Piperidone Derivatives Research Articles

Synthesis and pharmacological evaluation of polyamine-diarylidenyl piperidone derivatives as potent antitumor agents

Synthesis and pharmacological evaluation of polyamine-diarylidenyl piperidone derivatives as potent antitumor agents

Curcumin piperidone derivatives induce caspase-dependent apoptosis and suppress miRNA-21 expression in LN-18 human glioblastoma cells

BackgroundPreviously, we have reported on the two curcuminoid analogues with piperidone derivatives, namely FLDP-5 and FLDP-8 have more potent anti-proliferative and anti-migration effects than curcumin. In this study, we further investigated the mode of cell death and the mechanism involved in the cell death process induced by these analogues on human glioblastoma LN-18 cells.ResultsThe FLDP-5 and FLDP-8 curcuminoid analogues induced LN-18 cell death through apoptosis in a concentration-dependent manner following 24 h of treatment. These analogues induced apoptosis in LN-18 cells through significant loss of mitochondrial mass and mitochondrial membrane potential (MMP) as early as 1-hour of treatment. Interestingly, N-acetyl-l-cysteine (NAC) pretreatment did not abolish the apoptosis induced by these analogues, further confirming the cell death process is independent of ROS. However, the apoptosis induced by the analogues is caspases-dependent, whereby pan-caspase pretreatment inhibited the curcuminoid analogues-induced apoptosis. The apoptotic cell death progressed with the activation of both caspase-8 and caspase-9, which eventually led to the activation of caspase-3, as confirmed by immunoblotting. Moreover, the existing over-expression of miRNA-21 in LN-18 cells was suppressed following treatment with both analogues, which suggested the down-regulation of the miRNA-21 facilitates the cell death process.ConclusionThe FLDP-5 and FLDP-8 curcuminoid analogues downregulate the miRNA-21 expression and induce extrinsic and intrinsic apoptotic pathways in LN-18 cells.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 μM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 μM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

Synthesis and Biological Evaluation of Azacrownophanes Containing Tetrahydropyridine or Piperidone Subunits

AbstractHerein we presented the synthesis of azacrownophanes containing tetrahydropyridine or piperidone rings. The multicomponent reactions were performed and afforded tetrahydropyridine or piperidone derivatives which strongly depended on used substrates. Structure of tetrahydropyridine and piperidone derivatives was differentiated by spectrometry methods such as IR, HRMS, NMR and single‐crystal Xray diffraction. Eight synthesized compounds were evaluated for their cytotoxicity through Sulforhodamine B (SRB) assay. Three tetrahydropyridine derivatives displayed the most potent cytotoxic activity against Hep‐G2 and Lu‐1 cell lines with the IC50 values around 8 μM and 31.62 μM, respectively. The screening result of antimicrobial activities of all compounds showed negative values at a tested concentration of 50 μg/ml. The ADME study was calculated to provide some useful information about the structure and bioactivity relationship.

Curcumin piperidone derivatives induce anti-proliferative and anti-migratory effects in LN-18 human glioblastoma cells

Curcumin has demonstrated potential cytotoxicity across various cell lines despite its poor bioavailability and rapid metabolism. Therefore, our group have synthesized curcuminoid analogues with piperidone derivatives, FLDP-5 and FLDP-8 to overcome these limitations. In this study, the analogues were assessed on LN-18 human glioblastoma cells in comparison to curcumin. Results from cytotoxicity assessment showed that FLDP-5 and FLDP-8 curcuminoid analogues caused death in LN-18 cells in a concentration-dependent manner after 24-h treatment with much lower IC50 values of 2.5 µM and 4 µM respectively, which were more potent compared to curcumin with IC50 of 31 µM. Moreover, a significant increase (p < 0.05) in the level of superoxide anion and hydrogen peroxide upon 2-h and 6-h treatment confirmed the oxidative stress involvement in the cell death process induced by these analogues. These analogues also showed potent anti-migratory effects through inhibition of LN-18 cells’ migration and invasion. In addition, cell cycle analysis showed that these analogues are capable of inducing significant (p < 0.05) S-phase cell cycle arrest during the 24-h treatment as compared to untreated, which explained the reduced proliferation indicated by MTT assay. In conclusion, these curcuminoid analogues exhibit potent anti-cancer effects with anti-proliferative and anti-migratory properties towards LN-18 cells as compared to curcumin.

