Methylenebisphosphonates with Dienone Pharmacophore: Synthesis, Structure, Antitumor and Fluorescent Properties

Abstract

The synthesis and the antitumor activity and fluorescent properties screening of novel bisphosphonate conjugates with cytotoxic 3,5-bis((hetero)arylidene)-4-piperidone residues were performed. The facile and rapid synthetic route was based on the aza-Michael addition of NH-3,5-bis((hetero)arylidene)-4-piperidones to tetraethyl ethylidenebisphosphonate. The synthesized compounds displayed high inhibitory properties towards Caov3, A549, PC3, and KB 3-1 human carcinoma cell lines. Among those, compounds bearing 4-cyano-phenyl and 3-pyridinyl substituents were revealed as the most active drug candidates with IC(50) values in the range of 0.5-2.5 µM. Methylenebisphosphonate with 4-Me(2) N-C(6) H(4) groups in the piperidone framework possessing fluorescence properties may be of interest for visualization of BPs skeletal distribution and cellular uptake in bones and other tissues.

Novel Bisphosphonates Derived from 1H‐Indazole, 1H‐Pyrazolo[3,4‐b]Pyridine, and 1H‐Pyrazolo[3,4‐b]Quinoline

“…This is also the cause of the deformation from the tetrahedral shape of both phosphorus atoms, which present angles ranging from 116.77(8)-101.63(8)°f or P1, and 116.61(8)-100.02(8)°for P2, as observed for alkylphosphonic acids [30,38,40,41]. This is also the cause of the deformation from the tetrahedral shape of both phosphorus atoms, which present angles ranging from 116.77(8)-101.63(8)°f or P1, and 116.61(8)-100.02(8)°for P2, as observed for alkylphosphonic acids [30,38,40,41].…”

“…The P-C8 bond lengths are shorter than the corresponding 1hydroxybisphosphonic acid bonds [30] but still fall within the range of other alkylphosphonic acids and esters [30,38,40,41]. The P-C8 bond lengths are shorter than the corresponding 1hydroxybisphosphonic acid bonds [30] but still fall within the range of other alkylphosphonic acids and esters [30,38,40,41].…”

3,5‐Bis(arylidene)piperid‐4‐ones Containing 1,3,2‐Oxazaphosphorinane Moieties: Synthesis and Antitumor Activity

“…Antitumor properties of these compounds can be adjusted either by the variation of aromatic substituents or the introduction of different groups at the piperidone nitrogen atom. Indeed, we have recently shown that incorporation of a range of phosphorus‐containing moieties, such as phosphonate and methylenebisphonate groups, as well as phosphoric acid residues either directly bound with the heterocyclic nitrogen atom or connected with it via an alkylene linker, into the structure of 3,5‐bis(arylidene)piperid‐4‐ones, resulted in a pronounced increase of their in vitro cytotoxicity .…”

Synthesis, structure and luminescence of novel co-crystals based on bispyridyl-substituted α , β -unsaturated ketones with coformers

“…In addition, some 3,5-bis(arylidene)-4-piperidones have been reported to display good cytotoxic activities and interesting fluorescent properties because of their structural characteristic of double a,b-unsaturated ketone [16][17][18][19][20][21][22]. In Short's report, some 3,5-bis(arylidene)-4-piperidone derivatives might be potential twophoton sensitizers because of the donor-p-acceptor-p-donor structure in the molecules [19].…”