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Electrolysis of o -alkynyl- N -(formyl)anilides and sodium sulfinates on graphite electrodes delivers biologically sound 3-(sulfonyl)quinol-4-ones with moderate to good yields. The reaction is carried out in an undivided cell in the presence of silver(I) oxide with potassium iodide or sodium tetrafluoroborate as the supporting electrolyte. The reaction tolerates variously substituted anilides as well as aryl and alkyl sulfinates. The transformation proceeds as a domino sequence of oxysulfonylation and cyclocondensation steps.

Annulated azecines, mostly partially saturated benzo[d]azecine and dibenzo[c,g]azecine fusion isomers, constitute a unique class of alkaloids and nature-inspired azaheterocyclic compounds with interesting reactivity, physicochemical and biological properties. Due to difficulties associated with the synthesis of the benzazecine (or bioisosteric) scaffold they are not the focus of organic and medicinal chemists' consideration, whereas it is worth noting the range of their pharmacological activities and their potential application in medicinal chemistry. Herein, we reviewed the synthetic methodologies of arene-fused azecine derivatives known up to date and reported about the progress in disclosing their potential in drug discovery. Indeed, their conformational restriction or liberation drives their selectivity towards diverse biological targets, making them versatile scaffolds for developing drugs, including antipsychotic and anticancer drugs, but also small molecules with potential for anti-neurodegenerative treatments, as the recent literature shows., Competing Interests: Declaration of competing interest On behalf of all the co-authors, I declare that the authors of the manuscript entitled “Advances in synthesis of novel benzazecines and their unique pharmacological properties” have no competing interests to declare., (Copyright © 2024. Published by Elsevier Masson SAS.)

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1- a ]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base ( 8c ) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC 50 < 20 μM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC 50 s of 0.45 and 12.1 μM, respectively.

An easy synthesis of novel highly functionalized 5,6-dihydroindolo[2,1- a ]isoquinolines was developed via a pseudo four-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal α,β-ynones, and malononitrile. The selective formation of this biologically relevant heterocyclic core was achieved using a one-pot approach under microwave irradiation. The formation of the same skeleton through the reaction of 5,6-dihydropyrrolo[2,1- a ]isoquinolines with malonic acid dinitrile supports the proposed mechanism, involving the intermediate product of the three-component reaction. Furthermore, the disproval of an alternative reaction pathway, which involved the dimerization of malononitrile followed by three-component transformation, was demonstrated. Introducing the malononitrile dimer as a CH acid resulted in the formation of a different pyrido[3',4':4,5]pyrrolo[2,1- a ]isoquinoline core. Additionally, the synthesized 5,6-dihydroindolo[2,1- a ]isoquinolines were examined for their photophysical properties, revealing their attractive luminescent characteristics.

Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1- a ]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1- a ]isoquinolines.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines., (© 2023 Wiley-VCH GmbH.)

When azo coupling of aryldiazonium salts with indoles was carried out in aprotic nonpolar solvent on air, a pseudo-three-component reaction has been discovered. Azo coupling is followed by a nucleophilic addition of a second indole unit to the indolium intermediate; aromatization and oxidation are achieved under air.

Adducts of 1-alkyl-2-imidazolines and two molecules of alkyl propiolate, possessing an N -propargyl-β-enaminoester fragment, easily undergo a domino reaction to form pyridinium salts with β-(alkylammonio)ethyl group at the nitrogen atom in the presence of 2 equiv of a protic acid. Treatment of the above reaction mixture with a base gives 1,2,3,8 a -tetrahydroimidazo[1,2- a ]pyridines. Reaction of the latter compounds with acid chlorides affords pyridinium salts with β-(alkylamido)ethyl moiety at the nitrogen atom.

A new class of trifluoromethyl building blocks─2-trifluoromethyl allyl chlorides─have been obtained through a photoredox-catalyzed chlorotrifluoromethylation of aryl allenes. The reaction proceeded in a regio- and stereoselective manner. A trifluoromethylated analog of the flunarizine drug was synthesized.