Supported Anionic Gold Nanoparticle Catalysts Modified Using Highly Negatively Charged Multivacant Polyoxometalates

AbstractAlthough supported anionic gold nanoparticle catalysts have been theoretically investigated for their efficacy in activating O2 in aerobic oxidation reactions, limited studies have been reported due to the difficulty of designing these catalysts. Herein, we developed a feasible method for preparing supported anionic gold nanoparticle catalysts using multivacant lacunary polyoxometalates with high negative charges. We confirmed the strong and robust electronic interaction between gold nanoparticles and multivacant lacunary polyoxometalates, and the electronic states of the supported gold nanoparticle catalysts can be sequentially modulated. Particularly, the catalyst prepared using [SiW9O34]10− acted as an efficient reusable heterogeneous catalyst, showing superior catalytic performance for the oxidative dehydrogenation of piperidone derivatives to the corresponding enaminones and remarkably higher stability than supported gold nanoparticle catalysts without this modification.

Supported Anionic Gold Nanoparticle Catalysts Modified Using Highly Negatively Charged Multivacant Polyoxometalates.

Although supported anionic gold nanoparticle catalysts have been theoretically investigated for their efficacy in activating O2 in aerobic oxidation reactions, limited studies have been reported due to the difficulty of designing these catalysts. Herein, we developed a feasible method for preparing supported anionic gold nanoparticle catalysts using multivacant lacunary polyoxometalates with high negative charges. We confirmed the strong and robust electronic interaction between gold nanoparticles and multivacant lacunary polyoxometalates, and the electronic states of the supported gold nanoparticle catalysts can be sequentially modulated. Particularly, the catalyst prepared using [SiW9 O34 ]10- acted as an efficient reusable heterogeneous catalyst, showing superior catalytic performance for the oxidative dehydrogenation of piperidone derivatives to the corresponding enaminones and remarkably higher stability than supported gold nanoparticle catalysts without this modification.

Synthesis, Crystal Structure, and Insecticidal Activity of Steroidal N-Piperidone.

A series of steroidal piperidone derivatives were synthesized, and their agricultural activities were evaluated against Myzus persicae, Aphis citricola, Brevicoryne brassicae Linn., and Bemisia tabaci (Gennadius). Most of the tested compounds exhibited potent insecticidal activity against these four pests. Compound I-9 displayed the highest activity against M. persicae, A. citricola, and Brevicoryne brassicae, with LC50 values of 11.3, 10.4, and 8.68 μg/mL, respectively. The mode of action test indicated that these derivatives had superior contact and systemic insecticidal activity against M. persicae. In addition, we initially explored whether the foregut and midgut might be the action sites of the target derivatives against M. persicae. Furthermore, a field trial showed that the control of compound I-9 was similar to that of acetamiprid against M. persicae, at a dose of 50 μg/mL; the control rates were 97.8 and 99.2% after 14 and 21 days, respectively. The structure-activity relationship of these analogues provided some important insights for the discovery and development of new insecticides to solve the current pesticide resistance crisis.

Development of a [2 + 2]-Nitroso/Alkene Cycloaddition Using Sodium Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate Catalyst: Controlled Chemoselectivity of Two Equilibrating Isomeric Intermediates.

Sodium tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate (NaBArF) catalyzes the [2 + 2] cycloaddition of 1,4-disubstituted cyclopenta-1,3-dien-2-yl esters with nitrsobenzene in toluene, affording two isolable regioisomers of 6-oxa-7-azabicyclo[3.2.0] heptanes, which thermally rearrange into the same 4-aminocyclopent-1-en-3-ones. In the case of 4-substituted cyclopenta-1,3-dien-2-yl esters, their initial [2 + 2] cycloaddition intermediates undergo a rapid ring expansion to afford six-membered piperidone derivatives efficiently.

