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A novel sp 3 carbon-rich tricyclic 3D scaffold-based peptide mimetic compound library was constructed to target protein-protein interactions. T ricyclic framework 6 was synthesized from 9-azabicyclo[3,3,1]nonan-3-one 9 via a gold (I)-catalyzed Conia-ene reaction. The electron-donating group on the pendant alkyne of cyclization precursor 11b-e was the key to forming 6- endo - dig cyclized product 6 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 6 , a diazatricyclododecene 3D-scaffold 7a , which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 20a-h were synthesized via step-by-step installation of three substituents on diazatricyclododecene scaffold 7a . C o mpounds 20a-h were synthesized as α-helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z = Leu or Phe) and subjected to cell-based assays: antiproliferative activity, HIF-1 transcriptional activity which is considered to affect cancer malignancy , and antiviral activity against rabies virus. Compound 20a showed the strongest inhibitory activity of HIF-1 transcriptional activity (IC 50 = 4.1 ± 0.8 μM), whereas compounds 20a-g showed antiviral activity with IC 50 values of 4.2-12.4 μM, suggesting that the 3D-scaffold 7a has potential as a versatile peptide mimic skeleton.

This study was done to evaluate the effects of different dietary digestible lysine (dig Lys) levels on growth performance, blood metabolites, carcass and breast yield, and breast meat quality of broilers 23-38 days of age. Three hundred 23-day-old Cobb-500 male broiler chickens were allocated to a completely randomized design with five treatments (finisher diet containing 0.88%, 0.94%, 1.00%, 1.06% and 1.12% dig Lys) and six replicates of 10 birds each. Feed intake (FI) was not affected by different dietary dig Lys levels. Weight gain (WG) linearly increased and feed conversion ratio (FCR) linearly decreased with an increasing dietary dig Lys levels. With increasing dietary dig Lys levels, carcass and breast yield and breast meat hue angle (h* ) linearly increased, but abdominal fat decreased quadratically, whereas breast meat lightness (L* ) and ether extract composition linearly decreased. Dietary dig Lys levels did not show any significant effect on serum metabolites, breast meat cooking loss and water holding capacity. Based on the linear broken-line regression models, the weight gain, feed conversion ratio and breast yield were optimized when dietary dig Lys levels were 0.95%, 1.01% and 1.02% respectively. It is concluded that Lys requirements vary according to what productive parameter is taken for optimization. A minimum of 1.02% dig Lys concentration in the finisher diet is suggested to optimize breast yield, feed efficiency and performance in broiler chickens.

An efficient protocol for facile construction of 3,4-dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones has been developed by using a regio-and stereoselective iodolactonization reaction. Subsequent palladium cross-coupling reactions of 3,4-dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones readily afforded functionalized oxazinoindolones.

Highly facile, single-step synthetic approach of 3-iodoquinolines is developed for the first time from readily available 2-aminobenzophenones and terminal alkynes. The reaction involves a nucleophilic addition of terminal alkynes to 2-aminobenzophenones followed by intramolecular regioselective iodocyclization (6-endo dig) to furnish 2,4-disubstituted, 3-iodoquinolines in high yields. In case of 2,4-diaryl substitution, the products were isolated without a column chromatography

A base-mediated carbocyclization study has been performed between two allowed Baldwin cyclization modes (6-exo-trig and 6-exo-dig) and it was found that 6-exo-trig cyclization was preferred over 6-exo-dig. Allyl cyanide was found to be suitable and efficient pronucleophile for this investigation and two sp2–sp2 transition-metal-free C−C bond formations took place in a single operation to yield two differently functionalized biaryl compounds.

A novel series of naphtho-ferrocene derivatives were synthesized in high yields by an efficient gold-catalyzed intramolecular 6-endo-dig cyclization strategy. The salient features of this reaction include easy operation, broad substrate scope, high yields, mild conditions and it works well in wet solvent under air at room temperature.

