Cytotoxic 3,5-bis(benzylidene)piperidin-4-ones and N-acyl analogs displaying selective toxicity for malignant cells

A series of 3,5-bis(benzylidene)piperidin-4-ones 1, 1-acryloyl-3,5-bis(benzylidene)piperidin-4-ones 2 and adducts of 2 with sodium 2-mercaptoethanesulfonate (mesna), namely series 3, were prepared as candidate cytotoxic agents. These compounds were examined against neoplastic HSC-2, HSC-4 and HL-60 cells as well as HGF, HPC and HPLF normal cell lines and many of the compounds displayed selective toxicity for malignant cells. The CC50 values of the analogs in series 2 towards the cancer cell lines were mainly submicromolar. The relative potencies, selectivity and log P values were in the order of 2 > 1 > 3. The sulfonic acid group of a representative compound in series 3 was replaced by a thiol function to produce 4 leading to substantial increases in cytotoxic potencies and hydrophobicity indicating that the presence of a hydrophilic sulfonic acid group was disadvantageous in terms of potency. Molecular modeling suggested that the superior cytotoxicity of various members of series 1–3 over an acyclic analog 5 may have been due to the greater torsion angles θ1 and θ2 created between the arylidene aryl rings and the adjacent olefinic groups in series 1–3.

A number of 3,5-bis(benzylidene)piperidin-4-one derivatives 1–3 were prepared and screened as candidate cytotoxic agents. N-acryloyl-3,5-bis(benzylidene)piperidin-4-one 2 displayed promising cytotoxicity with noteworthy selectivity towards malignant cells.Figure optionsDownload as PowerPoint slide