DESIGN AND MOLECULAR DOCKING STUDIES OF PIPERIDIN-4-ONE DERIVATIVE AS ACTIVE AGENT AGAINST HELICOBACTER PYLORI INFECTION

Helicobacter pylori is one of the most common bacterial pathogens in the world and is an important global public health concern. Half of the world populations are seriously infected by Helicobacter pylori. In India, approximately 80% of the population is infected with the bacterium Helicobacter pylori by the age of 20. Among those, hundreds of millions of people are affected by peptic ulcer disease during their lifetime and tens of millions might develop to gastric cancer. Helicobacter pylori infections are very difficult to cure. This present work is aimed to find the solutions to overcome this problem. Black pepper is used to cure ulcer since it has piperine which has piperidin moiety. Piperidin-4-one is one of the most biological active moieties, used as drug. In the present work, more than thirty eight thousand, 2,6-diphenyl piperidone derivatives are theoretically designed and docked with 2B7N protein of Helicobacter pylori. PyRx virtual screening is used to dock protein with ligand to find lead molecules. The best docking piperidones are selected and their drug likeness properties are predicted computationally. Finally best lead molecule is identified.

Exploration of Noncovalent Interactions, Chemical Reactivity, and Nonlinear Optical Properties of Piperidone Derivatives: A Concise Theoretical Approach.

The organic compounds with a π-bond system lead to electric charge delocalization which enables them to reveal fascinating nonlinear optical properties. Mono-carbonyl curcuminoids also have an appealing skeleton from the conjugation view point. Interesting chemical structures of the 3,5-bis(arylidene)-N-benzenesulfonyl-4-piperidone derivatives motivated us to perform density functional theory (DFT)-based studies. Therefore, computations using the B3LYP/6-311G(d,p) functional of DFT were executed to explore geometric parameters, highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) energies, and natural bond orbital (NBO) analyses. Moreover, three different functionals such as HF, B3LYP, and M06 with the 6-311G(d,p) basis set were used to investigate the average polarizability ⟨α⟩ and first hyperpolarizability (βtot)-based properties of all compounds. A good concurrence among calculated and experimental parameters was obtained through root mean square error calculations. The molecular stability of piperidone derivatives was examined using the Hirshfeld surface and NBO analyses. Natural population analysis was also performed to obtain insights about atomic charges. Calculated HOMO–LUMO energies showed that charge transfer interactions take place within the molecules. Moreover, global reactivity parameters including electronegativity, chemical hardness, softness, ionization potential, and electrophilicity were calculated using the HOMO and LUMO energies. The average polarizability ⟨α⟩ and first hyperpolarizability (βtot) values of all compounds were observed to be larger in magnitude at the aforesaid functional than the standard compound.

A new fluorescent chemosensor for cadmium(II) based on a pyrene-appended piperidone derivative and its β-cyclodextrin complex.

We report, in this article, a piperidin-4-one derivative carrying pyrenyl fluorescent reporter groups which acts as a Cd2+ ion sensor. The compound is synthesized and characterized using IR and NMR spectral techniques. The compound forms an inclusion complex with β-cyclodextrin. It selectively binds to Cd2+ ions in water and aqueous β-cyclodextrin media. The stoichiometry of the host-guest complex of the compound with β-cyclodextrin is 1:2. The ligand-metal ion binding stoichiometry is 1:1 both in water and in β-cyclodextrin. The linear concentration range of detection of the metal ion is reported. Cyclodextrin complex formation does not affect the metal ion selectivity of the compound.

Anticancer potential of diarylidenyl piperidone derivatives, HO-4200 and H-4318, in cisplatin resistant primary ovarian cancer

