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All possible variants of β-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 n...

New mepregenol 17-acetate derivatives with potential cytotoxicity were synthesized. Mepregenol 17-acetate 3-acrylate (III) was shown to exhibit potent cytotoxicity although the ester of N-benzylpyrrolidine-3-carboxylic acid (IV) had weaker activity that was comparable with those of megestrol acetate and progesterone. The IC50 values for III, IV, progesterone, and megestrol acetate were 30, 200, 480, and 130 μMwith respect to native HeLa culture and 9.1, 180, 5.6, and 115 μm for an estradiol-stimulated culture of HeLa, respectively. The cytotoxicities of steroids III and IV correlated with their DNA-damaging effect in a DNA comet assay. Thus, III was promising for further research as an antitumor compound with respect to estradiol-dependent tumors.

All possible variants of β-proline functionalized tripeptides consisting of homo/hetero chiral monomeric all

4-l-menthyloxycarbonyl 5-aryl prolinates were studied as organocatalysts of a novel three-component reaction of cyclohexanone, benzoic acid, and β-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 β-nitrostyrene to cyclohexanone (the Michael adduct). Plausible chlorine effect is accounted for the specific interaction of the 5-aryl prolinate enamine intermediate with β-nitrostyrene in the transition state.

The title compound represents a chiral β-proline dipeptide. Corresponding stereogenic centres of constituting pyrrolidine units have opposite absolute configurations. The central amide fragment is planar within 0.1 Å and adopts a Z configuration along the N—CO bond., The title compound, C38H50N2O7, represents a chiral β-proline dipeptide. Corresponding stereogenic centres of constituting pyrrolidine units have opposite absolute configurations. The central amide fragment is planar within 0.1 Å and adopts a Z configuration along the N—CO bond. In the crystal, the hydrogen atoms of the methyl­ene groups form several short inter­molecular C—H⋯O contacts with the carbonyl oxygen atoms of an adjacent mol­ecule. The only active amino hydrogen atom is not involved in hydrogen bonding.

Polysubstituted derivatives of sterically hindered phenol were found to reduce accumulation of hydroperoxides in the lipid extract from fish feed after 8-week incubation. Feeding of juvenile Russian sturgeon with fish food containing these compounds showed no negative effect on hydrobionts. Both in vivo and in vitro experiments revealed inhibition of hepatic lipid oxidation in juvenile Russian sturgeon in the presence of new bis-pyrrolidine derivatives of 2,6-di-tert-butylphenol. A reliable positive correlation was observed between the concentration of hydroperoxides in the lipid extract from fish feed and accumulation level of secondary enzymatic oxidation products of hepatic lipids in hydrobionts.

// Mei-Ling Chan 1 , Chia-Chun Yu 1 , Jui-Ling Hsu 1 , Wohn-Jenn Leu 1 , She-Hung Chan 1 , Lih-Ching Hsu 1 , Shih-Ping Liu 2, 3 , Polina M. Ivantcova 4 , Ozdemir Dogan 5 , Stefan Brase 6, 7 , Konstantin V. Kudryavtsev 4, 8 and Jih-Hwa Guh 1 1 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Urology, National Taiwan University Hospital, Taipei, Taiwan 4 Department of Medicinal Chemistry, Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation 5 Department of Chemistry, Middle East Technical University, Ankara, Turkey 6 Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany 7 Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany 8 Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow region, Russian Federation Correspondence to: Konstantin V. Kudryavtsev, email: kudr@med.chem.msu.ru Jih-Hwa Guh, email: jhguh@ntu.edu.tw Keywords: β-dipeptide, c-Myc, PI3K/Akt, mTOR, hormone-refractory prostate cancer Received: October 21, 2016 Accepted: May 08, 2017 Published: May 20, 2017 ABSTRACT 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 β-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU145 cells with submicromolar IC 50 . 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 β-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.

β-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 β-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.

Heterocyclic derivatives of butylated hydroxytoluene (BHT) were studied as cryoprotectants of the basic media for cryopreservation of the Russian sturgeon sperm. Rates of lipid peroxidation of sturgeon sperm before and after cryopreservation were reduced in the presence of the studied compounds, exceeding the effects of BHT and water-soluble analogue of vitamin E, trolox. The most efficient antioxidant has the effective concentration of 0.1 mM. Novel antioxidant agents as cryomedium supplements not only reduced the level of lipid peroxidation, but also enhanced the translational motility of the sperm of the Russian sturgeon after defrosting.

We performed correction of endothelial dysfunction with phenol derivatives KUD-259 and KUD-974 containing heteroatomic and heterocyclic structures. Pharmacological activity of KUD-259 and KUD-974 surpassed that of L-norvaline, a non-selective arginase inhibitor.