A visible-light-mediated synthesis of 5-methylene-pyrrolidinones is reported. This constitutes to the first reported example of a 5-exo-dig hydroamination reaction involving a nitrogen-centered radical.

Cyclopropyl-tethered 3-alkynyl imines react with polarized-covalent-bond-containing compounds to give polyfunctionalized pyrroles. This provides a mild and effective method for the simultaneous introduction of halogen, chalcogen, or hydrogen groups to the 3-position of the pyrrole ring, together with the incorporation of halogen, azide, or alkoxy/aryloxy groups into the ethyl side-chain.

The present manuscript involves the synthesis of 5-prop-2-ynylsulfanyl-pyrimidin-4-ones 3a–i by [4 + 2] cycloaddition reactions of 1,3-diazabuta-1,3-dienes 1a–i with prop-2-ynyl-sulfanyl ketene 2. These 5-prop-2-ynylsulfanyl-pyrimidin-4-ones 3a–i were explored in iodocyclization for the synthesis of novel pyrimido[5,4-b][1,4]thiazines 4a–i in excellent yields. The iodocyclizations followed exo-dig ring-closure cyclizations to yield 6–6 bicyclic fused pyrimidinones, while corresponding endo-dig ring-closure iodoamination was not observed.

Cyclization of silylenolether-ynesulfonamides proceeds at ambient temperature under mild reaction conditions under silver catalysis. Bridged compounds were obtained exclusively through 7-exo-dig reactions. The protocol is applicable to a wide range of substrates, thus leading to azabicyclic frameworks.

We describe an extremely rare case of double pathology arising in an infant girl presenting with a history of intractable seizures, delayed milestones and enlarging head. The pathology included desmoplastic infantile ganglioglioma (DIG) and extensive focal cortical dysplasia in the overlying cortex. While tumors such as ganglioglioma have been commonly described to occur as concomitant pathology with cortical dysplasia, DIG in such an association has not been described in the literature. As DIG are voluminous supratentorial tumors, awareness about such an association is pertinent for correct diagnosis.

The subsequent double-bond isomerization in the synthesis of dibenzocycloheptenes and their heteroaromatic analogues was investigated. In the case of biphenyls, a basic additive completely prevented an isomerization to the thermodynamic product. With electron-rich intramolecular heteroaromatic nucleophiles, the isomerization was still observed, but the kinetic product can be obtained by careful control of the reaction times in most cases. Mechanistic studies demonstrated that a slow isomerization is also possible with the gold catalyst at elevated temperatures, but much faster isomerization rates were observed with acidic additives. An observed initiation period for the gold-catalyzed isomerization indicates that not the homogenous catalyst, but a decomposition product of it may be the catalytically active species.

A comprehensive study on gold- and silver-catalyzed cycloisomerizations of hydroxypropargylamides into oxazepines is described. Three different types of hydroxypropargylamide substrates derived from either amide coupling or Ugi reactions have been validated resulting in establishment of selective and general access to a medium-ring oxazepine core.

The gold(I)-catalysed reaction of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, which gives synthetically useful vinylogous amides (β-enaminones), has been studied in detail, in order to optimize the reaction conditions, enlarge the scope and gain insight into the mechanism and the structural features that selectively favour the 6-endo-dig oxyauration of the triple bond. Experimental studies and DFT calculations demonstrate that the 6-endo-dig approach is exclusive with substituted alkynes, whereas with terminal alkynes the 5-exo-dig cyclization prevails, despite the large angle (120°) at C-6. The same selectivity was observed with N-Cbz-protected 2-alkynylpiperidines. With these compounds, β-amino ketones are obtained as a consequence of the 6-endo-dig attack onto a substituted triple bond. Sedamine alkaloids are easily obtained by this approach.

An efficient palladium(II)-catalyzed method for the synthesis of alkylated pyridine-substituted pyrroles has been developed by a one-pot three component reaction of β-bromovinyl aldehydes, primary amines and 2-alkynylpyridines in good yields. The reactions can also provide an efficient route to 2-picolinoylpyrroles by slightly altering the reaction conditions.