An unprecedented electrochemical three-component reaction of phenylacetylene, sulfinate, and N -(formyl)anilide was discovered. The transformation occurs in an undivided cell with a graphite anode and cathode in DMF in the presence of tetrabutylammonium iodide as an electrolyte. The addition of silver(I) oxide and catalytic amounts of iodine facilitated the reaction significantly. The transformation was also carried out under photoredox-catalyzed conditions.

Interactions of N -(propargyl)indole-2-carbonitriles with nitrogen nucleophiles were studied. It was found that lithium hexamethyldisilazane (LiHMDS)-promoted reactions give mixtures of two product types, originating from an initial attack onto carbon-carbon or carbon-nitrogen triple bonds. Performing the reaction at reduced temperature and in the presence of catalytic amounts of LiHMDS delivered alkyne hydroamination products exclusively. On the contrary, the one-pot reaction of N -(propargyl)indole-2-carbonitriles with methanol and LiHMDS on heating, followed by the addition of a nitrogen nucleophile, allowed a selective domino cyclization sequence toward 1-aminopyrazino[1,2- a ]indoles. Anilines and nitrogen heterocycles could be employed as N -nucleophiles to obtain products of both types. Moreover, an alternative one-pot route toward a third product type has been developed. When N -(propargyl)indole-2-carbonitrile was first combined with aniline and LiHMDS at reduced temperature, further heating of the in situ generated hydroamination product led to the intramolecular cyclization into 1-imino-2-phenylpyrazino[1,2- a ]indoles. Thus, chemodivergent transformations of the same starting material into three compound classes were investigated. The possible reaction routes were studied, and N -(allenyl)indole-2-carbonitrile was identified as the key intermediate. Acyclic and cyclic products exhibit fluorescence emission in the blue to green range.

Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R 3 = CH 2 OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value ( K i = 4.9 μM), equipotent with the corresponding 6-phenyl derivative 3n (R 3 = Ph, K i = 4.5 μM), but 90-fold more water-soluble.

Various 4'-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products-new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (K i ) in the low micromolar range., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

The transformation of 2-imidazolines into 1,2,3,4-tetrahydropyrrolo[1,2- a ]pyrazines has been realized. A pseudo-three-component reaction of 2-imidazolines with terminal electron-deficient alkynes (2 equiv) first generates imidazolidines, containing an N -vinylpropargylamine fragment. The latter can then undergo a base-catalyzed domino aza-Claisen rearrangement/cyclization reaction sequence, simultaneously constructing pyrrole and pyrazine rings. The process works in a broad substrate scope, delivering pyrrolo[1,2- a ]pyrazines in good to excellent yields (45-90%). This two-step approach can be carried out in a one-pot fashion without a noticeable decrease in yield. Remarkably, a three-component protocol for the introduction of two different alkynes has been also developed.

Synthesis of novel C3-substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines via a three-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines, terminal alkynes and CH-acids under microwave irradiation in dry acetonitrile is described. The method developed enables the obtainment of highly functionalized compounds with pharmacophore groups, which are potentially biologically active., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

A convenient protocol for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines with various electron-withdrawing substituents at C-2 atom is described. This approach is based on the two-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines with α,β-unsaturated ketones, nitroalkenes and acrylonitrile. Depending on the selected substrates, the reaction was performed in TFE under reflux or under microwave irradiation. Only for the two examples, a transition metal catalyst was used., (© 2020. Springer Nature Switzerland AG.)

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N -bridged cyclopenta[ a ]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3-benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.