The study of endotelio- and cardioprotective activity of finished dosage forms - tablets, film-coated, containing 10 mg of phenolic nature KUD-975, was shown a statistically significant decrease in blood pressure and the coefficient of endothelial dysfunction on the background of simulation L-NAME-induced pathology. In the group of animals treated with KUD975 found a statistically significant increase in the concentrations of stable metabolites of nitric oxide, which in addition to the normalization of vasodilation says about endothelioprotektive action of the compounds studied. The initial values of the functioning of the left ventricle of the heart during treatment with KUD975 found hypodynamic action, which resulted in a decrease in the absolute values of the heart left ventricle pressure, + dp / dt, -dp / dt. Results of the study of the functional state of the myocardium during exercise testing, and histological evaluation of the myocardium revealed distinct cardioprotective effects in the study of KUD975 at a dose of 3 mg / kg, expressed in preventing the increase adrenoreactivity, exhaustion myocardial reserve during the sample to the load resistance and hypodynamic restructuring physiological response to the report on hypoxia / reoxygenation compared with animals that have modeled the endothelial dysfunction.

Functionalized oligomeric organic compounds with well-defined β-proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β-peptides was investigated by NMR spectroscopic and X-ray methods determining the conformational shapes of the β-proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β-peptide bonds between 5-arylpyrrolidine-2-carboxylic acid units existing in Z/E configurations. The whole library of short β-peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone-refractory prostate cancer cell line PC-3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine-substituted dimeric and trimeric acrylamides induced caspase-dependent apoptosis of PC-3 cells through cell-cycle arrest and mitochondrial damage.

A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and bispidine scaffolds (mean compound molecular weight is approximately 300 Da) with up to three stereocenters and four diversity points has been synthesized. Synthetic scaffold modifications leading to an increase in molecular complexity were studied. Well-defined stereochemical structures of both compound sets was confirmed by X-ray studies and halogenoaryl substituents were inserted appropriately for the design of novel non-basic serine protease inhibitors. Comprehensive molecular modeling has been performed for all synthesized compounds giving rationales of ligand–enzyme interactions with thrombin and trypsin. Biological testing confirmed moderate inhibitory activity of halogen-substituted saturated diazabicyclic small molecules towards thrombin.

Artificial structurally well-defined polymers have excited interest as functional mimetics of natural biomacromolecules, exhibiting additional properties not occurring in the living world. Specific conformational organization of natural and synthetic polymeric objects leading to unique folding accounts for the molecular recognition, which is one of the driving principles in important natural processes. Some nonnatural oligomeric species adopt specific and well-defined conformations dictated by the structure of monomeric units and intramolecular interactions and are defined as foldamers. One of the most studied unnatural foldamer types are bpeptides that adopt stable folded helical, sheet, and turn-like conformations. b-Peptides are stable towards natural enzymes, and appropriate design leads to discovery of bpeptide ligands for complicated pharmaceutical targets, such as protein–protein interactions. The application of pyrrolidine-3-carboxylic acid (Pca) for the construction of bpolypeptide chain rigidifies the molecular backbone and provides additional stabilization of the secondary structure of the oligomer in solution. The typical synthesis of a b-peptide backbone is based on the arsenal of peptide chemistry methods, including routine sequences of amino group protection–deprotection steps and multiple activations of carboxylic functionality for amide bond construction. Herein we disclose a fundamentally novel synthetic method towards well-defined highly functionalized short b-peptides that avoids protection, deprotection, and activation procedures and allows to generate efficiently stereoregular oligomeric pyrrolidine-based molecules. The developed method, called cycloadditive oligomerization, has been used for the synthesis of a set of racemic and enantiopure oligomers containing a Pca backbone. The realized approach determines highly diverse structural characteristics of b-peptide oligomers, which are characterized by various physicochemical methods, including X-ray analysis. The oligomerization utilized azomethine ylide 1,3-dipolar cycloaddition as a chain-growth approach (Scheme 1). 5Arylpyrrolidine-2,4-dicarboxylate units serve both as linked elements and as auxiliaries to determine stereoand enantioselectivities of the cycloaddition process. The starting 5arylpyrrolidine-2,4-dicarboxylic acid diesters 3a (X=H, Br) for oligomer synthesis were obtained from iminoesters 1 and tert-butyl acrylate in racemic and enantiopure forms by 1,3-dipolar cycloaddition using Lewis acids for the azomethine ylide generation step (Scheme 1, Table 1). Asymmetric synthesis of the monomer ( )-3a-H was effectively conducted with the enantiopure ligand 4 on a gram scale, and single recrystallization provided the target compound with more than 99% ee. Subsequent N-acryloylation of monomers 3a with acryloyl chloride transformed them into dipolarophiles 2b with a sterically hindered amide residue connected to the ethylene fragment. We supposed that these unique dipolarophiles would induce good diastereoand enantioselectivities under iterative cycloaddition steps with iminoesters 1 (Scheme 1). Indeed, dimers 3b were effectively synthesized by cycloaddition of acrylamides 2b with Schiff bases 1 (X=H, Br) in presence of AgOAc as a Lewis acid agent for azomethine ylide generation (Table 1, entries 4–6). Comparison of H NMR spectra of the cycloaddition reaction mixtures and

