3,5-Bis(Arylidene)-4-Piperidones Modified by Bisphosphonate Groups as Novel Anticancer Agents

GRAPHICAL ABSTRACT

Abstract

Synthetic approaches for conjugating 3,5-bis(arylidene)-4-piperidones with bisphosphonate moiety were elaborated. These approaches are based either on reaction of Grignard reagent containing dioxolane protected 4-piperidone with tetraethyl ethylidenbisphosphonate followed by crotonic condensation with aromatic aldehydes or on Cu(i) catalyzed 1,3-cycloaddition of tetraethyl but-3-yne-1,1-diylbisphosphonate to N-(2-azidoethyl)-3,5-bis(arylidene)-4-piperidones resulting in corresponding 1,2,3-triazole derivatives. Cytotoxic activity of the synthesized conjugates was dependent on the length of linker connecting piperidone nitrogen atom and bisphosphonate residue. Triazole derivatives of 3,5-bis(arylidene)-4-piperidone series displayed moderate in vitro inhibitory properties towards HCT116 and MCF7 human cancer cell lines with IC₅₀ values in the range of 5.0–7.5 μM, whereas conjugates with butylene linker between piperidone nitrogen atom and bisphosphonate moiety were significantly less active.

Keywords:

• 3,5-Bis(arylidene)-4-piperidones
• aminobisphosphonates
• bisphosphonates
• anticancer properties