A conformational and structure-activity relationship study of cytotoxic 3,5-bis(arylidene)-4-piperidones and related N-acryloyl analogues

A series of 3,5-bis(arylidene)-4-piperidones 1 and related N-acryloyl analo gues 2 were prepared as candidate cytotoxic agents with a view to discernin g those structural features which contributed to bioactivity. A number of t he compounds were markedly cytotoxic toward murine P388 and L1210 leukemic cells and also to human Molt 4/C8 and CEM neoplasms. Approximately 40% of t he IC50 values generated were lower than the figures obtained for melphalan . In virtually all cases, the N-acyl compounds were significantly more bioa ctive than the analogues 1. In general, structure-activity relationships re vealed that the cytotoxicity of series 1 was correlated positively with the size of the aryl substituents, while in series 2, a -sigma relationship wa s established. In particular, various angles and interatomic distances were obtained by molecular modeling, and the presence of an acryloyl group on t he piperidyl nitrogen atom in series 2 affected the relative locations of t he two aryl rings. This observation, along with some differences in distanc es between various atoms in series 1 and 2, may have contributed to the dis parity in cytotoxicity between 1 and 2. The results obtained by X-ray cryst allography of representative compounds were mainly in accordance with the o bservations noted by molecular modeling. Selected compounds interfered with the biosynthesis of DNA, RNA, and protein in murine L1210 cells, while oth ers were shown to cause apoptosis in the human Jurkat leukemic cell line. T his study has revealed the potential of these molecules for development as cytotoxic and anticancer agents.