Marine alkaloids belonging to the lamellarins family, which incorporate a 5,6-dihydro-1-phenylpyrrolo[2,1- a ]isoquinoline (DHPPIQ) moiety, possess various biological activities, spanning from antiviral and antibiotic activities to cytotoxicity against tumor cells and the reversal of multidrug resistance. Expanding a series of previously reported imino adducts of DHPPIQ 2-carbaldehyde, novel aliphatic and aromatic Schiff bases were synthesized and evaluated herein for their cytotoxicity in five diverse tumor cell lines. Most of the newly synthesized compounds were found noncytotoxic in the low micromolar range (<30 μM). Based on a Multi-fingerprint Similarity Search aLgorithm (MuSSeL), mainly conceived for making protein drug target prediction, some DHPPIQ derivatives, especially bis-DHPPIQ Schiff bases linked by a phenylene bridge, were prioritized as potential hits addressing Alzheimer's disease-related target proteins, such as cholinesterases (ChEs) and monoamine oxidases (MAOs). In agreement with MuSSeL predictions, homobivalent para -phenylene DHPPIQ Schiff base 14 exhibited a noncompetitive/mixed inhibition of human acetylcholinesterase (AChE) with K i in the low micromolar range (4.69 μM). Interestingly, besides a certain inhibition of MAO A (50% inhibition of the cell population growth (IC 50 ) = 12 μM), the bis-DHPPIQ 14 showed a good inhibitory activity on self-induced β-amyloid (Aβ) 1-40 aggregation (IC 50 = 13 μM), which resulted 3.5-fold stronger than the respective mono-DHPPIQ Schiff base 9 .

An interaction of homophthalonitrile with salicylaldehydes proceeds as a novel domino reaction and results in the formation of nineteen 12H-chromeno[2,3-c]isoquinoline-5-amine derivatives. Four new bonds and two cycles are forged in a single synthetic operation, employing cheap and eco-friendly ammonium formate, acting both as a catalyst and a reducing agent. The in vitro cytotoxicity tests revealed antiproliferative activities against five human tumor cell lines, including the cisplatin-resistant ovarian carcinoma one (A2780cp8), with inhibitory potency data (IC 50 ) in the low micromolar range in most cases. Molecular docking calculations and fluorescence quenching studies revealed possible binding properties with DNA of the active compounds., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pyridinium ylides are well recognized as dipoles for cycloaddition reactions. In its turn, the microwave-assisted interaction of N -(cyanomethyl)-2-alkylpyridinium salts with enaminones unexpectedly proceeds as a domino sequence of cycloisomerization and cyclocondensation reactions, instead of a 1,3-dipolar cycloaddition. The reaction takes place in the presence of sodium acetate as base and employs benign solvents. The optical properties of the resulting pyrido[2,3- b ]indolizines were studied, showing green light emission with high fluorescence quantum yields.

The reaction of 1,2-disubstituted 2-imidazolines with electron-deficient alkynes proceeds as a pseudo-three-component process and forms imidazolidines with an N -vinylpropargylamine fragment. Heating the resulting imidazolidines in xylene on air leads to an effective formation of polysubstituted pyrroles through a domino sequence of aza-Claisen rearrangement/transannular nucleophilic addition/oxidative ring opening reactions. The direct one-pot transformation of 2-imidazolines to pyrroles has been also realized.

N-(Propargyl)indole-2-carbonitriles undergo DBU-catalyzed addition of CH-acids to nitriles, followed by cyclization to give 9-aminopyrido[1,2-a]indoles. The reaction proceeds through the initial formation of a push-pull enamine, alkyne-allene rearrangement and intramolecular nucleophilic cyclization. Nitromethane and malonate esters can be employed as the CH-acids. The resulting compounds were found to exhibit fluorescence properties.

(Het)Arylallenes undergo hydrosulfonylation under photoredox-catalyzed conditions. The reaction gives vinyl sulfones in a regio- and diastereoselective manner, employing sodium sulfinates as the sulfonyl source and eosin Y as the photocatalyst. Indol-1-yl, pyrrol-1-yl, phenyl, and naphtylallenes might be used. Aliphatic allenes are incompatible with the reaction conditions.

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure-activity relationships (SARs) pointed out that CO 2 Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC 50  = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.

A novel isocyanide-based multicomponent synthesis of alkyl aryl(indol-3-yl)acetimidates has been established. Starting from aryl(indol-3-yl)methylium tetrafluoroborates, aromatic isocyanides and alcohols, the imidates were obtained in moderate to very good yields. Consecutive four-component synthesis of the above mentioned imidates from N-alkylindoles, aromatic aldehydes, aromatic isocyanides and alcohols was also proposed. In addition, it was shown that in the presence of water, aryl(indol-3-yl)methylium tetrafluoroborates reacted with isocyanides to furnish aryl(indol-3-yl)acetamides.