Humanized hapten-binding IgGs were designed with an accessible cysteine close to their binding pockets, for specific covalent payload attachment. Individual analyses of known structures of digoxigenin (Dig)- and fluorescein (Fluo) binding antibodies and a new structure of a biotin (Biot)-binder, revealed a “universal” coupling position (52+2) in proximity to binding pockets but without contributing to hapten interactions. Payloads that carry a free thiol are positioned on the antibody and covalently linked to it via disulfides. Covalent coupling is achieved and driven toward complete (95–100%) payload occupancy by spontaneous redox shuffling between antibody and payload. Attachment at the universal position works with different haptens, antibodies, and payloads. Examples are the haptens Fluo, Dig, and Biot combined with various fluorescent or peptidic payloads. Disulfide-bonded covalent antibody-payload complexes do not dissociate in vitro and in vivo. Coupling requires the designed cysteine and matching payload thiol because payload or antibody without the Cys/thiol are not linked (

A cascade transformation involving the Ugi reaction followed by 5-endo-dig carbocyclization and retro-Claisen fragmentation providing access to a 1H-pyrrol-2(5H)-one core is described. The operating protocol is very similar to the typical Ugi reaction settings, while the overall outcome results from the application of a 3-substituted propiolic acid and a phenylglyoxal as acid and aldehyde components, respectively. The utility of process is demonstrated through the synthesis of a small library of 5-oxo-2,5-dihydro-1H-pyrrole-2-carboxamides.

A new and straightforward base-catalyzed 5-exo-trig cyclization of 2-propynyl-1,3-dicarbonyl compounds leads to the corresponding stereodefined 2-methylene-2,3-dihydrofurans in excellent yields.

A number of 3-(4,4,5,5-tetraethoxy-1-hydroxy-1-arylpent-2-ynyl)quinoxalin-2(1H)-ones, obtained by reacting the lithium acetylide of 3,3,4,4-tetraethoxybut-1-yne (TEB) with 3-aroylquinoxalin-2(1H)-ones, appeared to undergo stereoselective cyclization in the 5-exo-Dig manner when heated at reflux in acidic, aqueous THF. In each case, the products were the corresponding (E)-1,1-diethoxy-3-(3-hydroxy-3-arylfuro[2,3-b]quinoxalin-2(3H)-ylidene)propan-2-ones and 1,1-diethoxy-3-hydroxy-3-(3-arylfuro[2,3-b]quinoxalin-2-yl)propan-2-one, which were isolated in an approximate ratio of 2:1 in high total yield. Irrespective of the structure of the aryl group, both compounds were stable solids when kept in a refridgerator (3 °C), but when the latter product was dissolved in chloroform and stored at room temperature, it rearranged smoothly and quantitatively to the former compound within a few days.

A tandem gold-catalyzed 5-endo-dig/spirocyclization of 2-[(2-aminophenyl)ethynyl]phenylamines with isatins was achieved to produce the corresponding 5′,11′-dihydrospiro[indoline-3,6′-indolo[3,2-c]quinolin]-2-one derivatives in good yields with high regioselectivity. This reaction proceeded well at ambient temperature under mild conditions. Ketones also participated smoothly under similar conditions to produce 6,6-disubstituted-6,11-dihydro-5H-indolo[3,2-c]quinolones.

Aims Desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG) is a rare primary neuroepithelial brain tumour typically affecting paediatric patients younger than 24 months. Knowledge about genetic alterations in DIA/DIG is limited. However, a previous study on BRAF V600E mutation in paediatric glioma revealed a BRAF mutation in one of two tested DIAs/DIGs. The limited number of cases in that study did not allow any conclusion about mutation frequency of BRAF in this tumour entity. Methods We collected a series of 18 DIAs/DIGs for testing BRAF V600E mutational status by BRAF V600E immunohistochemistry (clone VE1). Cases with sufficient DNA were tested for BRAF V600E mutation by pyrosequencing. Results Three out of 18 DIAs/DIGs presented with VE1 binding. A considerable proportion of BRAF V600E mutated tumour cells was detected in the cortical tumour component, whereas the pronounced leptomeningeal tumoural stroma was predominantly negative for VE1 binding. Pyrosequencing confirmed BRAF V600E mutation in two of three VE1-positive cases. Conclusion BRAF V600E mutation affects a subset of DIAs/DIGs and offers new therapeutic opportunities.