The (2 R ,4 R ,5 S )- and (2 S ,4 S ,5 R )-enantiomers of 4-( tert -butyl) 2-methyl 5-(4-bromophenyl)-pyrrolidine-2,4-dicarboxylate 3 were synthesized efficiently with an ee of >90% on a gram scale using a FAM -catalytic methodology. Subsequent modification afforded enantiopure N -((4-chlorophenyl)thio)acetyl pyrrolidine derivatives 4 , which are potential thrombin inhibitors according to comprehensive molecular docking studies.

The fundamental possibility of acylative kinetic resolution of racemic heterocyclic amines was demonstrated by the example of all- cis -5-(4-bromophenyl)-4- tert -butoxycarbonyl-2-methoxycarbonylpyrrolidine. Individual enantiomers ( ee >99%) were obtained in high yields via preparative chiral HPLC.

Phenyl α-bromovinyl sulfone reacts with glycine ester Schiff bases regioselectively in the presence of catalytic amounts of AgOAc and DBU yielding polysubstituted pyrrolidine cycloadducts. Utilization of excess DBU induces subsequent facile aromatization of the cycloadducts and affords 5-arylpyrrole-2-carboxylic acid esters in 39–85% yields in a single step.

To produce a novel class of structurally ordered poly-β-prolines, an emergent method for synthesizing chiral β-peptide molecular frameworks was developed based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Functionalized short β-peptides with up to six monomeric residues were efficiently synthesized in homochiral forms using a cycloadditive oligomerization approach. X-ray, NMR, and CD structural analyses of the novel β-peptides revealed secondary structure features that were generated primarily by Z/E-β-peptide bond isomerism. Anticancer in cellulo activity of the new β-peptides toward hormone-refractory prostate cancer cells was observed and was dependent on the absolute configuration of the stereogenic centers and the chain length of the β-proline oligomers.

The method of cyclic voltammetry on a platinum electrode in acetonitrile is used to study the redox properties of a number of novel pyrrolidine derivatives containing a sterically hindered phenol fragment. It is found that the obtained derivatives of (3,5-di-tert-butyl-4-hydroxyphenyl)pyrrolidine-2-carboxylic acid are irreversibly oxidized in two stages with formation of a phenoxy radical. The structural analogue containing no phenyl fragment is irreversibly oxidized under similar conditions in a single stage. Formation of a stable phenoxy radical from synthesized (3,5-di-tert-butyl-4-hydroxyphenyl)pyrrolidines under PbO2 oxidation is confirmed by ESR spectroscopy. Application of the synthesized compounds as antioxidant agents has been suggested.

Novel derivatives of 4-(vinylsulfonyl)pyrrolidine-2-carboxylic acids inhibit the exposure of phosphatidylserine by platelets upon activation with thrombin. The heterocyclic inhibitors were synthesized by 1,3-dipolar cycloaddition of divinyl sulfone to azomethine ylides followed by functionalization of the endocyclic nitrogen atom.

cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensation with formation of bicyclic imides having a 3,6-diazabicyclo[3.2.1]octane skeleton. The use of copper(I) cyanide as catalyst ensures high yields of 3,6-diazabicyclo[3.2.1]octane-2,4-diones substituted at the 3-, 5-, 6-, and 7-positions. (1R*,5R*,7S*)-7-(4-Chlorophenyl)-5,6-dimethyl-3,6-diazabicyclo[3.2.1]octane-2,4-dione was found to inhibit thrombin in a buffer solution at a millimolar concentration.

cis-5-Phenyl prolinates with electrophilic substituents at the fourth position of a pyrrolidine ring were synthesized by 1,3-dipolar cycloaddition of arylimino esters with divinyl sulfone and acrylonitrile. 4-Vinylsulfonyl 5-phenyl prolinates inhibit Staphylococcus aureus sortase SrtA irreversibly by modification of the enzyme Cys184 and could be used as hits for the development of antibacterials and antivirulence agents.

