piperidines and 2-oxindole

A facile, multicomponent (MCR) atom-economic synthesis of novel spiro-oxindolo pyrrolizidine adducts of piperine has been achieved via an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction. Either of the two conjugated double bonds in piperine takes part in the reaction to produce two regioisomeric adducts in racemic form. Acenaphthoquinone, ninhydrin and different isatin derivatives were reacted with proline and piperine to afford a never before reported library of 22 compounds. The structures of the products were determined by 1D/2D NMR, mass spectral analysis and confirmed by X-ray crystallography of selected products. Chiral HPLC separation was performed to measure the specific rotation and CD spectra of the enantiomers for two racemic compounds.

Topics: Alkaloids; Azo Compounds; Benzodioxoles; Cycloaddition Reaction; Models, Molecular; Molecular Conformation; Oxindoles; Piperidines; Polyunsaturated Alkamides; Pyrroles; Spiro Compounds; Stereoisomerism; Thiosemicarbazones

Asymmetric synthesis of pharmacologically interesting piperidine-fused spiro-oxindole derivatives has been achieved via an organocatalytic Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds synthesized by this strategy potently inhibited the proliferation of several breast cancer cell lines. Mechanistic studies suggest that the most potent compound 9e can directly interfere with MDM2-p53 interactions and elevate protein levels of p53 and p21, thereby inducing cell cycle arrest and mitochondrial apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Binding Sites; Catalysis; Cell Proliferation; Humans; MCF-7 Cells; Molecular Dynamics Simulation; Oxindoles; Piperidines; Proto-Oncogene Proteins c-mdm2; Spiro Compounds; Stereoisomerism; Tumor Suppressor Protein p53

A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant cholinesterase inhibitory activity. Among the compounds screened, 8g and 8e, showed maximum inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE) with IC50 values of 3.33 and 3.13μM, respectively.

Topics: Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterases; Cyclization; Dose-Response Relationship, Drug; Indoles; Models, Molecular; Molecular Structure; Oxindoles; Piperidines; Pyrroles; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship

Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described. These three-dimensional frameworks, which conform to the "rule of three", are suitably protected to allow for site-selective manipulation and functionalization. Different modes of substrate control were explored, which allow for good to excellent levels of diastereoselectivity and dispense with the need for additional chiral reagents or catalysts. The concepts developed were applied in short, formal syntheses of (±)-coerulescine and (±)-horsfiline.

Topics: Aniline Compounds; Catalysis; Indoles; Lactams; Molecular Structure; Oxindoles; Piperidines; Pyrrolidines; Spiro Compounds; Stereoisomerism