An unusual, but clinically significant, digoxin (DIG)-bupropion (BUP) drug interaction (DDI), in which BUP increased DIG renal clearance by 80% is reported. To investigate the mechanism(s) of this unusual DDI, first the effect of BUP, its circulating metabolites or their combination on [(3) H]-DIG transport by cells expressing human P-gp or human OATP4C1 was determined. Second, the study asked whether this DDI could be replicated in the rat so that it could be used to conduct mechanistic studies. Then, the effect of BUP and its rat metabolites on [(3) H]-DIG transport were tested by cells expressing rat Oatp4c1. Bupropion and its metabolites had no effect on human P-gp mediated transepithelial transport of [(3) H]-DIG. Bupropion and hydroxybupropion (HBUP) significantly stimulated H-OATP4C1 mediated transport of [(3) H]-DIG. In addition, BUP cocktail (BUP plus its metabolites) significantly increased the H-OATP4C1 mediated transport of [(3) H]-DIG, and partially reversed the inhibition by 100 µm DIG. However, erythro-hydrobupropion (EBUP) and threo-hydrobupropion (TBUP) did not affect the [(3) H]-DIG uptake by H-OATP4C1 cells. Bupropion administration significantly increased digoxin renal clearance in rats. Surprisingly, bupropion significantly inhibited r-Oatp4c1 mediated transport of [(3) H]-DIG at clinically relevant unbound plasma concentrations of BUP or those observed in the rat study, while HBUP or TBUP did not. These data support our hypothesis that at clinically relevant plasma concentrations, bupropion and its metabolites activate H-OATP4C1 mediated DIG tubular secretion, and could possibly explain the increase in digoxin renal clearance produced by bupropion. While bupropion increased digoxin renal clearance in the rat, it appeared to do so by inhibiting r-Oatp4c1-mediated digoxin renal reabsorption.

The scalable title cyclization offers access to variously functionalized pyrrolidinone derivatives.

A series of arylynamides with alkyloxy groups at the ortho position of the aryl group was prepared through a short alkylation/cross-coupling/amidation sequence. The gold-catalyzed conversion of these substrates combined both C-O and C-C formation steps, thus providing benzofurans with amine functionalities at the 2-position and alkyl groups at the 3-position. Cross-over experiments showed that the alkyl-migration step was an intermolecular process. X-ray crystal-structure analysis of two of the products supported our structural assignment. In some cases, the corresponding benzofurans without the alkyl group at the 3-position were obtained as side-products, which were formed through a competing protodeauration process.

A one-pot protocol for the synthesis of indole-based annulated polyheterocycles involving consecutive 7-endo-trig and electrophilic 6-endo-dig cyclizations is described. The reaction proceeds initially through annulation of 5-methoxyindole, 2-amino benzyl alcohol and 2-alkynylbenzaldehyde

A one-pot Sonogashira cross-coupling/5-endo-dig cyclization procedure leading to 2-aryl-4,5,6,7-tetrahydroindoles was developed. This short (only two steps from commercially available compounds) sequence avoids harsh conditions and expensive catalysts. Our procedure is highly tolerant to a range of functional groups (amino, nitro, carboxy, cyano, hydroxy, and bromo). A family of 21 tetrahydroindoles was synthesized on a gram scale in a good to excellent yields, which is indicative of the general character and scalability of this reaction. This methodology allows access to indoles bearing miscellaneous substituents at the C2 position (by variation of ArI) and at the nitrogen atom (by variation of RNH2, including chiral moieties).

A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine.