 1 . In general these new hybrid molecules are potent cytotoxins towards human HCT116 colon cancer cells. A number of lead molecules emerged having the IC 50 values in the double digit nanomolar range. Most of these compounds are less toxic to human CRL1790 non-malignant colon cells and hence the selectivity index (SI) figures for most of the compounds are huge; in the case of 2c - g , m, n , the SI values are in excess of 100. Compounds 2g , 2j , 2m and 2n displayed >100-fold higher potency than the reference drug 5-FU. Quantitative structure-activity relationships revealed that the potencies of the compounds in series 2 increase as the magnitude of the Hammett σ and Taft σ* values rise. X-ray crystallographic of a representative compound 2c revealed various structural features which may influence cytotoxic potencies. Several representative compounds lowered the mitochondrial membrane potential and increased the production of reactive oxygen species in HCT116 cells. A minimal effect was noted in altering the percentage of cells in different phases of the cell cycle. Some future directions have been outlined for analog development.