Methylenebisphosphonates with dienone pharmacophore: synthesis, structure, antitumor and fluorescent properties.

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.

Structure-cytotoxicity relationship in a series of N-phosphorus substituted E,E-3,5-bis(3-pyridinylmethylene)- and E,E-3,5-bis(4-pyridinylmethylene)piperid-4-ones.

In order to give further insight on the influence of the aromatic ring nature and the presence of the phosphorus substituent at the piperidone nitrogen atom of E,E-3,5-bis((hetero)arylidene)piperid-4-ones on their antitumor properties, a series of phosphorus substituted E,E-3,5-bis(pyridinylmethylene)piperid-4-ones bearing either 3-pyridine or 4-pyridine rings was obtained. Novel NH-3,5-bis(pyridinylmethylene)piperid-4-ones 1a,b were converted into the corresponding N-phosphorylated derivatives 3a-c, 4a-c differing in the substitution at the phosphorus atom (amidophosphates and amidophosphonates), via direct phosphorylation while N-(ω-phosphorylalkyl)-substituted compounds 8a-c were obtained via aldol-crotonic condensation of preformed N-phosphorylalkyl substituted piperidones with the corresponding pyridinecarboxaldehyde. The cytotoxicity screen has revealed that phosphorylated compounds based on E,E-3,5-bis(4-pyridinylmethylene)piperid-4-one framework displayed higher inhibitory properties toward Caov3, A549, KB 3-1 and KB 8-5 human carcinoma cell lines comparing with their analogues with 3-pyridine rings. Introduction of the phosphorus moiety substantially increased the antitumor properties in the case of E,E-3,5-bis(3-pyridinylmethylene)piperid-4-ones derivatives but this influence less pronounced for more active analogues bearing 4-pyridinyl rings. Most of the compounds tested are potent against multi-drug resistant cell line KB 8-5 affording some guidelines for the search of perspective drug-candidates among phosphorus substituted E,E-3,5-bis((hetero)arylidene)piperid-4-ones.

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-omega-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 (1)H, (31)P, (13)C 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 CDCl(3) 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.

Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E,E-3,5-bis(arylidene)piperid-4-ones.

A series of E,E-N-phosphorylalkylene-3,5-bis(arylidene)piperid-4-ones 7a-k was prepared via the condensation of aromatic aldehydes with omega-aminophosphonates 5a-c and 6a,b bearing piperidone or a protected piperidone moiety, respectively. The synthetic routes to the starting aminophosphonates 5a-c and 6a,b varied depending on the number of methylene groups in the alkylene chain and comprised the Kabachnik-Fields reaction (n=1), the aza-Michael reaction (n=2) or alkylation of 4-piperidone hydrochloride with diethyl omega-bromoalkylphosphonates under phase transfer catalysis conditions (n=3,4). Phosphoryl substituted 3,5-bis(arylidene)piperid-4-ones 7b,c,e,f,h,i,k bearing both nitro groups and fluorine atoms in the para-position of the arene rings possess cytotoxicity toward human carcinoma cell lines CaOv3, Scov3, PC3 and A549 in the low micromolar range while their analogues having para-dimethylamino groups had IC(50) values greater than 50 microM. In contrast, only Me(2)N-substituted phosphonates 7g,j (n=3 and 4) and the salts of Me(2)N-substituted phosphonic acids 10c,f (n=2 and 3) display fluorescence.

o-Semiquinonic PCP-pincer nickel complexes with alkyl substituents: versatile coordination sphere dynamics.

o-Semiquinonic nickel pincer complexes (R2PCP)Ni(SQ) show a versatile coordination sphere dynamics via "swing" or "fan" oscillations depending on the steric properties of the phosphorus substituents.