The sequential three-component reaction between o -hydroxybenzaldehydes, N -(cyanomethyl)pyridinium salts and a nucleophile towards substituted chromenoimidazopyridines under oxidative conditions has been developed. The employment of Mn(OAc) 3 ·2H 2 O or KMnO 4 as stoichiometric oxidants allowed the use of a wide range of nucleophiles, such as nitromethane, (aza)indoles, pyrroles, phenols, pyrazole, indazole and diethyl malonate. The formation of the target compounds presumably proceeds through a domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction sequence.

Malononitrile is a useful reagent for multicomponent reactions with hundreds of methods developed. In this paper, we suggest α-(cyano)- o -tolunitrile (homophtalonitrile) to work as a vinylogous malononitrile. Thus, a organocatalytic pseudo-three-component reaction of homopthalonitrile (2 equiv) and o -hydroxybenzaldehyde, leading to the diastereoselective formation of 5-amino-12 H -chromeno[2,3-c]isoquinolin-12-yl)(cyano)methyl)benzonitriles, was discovered. The possibility to employ other nucleophiles was demonstrated for indoles, and a sequential three-component reaction of homophtalonitrile, o -hydroxybenzaldehyde, and (aza)indole, giving 12-(1 H -Indol-3-yl)-12 H -chromeno[2,3- c ]isoquinolin-5-amines, was developed. The photophysical properties of the synthesized compounds have been studied, revealing high fluorescence quantum yields (42-70 %) for indol-3-yl substituted 12 H -chromeno[2,3- c ]isoquinolin-5-amines and reversible fluorescence quenching under acidic conditions.

1-( p -Methoxyphenyl)tetrazolyl-substituted 6,7-dimethoxy(6,7-methylenedioxy)-1,2,3,4-tetrahydroisoquinolines formed tetrazolyl-substituted azocines in high yields by using activated alkynes. Unsubstituted at 6,7,8-aromatic fragment 1-tetrazolylisoquinoline interacted in several pathways forming tetrazolyl-substituted azocines, 1-tetrazolyl-1-R-vinylisoquinolines and 3-azaspiro[5.5]undeca-1,7,9-triene.

1-(Propargyl)indol-2-carbonitriles react with alcohols to afford 1-alkoxypyrazino[1,2- a]indoles under DBU-catalyzed microwave-assisted conditions. The reaction scope includes a wide range of indoles, primary and secondary alcohols, and a thiol. The initial mechanistic study shows that the domino process presumably proceeds through an alkyne-allene rearrangement, imidate formation, and nucleophilic cyclization reaction sequence.

The tandem [4+2] cycloaddition between hexafluoro-2-butyne and bis-furyl dienes, like difurfuryl ester, at room temperature leads to the kinetically controlled "pincer"-adducts - annulated 4a,8a-bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes. On the other hand, if these reactions proceed at 140 °C, only the thermodynamically controlled "domino"-adducts - annulated 2,3-bis(trifluoromethyl)hexahydro-1,4:5,8-diepoxynaphthalenes - are formed. Therefore, a very rare and unexpected example of full kinetic and thermodynamic control in the Diels-Alder reaction is reported in this paper.

The title compound, C 25 H 27 NO 4 (I), the product of the unusual thermolysis of aza-cyclic allene methyl 10,11-dimeth-oxy-3,8-dimethyl-6-phenyl-3-aza-benzo[ d ]cyclo-deca-4,6,7-triene-5-carboxyl-ate, represents a bicyclic heterosystem and crystallizes in the monoclinic space group P 2 1 / c with three crystallographically independent mol-ecules in the unit cell. These independent mol-ecules adopt very similar geometries and differ only in the conformations of the two meth-oxy substituents on the benzene ring. In two of the three independent mol-ecules, both meth-oxy groups are almost coplanar with the benzene ring [the C-C-O-Me torsion angles are 10.8 (2), 12.3 (2), 9.1 (2) and 13.6 (3)°], whereas in the third mol-ecule, one of the meth-oxy groups is practically coplanar to and the other meth-oxy group is roughly perpendicular to the benzene ring, the C-C-O-Me torsion angles being 14.1 (2) and 76.5 (2)°. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two five-membered rings (cyclo-pentenes) and two six-membered rings (piperidine and benzene). The five-membered rings have the usual envelope conformation, with the methyl-subsituted C atom as the flap in each molecule, and the six-membered piperidine ring has a chair conformation. The methyl substituent at the N atom occupies the sterically favourable equatorial position. The carboxyl-ate group lies almost within the basal plane of the parent cyclo-pentene ring [making dihedral angle of 11.68 (8), 18.94 (9) and 15.16 (9)° in the three independent mol-ecules], while the phenyl substituent is twisted by 48.26 (6), 42.04 (6) and 41.28 (6)° (for the three independent mol-ecules) relative to this plane. In the crystal, mol-ecules of (I) form stacks along the b -axis direction. The mol-ecules are arranged at van der Waals distances.