Tricyclic lactams containing the pyrrolizidin-3-one moiety were synthesized by the three-component reaction of aromatic aldehydes, glutamic acid (or glutamine), and N-methylmaleimide. The cascade reactions involve the stereospecific generation of azomethine ylides, the 1,3-dipolar endo- and exo-cycloaddition of a dipolarophile to the ylides, and the lactamization and afford two series of stereoisomeric pyrrolizidin-3-ones. The alkaline hydrolysis of the products of the mulitcomponent reaction gives oxopyrrolizidinedicarboxylic acid derivatives.

L-α-Amino acids catalyze 1,3-dipolar cycloaddition of methyl α-benzylideneamino acids to electron-deficient olefins in different solvents at room temperature. L-α-Amino acids ensure stereoselective formation of the corresponding syn,syn-azomethine ylides. The subsequent reaction with an active dipolarophile is stereospecific; it occurs as endo-cycloaddition with low asymmetric induction (up to ee 12%.). 3,4-Substituted 5-arylprolines were obtained in preparative yields using L-pyroglutamic acid or L-proline as catalyst.

Methyl esters of 5-phenylprolines with the vinylsulfonyl or cyano group in the 4-position of the pyrrolidine ring have been synthesized. X-ray crystallography shows that all substituents in the vinylsulfonyl derivatives are cis to each other. All compounds are inhibitors of Staphylococcus aureus sortase SrtA.

Background Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded. Results KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr161 (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr15 (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades. Conclusions The data suggest that KUD773 induces apoptotic signaling in a sequential manner. It inhibits tubulin polymerization associated with an anti-Aurora A activity, leading to Cdk1 activation and mitotic arrest of the cell cycle that in turn induces Bcl-2 degradation and a subsequent caspase activation in HRPCs.

The docking study of ferrocene-substituted bispidines to binding sites of thrombin and factor Xa has shown that bispidine scaffold provides a 3D-arranegment of all substituents and a direction for the ferrocene group to fill the S4 pocket for both thrombin and factor Xa.

This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluatedin vivoat water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives ofL-lysine andL-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives ofL-lysine andL-proline at least partially depends on the correction of gastric mucosa oxidative balance.

A reaction of racemoc methyl 4-oxo-2-phthalimidobutanoate, diethyl aminomalonate, and phenyl vinyl sulfone in the presence AgOAc occurred stereospecifically to form tetrasubstituted pyrrolidine including structural elements of all three initial compounds. The relative stereochemistry of the asymmetrical carbon atoms in the molecule was established by XRD analysis, and it coincided with two stereogenic centers in the left part of kaitocephalin molecule. Therefore the developed three-component process can be recommended for an effective total synthesis of kaitocephalin.

Both enantiomers of pyrrolidine (III) are readily prepared by a zinc-catalyzed asymmetric 1,3-dipolar cycloaddition of tert-butyl acrylate (II) with aldimine (I).

1,3-Dipolar cycloaddition of azomethine ylides with vinyl sulfone (I) proceeds in the presence of catalytic amounts of silver acetate and DBU to give pyrrolidine cycloadducts (IV) and (V) regioselectively.

In the title compound, C14H13N3O2, the relative stereochemistry of the three stereogenic C atoms has been determined. In the crystal, N—H...O hydrogen bonds link the molecules into chains of inversion dimers running along the b axis.

Cycloaddition of divinyl sulfone (II) to the azomethine ylides, generated from imino esters (I) under action of Lewis acids, proceeds stereoselectively to form racemic pyrrolidines (III).

Molecular docking studies, analysis of ligand-protein interactions, followed by multistage targeted syntheses and biochemical investigations provide a series of novel nonbasic small-molecule compounds based on the cis-5-phenylproline molecular scaffold.

In the title compound, [Cu(C16H19BrNO4)2]·2H2O, the CuII ion resides on an inversion centre and is coordinated by two O and two N atoms from two enantiomeric 5-(4-bromophenyl)-4-(tert-butoxycarbonyl)pyrrolidine-2-carboxylate ligands in a distorted square-planar geometry. The relative stereochemistry of the three stereogenic C atoms in each ligand has been determined. In the crystal, intermolecular N—H...O and O—H...O hydrogen bonds link the molecules into layers parallel to the bc plane. The crystal studied was twinned by pseudomerohedry with twin fractions of 0.719 (3) and 0.281 (3).

Octahydropyrrolo[3,4-b]pyrroles (V) are synthesized by 1,3-dipolar addition of maleic anhydride (II) to benzylidene amino acid esters (I) followed by opening of the anhydride fragment and recyclization.