ABSTRACTWe have previously developed a novel class of bi-functional compounds based on a diarylidenyl-piperidone (DAP) backbone conjugated to an N-hydroxypyrroline (-NOH; a nitroxide precursor) group capable of selectively inhibiting STAT3 activation, translocation, and DNA binding activity. HO-4200 and H-4318 are 2 such derivatives capable of inducing apoptosis in ovarian cancer cells through this mechanism and demonstrated efficacy in platinum resistant primary ovarian cancer cell populations and tumor tissues. The improved absorption and cellular uptake of HO-4200 by cancer cells was determined using optical and electron paramagnetic resonance spectrometry. Treatment of ovarian cancer cells with HO-4200 and H-4318 resulted in cleavage of caspase proteins 3, 7, and 9, as well as PARP and inhibition of the pro-survival protein, Bcl-xL, resulting in significantly decreased cell survival and increased apoptosis. HO-4200 and H-4318 significantly inhibit fatty acid synthase (FAS) and pSTAT3 and decreased the expression of STAT3 target proteins: Survivin, c-myc, Bcl-xl, Bcl-2, cyclin D1/D2, and VEGF were suppressed as analyzed using quantitative real time PCR. In addition, HO-4200 and H-4318 significantly inhibited migration/invasion, in primary ovarian cancer cell populations isolated from primary and recurrent ovarian cancer patients. Treatment of freshly collected human ovarian tumor sections with HO-4200 demonstrated significant suppression of pSTAT3 Tyr 705, angiogenesis (VEFG), and markers of proliferation (Ki-67) in ex vivo models. We have shown, for the first time, that the DAP compounds, HO-4200 and H-4318, inhibit cell migration/invasion and induce apoptosis by targeting FAS/STAT3 in human ovarian cancer cells, including primary ovarian cancer cell populations and tumor tissues. Therefore, our results highlight the clinical anti-cancer potential of HO-4200 and H-4318.

A High Affinity hRpn2-Derived Peptide That Displaces Human Rpn13 from Proteasome in 293T Cells.

Rpn13 is a proteasome ubiquitin receptor that has emerged as a therapeutic target for human cancers. Its ubiquitin-binding activity is confined to an N-terminal Pru (pleckstrin-like receptor for ubiquitin) domain that also docks it into the proteasome, while its C-terminal DEUBAD (DEUBiquitinase ADaptor) domain recruits deubiquitinating enzyme Uch37 to the proteasome. Bis-benzylidine piperidone derivatives that were found to bind covalently to Rpn13 C88 caused the accumulation of polyubiquitinated proteins as well as ER stress-related apoptosis in various cancer cell lines, including bortezomib-resistant multiple myeloma lines. We find that a 38-amino acid peptide derived from the C-terminus of proteasome PC repeat protein hRpn2/PSMD1 binds to hRpn13 Pru domain with 12 nM affinity. By using NMR, we identify the hRpn13-interacting amino acids in this hRpn2 fragment, some of which are conserved among eukaryotes. Importantly, we find the hRpn2-derived peptide to immunoprecipitate endogenous Rpn13 from 293T cells, and to displace it from the proteasome. These findings indicate that this region of hRpn2 is the primary binding site for hRpn13 in the proteasome. Moreover, the hRpn2-derived peptide was no longer able to interact with endogenous hRpn13 when a strictly conserved phenylalanine (F948 in humans) was replaced with arginine or a stop codon, or when Y950 and I951 were substituted with aspartic acid. Finally, over-expression of the hRpn2-derived peptide leads to an increased presence of ubiquitinated proteins in 293T cells. We propose that this hRpn2-derived peptide could be used to develop peptide-based strategies that specifically target hRpn13 function in the proteasome.

Anticancer potential of diarylidenyl piperidone derivatives, HO-4200 and HO-4318, in ovarian cancer

Anticancer potential of diarylidenyl piperidone derivatives, HO-4200 and HO-4318, in ovarian cancer

Electrochemical Access to 8-(1-Phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-7-carbonitrile. Application to the Asymmetric Syntheses of (+)-Myrtine and Alkaloid (+)-241D

The total syntheses of both enantiomers of trans-quinolizidine (+)-myrtine and cis-2,4,6-trisubstituted piperidine alkaloid (+)-241D are reported here. Our approach was based on the N-Boc-directed metalation of enantiopure 4-piperidone (-)-11, which was prepared in four steps from α-amino nitrile 6 through a stereoselective alkylation-reduction decyanation process. α-Amino nitrile 6 was prepared at the anode through electrochemical oxidation of 4-piperidone (+)-5. In our study, α-phenylethylamine (α-PEA) allowed an efficient 1-3 stereoinduction, and an orthogonal cleavage of the N-Boc protecting group in piperidone derivatives was carried out by stirring them in a suspension of SnCl4·(Et2O)2 complex in diethyl ether. When appropriate, the er's were determined by proton and carbon NMR spectroscopy utilizing (+)-tert-butylphenylphosphinothioic acid and (+)-DBTA as chiral solvating agents.