The title compound, C 19 H 19 NO 5 , (I), is the product of a domino reaction between cotarnine chloride and acetyl-acetylene catalysed by copper(I) iodide. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two terminal five-membered rings (pyrrole and 1,3-dioxole) and two central six-membered rings (di-hydro-pyridine and benzene). The five-membered 1,3-dioxole ring has an envelope conformation and the central six-membered di-hydro-pyridine ring adopts a twist-boat conformation. The acyl substituent is almost coplanar with the pyrrole ring, whereas the meth-oxy substituent is twisted by 27.93 (16)° relative to the benzene ring. The 2-oxopropan-1-yl substituent is roughly perpendicular to the pyrrole ring. In the crystal, mol-ecules are stacked along the a -axis direction; the stacks are linked by weak C-H⋯O hydrogen bonds into puckered layers lying parallel to (001).

Aim: to study changes in the expression of angio- and vasculogenesis markers in colorectal adenocarcinoma metastases to the liver during combined cytotoxic and targeted anti-VEGF therapy versus cytotoxic monotherapy., Subjects and Methods: Intraoperative samples from 96 patients with colorectal adenocarcinomas metastases to the liver were immunohistochemically examined. The investigation enrolled patients who had preoperatively received either combined FOLFOX6 cytotoxic therapy and targeted anti-VEGF therapy with bevacizumab or only FOLFOX6 therapy, as well as patients who had not received preoperative anti-tumor drug treatment. The expression of SDF1α, CXCR4, CXCR7, and VEGF-A was compared in these groups. Statistical significance was accepted at p<0.05., Results: The expression of CXCR4 in the vessel endothelial cells was significantly less frequently detected in the patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy as compared to those had not drug therapy. Comparing the patients treated with cytotoxic drugs with those who had not received anti-tumor therapy revealed similar results in the women. CXCR7 expression in the tumor cells and stromal cells from the metastatic foci was significantly more common in the group of male patients treated with cytotoxic drugs according to the FOLFOX6 regimen. The expression of SDF1α in the tumor cells was significantly more often observed in the male patients who had received combined cytotoxic therapy and targeted anti-VEGF therapy than in those who had not drug therapy. VEGF expression in the stromal cells was significantly less frequently seen in the patients who had received the combined therapy., Conclusion: Combined cytotoxic therapy and targeted anti-VEGF therapy for colorectal adenocarcinoma metastases to the liver leads to some suppression of the alternative pathway in the formation of new vessels, by reducing the expression of CXCR4 in the vessel endothelial cells and that of VEGF in the stromal cells from the metastatic foci. In men, this therapy simultaneously causes an increase in the expression of SDF1α in the tumor cells and in that of CXCR4 in the stroma. Preoperative FOLFOX6 therapy significantly increases the expression of CXCR7 in the tumor cells and stromal cells in the male patients, which may suggest that this pathway in vessel formation can be activated.

