RESUMEN
All possible variants of ß-proline functionalized tripeptides consisting of homo/hetero chiral monomeric all-cis 5-arylpyrrolidine-2,4-dicarboxylate units were synthesized for the first time by a nonpeptidic coupling method based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Secondary structures of ß-proline tripeptides in solution were determined using the NMR spectroscopy data. o-(Trifluoromethyl)phenyl substituent contributes to stereoselectivity of 1,3-dipolar cycloaddition and structural features of ß-proline tripeptides. A ß-proline CF3-tripeptide with alternating absolute chirality between adjacent pyrrolidine units mimics natural PPII helix secondary structure.
RESUMEN
4-l-menthyloxycarbonyl 5-aryl prolinates were studied as organocatalysts of a novel three-component reaction of cyclohexanone, benzoic acid, and ß-nitrostyrene. The presence of ortho-halogen atom in 5-aryl fragment of the catalyst is favored for driving the formation of chiral 7a-hydroxyoctahydro-2H-indol-2-one scaffold. 5-(o-Chlorophenyl) prolinate selectively afforded 3-phenyl-7a-hydroxyoctahydro-2H-indol-2-one with ee 63%, whereas 5-phenyl prolinate led to conjugation of ß-nitrostyrene to cyclohexanone (the Michael adduct). Plausible chlorine effect is accounted for the specific interaction of the 5-aryl prolinate enamine intermediate with ß-nitrostyrene in the transition state.
Asunto(s)
Ácido Benzoico/química , Ciclohexanonas/química , Estirenos/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
N-Heterocyclic carbenes (NHC) are well-recognized ligands of choice for preparing robust transition metal species. However, their use for fabrication of biomedically relevant nanoparticles has been limited to the synthesis of non-targeted particles showing increased tolerance to different aqueous coagulants. In this work, the first example of carbene-coated metal nanoparticles suitable for in vivo applications is presented. Directed design of a novel biscarbene NHC ligand allowed to prepare the first magnetite/gold (Fe3O4@AuNP@NHC) nanostructures and carbene gold (AuNP@NHC) nanoparticles with significant stability in aqueous solutions and enhanced ability to form bioconjugates. Furthermore, these nanoparticles exhibit an extraordinary property for inorganic nanoparticles: they can endure several additive-free air drying/redispersion cycles without deterioration of their colloidal behavior. Bioconjugated AuNP@NHC and multimodal Fe3O4@AuNP@NHC demonstrated a successful performance in three distinct applications: lateral flow tests, specific cancer cell targeting, and bioimaging. Thus, the results show the notable advantages of the N-heterocyclic carbene coating of inorganic nanoparticles and their utility for complex biomedical applications.
Asunto(s)
Oro , Nanopartículas del Metal , Metano , Metano/química , Metano/análogos & derivados , Oro/química , Nanopartículas del Metal/química , Humanos , Tamaño de la PartículaRESUMEN
In the title compound, C(16)H(15)F(3)N(2)O(4), the relative stereochemistry of the four stereogenic C atoms has been determined. The carb-oxy-methyl and 2-(trifluoro-meth-yl)-phenyl substituents of the pyrrolidine cycle have a cis mutual arrangement. The five-membered saturated aza-cycle adopts an envelope conformation with the N atom occupying the flap position. In the crystal, adjacent mol-ecules are combined in centrosymmetric dimers by two weak N-Hâ¯O hydrogen bonds.
RESUMEN
5-Arylpyrrolidine-2-carboxylates with an ortho-halogen substituent at 5-aryl and an electron-withdrawing group at the C4 position of the pyrrolidine ring were transformed into 1H-benzo[b]azepine-2-carboxylates under Cu(I) promotion and microwave activation. Reaction promoter copper(I) thiophene-2-carboxylate has been generated in situ in the reaction's environment from Cu2O and thiophene-2-carboxylic acid. Functionalized 1H-benzo[b]azepine-2-carboxylates were obtained in racemic and optically active forms in 67-89% yields. Subsequent stereoselective 1,3-dipolar cycloaddition and an Ullmann-type annulation/rearrangement cascade (UARC) ensure a synthetic route to oligomeric optically active benzazepine species with a well-defined 3D-structure.
RESUMEN
The title compound, C38H50N2O7, represents a chiral ß-proline dipeptide. Corresponding stereogenic centres of constituting pyrrolidine units have opposite absolute configurations. The central amide fragment is planar within 0.1â Å and adopts a Z configuration along the N-CO bond. In the crystal, the hydrogen atoms of the methyl-ene groups form several short inter-molecular C-Hâ¯O contacts with the carbonyl oxygen atoms of an adjacent mol-ecule. The only active amino hydrogen atom is not involved in hydrogen bonding.
RESUMEN
Synthetic ß-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of ß-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z/E isomerism of ß-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of ß-proline oligopeptides. Preferences in their structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied ß-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the ß-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating ß-proline pentapeptide, the presence of an E configuration for at least of one ß-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of ß-peptide bonds forming a wave-like extended structure.
RESUMEN
The use of peptides that target cancer cells and induce anticancer activities through various mechanisms is developing as a potential anticancer strategy. KUD983, an enantiomerically pure ß-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU145 cells with submicromolar IC50. KUD983 induced G1 arrest of the cell cycle and subsequent apoptosis associated with down-regulation of several related proteins including cyclin D1, cyclin E and Cdk4, and the de-phosphorylation of RB. The levels of nuclear and total c-Myc protein, which could increase the expression of both cyclin D1 and cyclin E, were profoundly inhibited by KUD983. Furthermore, it inhibited PI3K/Akt and mTOR/p70S6K/4E-BP1 pathways, the key signaling in multiple cellular functions. The transient transfection of constitutively active myristylated Akt (myr-Akt) cDNA significantly rescued KUD983-induced caspase activation but did not blunt the inhibition of mTOR/p70S6K/4E-BP1 signaling cascade suggesting the presence of both Akt-dependent and -independent pathways. Moreover, KUD983-induced effect was enhanced with the down-regulation of anti-apoptotic Bcl-2 members (e.g., Bcl-2, and Mcl-1) and IAP family members (e.g., survivin). Notably, KUD983 induced autophagic cell death using confocal microscopic examination, tracking the level of conversion of LC3-I to LC3-II and flow cytometric detection of acidic vesicular organelles-positive cells. In conclusion, the data suggest that KUD983 is an anticancer ß-dipeptide against HRPCs through the inhibition of cell proliferation and induction of apoptotic and autophagic cell death. The suppression of signaling pathways regulated by c-Myc, PI3K/Akt and mTOR/p70S6K/4E-BP1 and the collaboration with down-regulation of Mcl-1 and survivin may explain KUD983-induced anti-HRPC mechanism.
RESUMEN
ß-Proline-functionalized dimers consisting of homochiral monomeric units were synthesized by a non-peptidic coupling method for the first time. The applied synthetic methodology is based on 1,3-dipolar cycloaddition chemistry of azomethine ylides and provides absolute control over the ß-proline backbone stereogenic centers. An o-(trifluoromethyl)phenyl substituent contributes to appropriate stabilization of the definite acrylamide chiral cis conformation and to achieve the dipole reactivity that is not observed for aryl groups lacking strong electronegative character.