2-Chlorotetrafluoroethanesulfinamide induced asymmetric vinylogous Mannich reaction

The generality of (S)-2-chlorotetrafluoroethanesulfinamide (CTFSA) induced asymmetric vinylogous Mannich (AVM) addition reaction has been investigated. The reaction of aldimines derived from (S)-CTFSA with 2-(tert-butyldimethylsilyloxy) furan (TBSOF) took place regioselectively at the γ-site at room temperature in DMSO under air atmosphere to give the desired addition products in syn-configuration with high diastereoselectivities (up to 98:2 dr). However, anti-configuration product as major isomer was obtained in the presence of tetra-butyl ammonium fluoride (TBAF) at −78 °C. Facile removal of the auxiliary group without epimerization demonstrated their synthetic potential for piperidone derivatives.

Three-Component Reaction of Tautomeric Amidines with 3-Ferrocenylmethylidene-2,4-pentanedione. Formation of Polymeric Coordination Complexes of Potassium Ferrocenyl-(hexahydro)pyrimidoxides

Acetamidine hydrochloride and p-aminobenzamidine dihydrochloride interact with 3-ferrocenylmethylidene-2,4-pentanedione at 80–82 °C in the presence of K2CO3 in the water–alcohol medium in two tautomeric forms (the amidoimine and enediamine ones) with formation of mixtures of pyrimidine and piperidone derivatives and polymeric coordination complexes of potassium ferrocenyl(hexahydro)pyrimidoxides. The structure of the resultant compounds is elucidated on the basis of IR, 1H- and 13C-NMR spectroscopy, mass spectrometry and elemental analysis data. The crystal structures of 6-ferrocenyl-4-hydroxy-4-methyl-2-piperidone, potassium 6-ferrocenyl-4-methyl-2-methylidene(hexahydro)pyrimidin-4-oxide and 2-(4-aminophenyl)-4-ferrocenyl-6-methyl-pyrimidine were determined by X-ray analysis of suitable single crystals.

Supramolecular synthesis based on piperidone derivatives and pharmaceutically acceptable co-formers

The target complexes, bis{(E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-oxopiperidinium} butanedioate, 2C27H36N3O(+)·C4H4O4(2-), (II), and bis{(E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-oxopiperidinium} decanedioate, 2C27H36N3O(+)·C10H16O4(2-), (III), were obtained by solvent-mediated crystallization of the active pharmaceutical ingredient (API) (E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-piperidone and pharmaceutically acceptable dicarboxylic (succinic and sebacic) acids from ethanol solution. They have been characterized by melting point, IR spectroscopy and single-crystal X-ray diffraction. For the sake of comparison, the structure of the starting API, (E,E)-3,5-bis[4-(diethylamino)benzylidene]-4-piperidone methanol monosolvate, C27H35N3O·CH4O, (I), has also been studied. Compounds (II) and (III) represent salts containing H-shaped centrosymmetric hydrogen-bonded synthons, which are built from two parallel piperidinium cations and a bridging dicarboxylate dianion. In both (II) and (III), the dicarboxylate dianion resides on an inversion centre. The two cations and dianion within the H-shaped synthon are linked by two strong intermolecular N(+)-H···(-)OOC hydrogen bonds. The crystal structure of (II) includes two crystallographically independent formula units, A and B. The cation geometries of units A and B are different. The main N-C6H4-C=C-C(=O)-C=C-C6H4-N backbone of cation A has a C-shaped conformation, while that of cation B adopts an S-shaped conformation. The same main backbone of the cation in (III) is practically planar. In the crystal structures of both (II) and (III), intermolecular N(+)-H···O=C hydrogen bonds between different H-shaped synthons further consolidate the crystal packing, forming columns in the [100] and [101] directions, respectively. Salts (II) and (III) possess increased aqueous solubility compared with the original API and thus enhance the bioavailability of the API.

Highly Enantioselective Conjugate Addition of Malononitrile to 2-Enoylpyridines with Bifunctional Organocatalyst

An efficient enantioselective conjugate addition of malononitrile to a range of β-substituted 2-enoylpyridines catalyzed by cinchona alkaloid-based bifunctional urea catalysts has been developed. Both enantiomers of the products could be achieved with the same level of enantioselectivity by using pseudoenantiomeric catalysts in up to 97% ee and in excellent yields. One of the enantioenriched products has been transformed to a highly functionalized piperidone derivative.