New composite matrices have been suggested for the analysis of mixtures of different synthetic organic compounds (N-containing heterocycles and erectile dysfunction drugs) by thin layer chromatography/matrix-assisted laser desorption ionization time-of-flight mass spectrometry (TLC/MALDI-TOF). Different mixtures of classical MALDI matrices and graphite particles dispersed in glycerol were used for the registration of MALDI mass spectra directly from TLC plates after analytes separation. In most of cases, the mass spectra possessed [M+H] + ions; however, for some analytes only [M+Na] + and [M+K] + ions were observed. These ions have been used to generate visualized TLC chromatograms. The described approach increases the desorption/ionization efficiencies of analytes separated by TLC, prevent spot blurring, simplifies and decrease time for sample preparation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: to determine the advantages of contrast-enhanced computed tomography (CT) over contrast-free studies in the differential diagnosis of hepatic, renal, and pancreatic space-occupying lesions. MATERIAL AND METHODS. A team of experienced radiologists retrospectively used CT data of patients with different space-occupying lesions of the abdomen and retroperitoneal space (liver, kidney, and pancreas)., Results: The diagnostic value of CT of the liver, kidney, and pancreas substantially decreases without using radiopaque contrast agents; at the same time not only the differential diagnosis, but also visualization of some neoplasms are frequently impossible., Conclusion: The potential benefit of contrast-enhanced CT virtually always outweighs the risks associated with the injection of a contrast agent.

Aim: To improve the results of treatment of a widespread purulent peritonitis in children by optimizing fluid therapy includes the use of combined treatment: reamberin and remaxol., Material and Methods: We studied 269 patients aged 1 to 15 years with a widespread purulent peritonitis treated at the children's surgical departments in Samara from 2001 to 2015. The study group included 179 children who used the optimized infusion therapy. In the study group was allocated to 2 groups: 69 children in infusion therapy which used reamberin and 110 patients in which treatment was applied reamberin and remaxol. The surgical treatment used laparoscopic sanation of the abdomen. Comprehensive survey included a study of dynamics of the white blood cell count, leukocyte index Kalf-Caliph, erythrocyte sedimentation rate, temperature, total albumin concentration, transaminase levels. Catamnesis studied 48 patients with the definition of complex intima-media thickness in the projection of basilar, brachial and femoral arteries., Results: A study compared indicators of both groups, revealed a more rapid reduction of intoxication symptomps (leukocytosis, LII, body temperature), the disappearance of enteric disease, recovery of protein-synthetic function of the liver, decrease of cytolytic and mesenchymal-inflammatory syndromes in the main group, especially in the subgroup in which treatment was included remaxol., Conclusion: The use of reamberin and remaxol in infusion therapy led to improvement of the results of the treatment of common purulent peritonitis in children. Study catamnesis with the study of the intima-media revealed that children undergoing widespread purulent peritonitis further develop signs of endothelial dysfunction. The developed clinical recommendations to significantly reduce the risk of developing signs of endothelial dysfunction, thereby reducing the possible appearance of vascular pathology in patients who underwent childhood widespread purulent peritonitis.

Aim: To optimize diagnostics and treatment of cystic liver tumors., Material and Methods: The analysis included outcomes of 46 patients with liver cystic tumors., Results and Discussion: The use of abdominal Doppler-sonography (37 patients), abdominal contrast-enhanced CT (44 patients) and MRI of abdominal cavity with MR-cholangiography (24 patients) defined radiological semiotics of cystic liver diseases. The most important features of cystic tumors are intraluminal septums with blood flow (82% of patients), solid component (6.8%), daughterly cysts (11.3%), as well as biliary hypertension (39.2% of patients). Research of oncomarkers (CEA, SA 19-9, AFP) in 40 patients showed increased level of SA 19-9 only in case of cystadenocarcinoma and intraductal papillary mucinous neoplasm of biliary type. Benign and malignant cystic tumors had increased contents of oncomarkers in all cases. Surgical treatment was used in 42 patients. Extended liver resections were performed in 10 (23.8%) patients, atypical and anatomical resections (removal of less than 3 segments) - in 31 (73.8%) patients. In one case we applied cryoablation of CA in segment I of the liver in view of invasion into the wall of inferior vena cava and hepatoduodenal ligament. In 2 cases surgery was carried out laparoscopically. Also robot-assisted technique was used in 3 patients. Immunohistochemical study was performed in 22 (44.8%) patients. The diagnosis of CAC and biliary type of IPMN was confirmed in case of high expression of CK7, SK19, MUC1, S100p, SDH2, p53 antibodies. Cystadenomas were associated with moderate expression of ER, PR and p53 antibodies by stroma and CK7, SK19, CDX2, MUC1, S100p antibodies by epithelium., Conclusion: There are considerable difficulties of differential diagnosis of liver cystic tumors. Therefore, the use of single algorithm of diagnostics and treatment is necessary to confirm accurately the diagnosis at the perioperative stage. Cystic tumor is more likely to be assumed in women with solitary cyst in segment IV of liver. If the diagnosis is suspected or confirmed anatomical liver resection with complete tumor removal is necessary to prevent the recurrence.

