Synthesis, characterization and structure–activity relationship of novel N-phosphorylated E,E-3,5-bis(thienylidene)piperid-4-ones

In order to design the agents with improved antitumor activity of 3,5-bis(thienylidene)piperid-4-one type, E,E-N-phosphoryl-3,5-bis(thienylidene)piperid-4-ones 6a-c and E,E-N-ω-phosphorylalkyl-3,5-bis-(thienylidene)piperid-4-ones 7a-c were obtained via the direct phosphorylation of the parent NH-3,5-bis(thienylidene)piperid-4-one and by condensation of preformed N-phosphorylalkyl substituted piperidones with thiophene 2-carbaldehyde, respectively. The structures of the compounds were elucidated by 1H, 31P, 13C NMR along with a single crystal X-ray diffraction analysis. Under the action of visible light thermodynamically more stable E,E-isomers slowly undergo photochemical conversion in CDCl3 solution to the corresponding E,Z-isomers and E,Z-N-methyl-3,5-bis(thienylidene)piperid-4-one 5 was isolated in individual state. The importance of phosphorylation for cytotoxic properties of 3,5-bis(thienylidene)piperid-4-ones towards human carcinoma cell lines Caov3, Scov3, and A549 and influence of olefin configuration on antitumor activity were demonstrated.

Graphical abstractDirect phosphorylation of NH-bis(thienylidene)-4-piperidone and condensation of ω-aminophosphonates bearing piperidone or a protected piperidone moiety with thiophen 2-carbaldehyde provide a convenient approach to phosphorus substituted 3,5-bis(thienylidene)piperid-4-ones possessing high cytotoxicity towards human carcinoma cell lines CaOv3, Scov3, and A549. The importance of phosphorylation for cytotoxic properties and influence of olefin configuration on antitumor activity were demonstrated.Figure optionsDownload full-size imageDownload as PowerPoint slide