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

Makarov, Mikhail V.; Rybalkina, Ekaterina Yu.; Röschenthaler, Gerd‐Volker; Short, Kurt W.; Timofeeva, Tatiana V.; Odinets, Irina L.

doi:10.1016/j.ejmech.2008.10.019

Cited by 41 publications

(19 citation statements)

References 28 publications

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“…14,15 In all caseses the toxicity can be increased by modifying the 3,5-bis(arylidene)-4-piperidone compounds with nitroxides by acylation (3a, 3b) and by alkylation (5a-h, 7, 9, 11). In particular 3a, 3b demonstrated a substantial cytotoxic effect against A2780 and MCF-7 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Based on earlier X-ray crystallography data we propose compounds 1, 6, 8, 10 possess E stereochemistry. 10,14,15 The new N-acyl-3,5 bis(4-fluorobenzilydene)piperidin-4-ones were prepared by treatment of compound 1 with freshly prepared paramagnetic acyl chloride 2a 29 acetonitrile in the presence of K 2 CO 3 to give compounds 5a, 5b, 5c, 5d, , 5f, 5g, 5h. …”

Section: Chemistrymentioning

confidence: 99%

“…The 1,5-diaryl-3-oxo-1,4-pentadienyl groups considered to react at a primary binding site, however the bioactivity will be influenced by others structural units: such as acylating piperidone nitrogen increased cytotoxic potencies and increasing the electron-withdrawing properties of substituents on aromatic ring has advantageous effect on cytotoxicity. [14][15][16][17][18] However, dimethylenbridge between C2-C6 atoms in piperidone was accompanied by reduction of cytotoxic properties exerting a steric impedance to alignment at one or more binding sites as well as variation of hydrophobicity and hence membrane transportation properties. 16 In general the DAP compounds were more effective than curcumin in inhibiting the proliferation of a variety of cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

et al. 2011

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A series of 3,5-bis(arylidene)-4-piperidones (DAP compounds) are considered as synthetic analogs of curcumin for anticancer and anti-inflammatory properties. We performed structureactivity relationship studies by synthesizing a number of 3,5-bis(arylidene)-4-piperidones Nalkylated or acylated with nitroxides or their amine precursors as potent antioxidant moieties.Both subtituents on arylidene rings and on piperidone nitrogen (five-or six-membered, 2-or 3-or 3,4-disubstituted, isoindoline nitroxides) were varied. The anticancer efficacy of the new DAP compounds was tested by measuring their cytotoxicity to cancer cell lines A2780 (human epithelial ovarian cancer cell line) and MCF-7 (human breast cancer cell line) and to H9c2, a noncancerous (healthy) cardiac cell line. The results showed that all DAP compounds induced a significant loss of cell viability in both the human cancer cell lines tested, however only pyrroline appended nitroxides (5c, 1 5e, 7, 9) showed limited toxicity toward noncancerous cell lines. Computer docking simulations support the biological activity tested.These results suggest that antioxidant-conjugated DAPs will be useful as a safe and effective anticancer agent for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

et al. 2011

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“…However, the syntheses of such phosphorylated compounds via the condensation of w-aminophosphonates bearing piperidinone or a protected piperidinone moiety with aromatic aldehydes under the action of protic acids or strong bases resulted in rather low yields (typically in the range of 27 -40%) of the products due to the presence of hydrolytically unstable ester groups at the P-atom [17]. Therefore, we tested the Lewis acid-mediated synthesis for aldolcrotonic condensation using b-aminophosphonates 1d, 1e and 4-fluorobenzaldehyde as model substrate (Table 3).…”

mentioning

confidence: 98%

“…Recently, we demonstrated that introduction of the alkyl phosphonate moiety at the N-atom of 3,5-bis[(hetero)arylidene]piperidin-4-ones resulted in a dramatic increase Scheme of their cytotoxicity and bioavailability [16] [17]. However, the syntheses of such phosphorylated compounds via the condensation of w-aminophosphonates bearing piperidinone or a protected piperidinone moiety with aromatic aldehydes under the action of protic acids or strong bases resulted in rather low yields (typically in the range of 27 -40%) of the products due to the presence of hydrolytically unstable ester groups at the P-atom [17].…”

mentioning

confidence: 99%

Lewis Acids as Mild and Effective Catalysts for the Synthesis of 3,5‐Bis[(hetero)arylidene]piperidin‐4‐ones

Leonova

Makarov

Klemenkova

et al. 2010

Helvetica Chimica Acta

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The aldol-crotonic condensation reactions of N-alkyl-and NH-piperidin-4-one derivatives with (hetero)aromatic aldehydes promoted by Lewis acids or bases were examined. This comparative study has revealed three effective catalytic systems based on Lewis acids, i.e., LiClO 4 and MgBr 2 (in the presence of tertiary amine), and BF 3 · Et 2 O, for the synthesis of N-alkyl-substituted 3,5-bis(heteroarylidene)piperidin-4-ones, including those bearing acid-or base-labile groups both in the (hetero)aromatic groups and in the alkyl substituent at the N-atom. The highest reaction rate was observed for LiClO 4 -mediated synthesis. Both MgBr 2 -and LiClO 4 -mediated syntheses were inefficient in the case of NH-piperidin-4-one, while BF 3 · Et 2 O provided the final compounds in high yields. This catalyst is especially advantageous as it allows simultaneous condensation and deprotection in the case of Oprotected piperidin-4-one.

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

Makarov

Leonova

Rybalkina³

et al. 2012

Archiv der Pharmazie

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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.

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

Cited by 41 publications

References 28 publications

Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

Lewis Acids as Mild and Effective Catalysts for the Synthesis of 3,5‐Bis[(hetero)arylidene]piperidin‐4‐ones

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

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