Aim: to estimate the expression of p53 protein, effector caspases-3 and -7, and the antiapoptotic protein survivin in colorectal adenocarcinoma metastases to the liver in patients who have received preoperative cytotoxic and combined cytotoxic and target anti-VEGF therapies., Subjects and Methods: Intraoperative samples from 122 patients with colorectal carcinoma metastases to the liver were immunohistologically examined. The investigation included patients who had received preoperative treatment with cytotoxic drugs, combined cytotoxic and targeted anti-VEGF therapy. A control group consisted of patients who had not received preoperative anti-tumor drug treatment., Results: Expression of Caspase 3, including that of survivin, was significantly more frequently detected in the patients who had received combined cytotoxic and anti-VEGF therapy as compared to both those treated with only cytotoxic agents (p=0.00004) and the control group (p=0.0008) As compared to the latter, the women who had received cytotoxic therapy were found to have no survivin expression (p=0.015). Investigation of the expression of caspase-7 and p53 revealed no statistically significant differences between the three groups., Conclusion: Addition of bevacizumab to preoperative standard therapy regimens for colorectal adenocarcinoma metastases to the liver leads to activated apoptosis in tumor cells, by enhancing the expression of effector caspase 3. At the same time, standard cytotoxic chemotherapy regimens in women results in activated apoptosis, by decreasing the expression of the antiapoptotic protein survivin.

Objective: To study E-cadherin and β-catenin expression in colorectal cancer (CRC) liver metastases in order to assess the impact of different drug therapy regimens on the adhesive properties of tumor cells., Material and Methods: Intraoperative metastatic CRC samples from patients who had received preoperative cytotoxic chemotherapy or combined cytotoxic and targeted anti-VEGF (vascular endothelial growth factor) therapy were immunohistochemically examined using antibodies to E-cadherin and β-catenin. A comparison group consisted of patients who had not received drug therapy., Results: Combined therapy with cytotoxic and anti-VEGF agents was shown to result in a significant increase in the number of cases of normal membrane localization of E-cadherin as compared with control (p = 0.00043) and cytotoxic therapy-alone (p = 0.01) groups. A comparison of β-catenin levels in three patient groups revealed no significant differences, but addition of an anti-VEGF agent caused some decrease in the number of cases of abnormal nuclear localization of the protein as compared to both the control group and the cytotoxic therapy groups. The comparison of E-cadherin and β-catenin localization in tumor cells showed that a combination of normal E-cadherin membrane localization and β-catenin membrane-cytoplasmic expression prevailed in the combined therapy group compared to the control (p = 0.009) and cytotoxic therapy (p = 0.04) groups., Conclusion: The addition of a targeted anti-VEGF agent to the drug therapy of metastatic CRC has a positive impact on the cadherin-catenin complex, leading to increased intercellular contacts and suppressed β-catenin functioning as a transcription factor that enhances tumor cell proliferation.

The Purpose of the Study: Improving the treatment of advanced peritonitis via use in therapy antihypoxant Reamberin and hepatoprotector Remaxol, nutritional support, sanitation laparoscopic abdominal cavity., Subjects: A total of 232 children aged 1 to 15 years with generalized purulent peritonitis treated at the children's surgical departments of Samara from 2001 to 2014. A study group comprised 148 patients who used the optimized pathogenetic therapy. In the study group was allocated two groups: 64 patients in the pathogenetic therapy that used antihypoxant reamberin, and 84 children in the treatment of which reamberin and hepatoprotector remaxol. All the children of the main group received nutritional support (trophic feedings), used in the surgical treatment of abdominal laparoscopic sanitation. Comprehensive survey includes the study of the dynamics of the level of white blood cells, leukocyte index on Kalf-Caliph, erythrocyte sedimentation rate, temperature, total albumin concentration, transaminase levels., Results: Comparison of the studied parameters in the study and control groups, showed a more rapid decrease in the symptoms and signs of intoxication (leukocytosis, LII, body temperature), relief of enteric disease, recovery of protein-synthetic function of the liver, a decrease of cytolytic and mesenchymal-inflammatory syndrome in the study group, especially in the subgroup in which therapy was included remaxol., Conclusions: Optimization of treatment involving the application of the combined drugs--antihypoxant reamberin, hepatoprotector remaxol, nutritional support and implementation of laparoscopic abdominal sanitation led to improved results of therapy common purulent peritonitis in children.

A number of C-3 spirocyclic 2-benzazepine analogs of α-phenyl-N-tert-butyl nitrone (PBN) were synthesized and tested for their activity in protecting rat brain mitochondria and dopaminergic (DA) neurons against 6-hydroxydopamine (6-OHDA), a toxin inducing destruction of the DA nigro-striatal pathway in rodent models of Parkinson's disease. The newly synthesized nitrone derivatives were firstly investigated for their activity in decreasing the level of hydroxyl radicals generated during 6-OHDA oxidation, and inhibit lipid peroxidation (TBARS assay) and protein carbonyl content (PCC) in rat brain mitochondria. Most of the studied 2-benzazepine nitrones showed inhibitory potencies in both TBARS and PCC assays at least two magnitude orders higher than that of PBN. The data obtained usefully complemented the known structure-activity relationships. In particular, 5 and 10, bearing C-3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8 µM concentration proved to be significantly more effective than PBN in protecting cultured DA neurons exposed to 6-OHDA, which alone causes about 45% cell loss in 24 h. In addition, we found that 5 inhibited butyrylcholinesterase with an IC(50) value of 16.8 µM, which would enhance its potential as neuroprotective agent in Alzheimer's neurodegeneration. These findings extend the utility of benzazepine-based PBN analogs in the treatment of age-related free radical-mediated disorders., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Reaction of 10-cyanotetrahydrobenzo[b][1,6]naphthyridines (1-6) with activated alkynes affords stable benzo[b]pyrrolo[2,1-f][1,6]naphthyridine-4-ium ylides (7-14) in moderate yields. A proposed mechanism for their formation consists of a new tandem multistage process.

A number of new analogs of 3,3-dimethyl-4,5-dihydro-3H-2-benzazepine 2-oxide, structurally related to the nitrone spin trap alpha-phenyl-N-tert-butylnitrone (PBN), were synthesized and evaluated for their activity in vitro as protectants against oxidative stress induced in rat brain mitochondria by 6-hydroxydopamine (6-OHDA), a neurotoxin producing experimental model of Parkinson's disease (PD). As assessed by a fluorimetric assay, all 2-benzazepine-based nitrones were shown to decrease hydroxyl radicals (OH) generated during 6-OHDA autoxidation. The inhibition effects on the OH formation shown by the 5-gem-dimethyl derivatives, 2-4 times higher than those of the corresponding 5-methyl derivatives, were attributed to the flattening effect of the 5-gem-dimethyl group on the azepine ring, which should enhance nitrone reactivity and/or increase stability of the radical adducts. In contrast, owing to steric hindrance, a methyl group to C-1 diminishes the OH-scavenging activity of the nitrone group. All the assayed compounds were more potent than PBN as inhibitors of 6-OHDA-induced lipid peroxidation (LPO) and protein carbonylation (PCO), taken as an indicator of mitochondrial protein oxidative damage. The most promising antioxidant (compound 11), bearing 5-gem-dimethyl and spiro C-3 cyclohexyl groups, highlighted in this study as the best features, inhibited LPO and PCO with IC50 values of 20 and 48 microM, respectively, showing a potency improvement over PBN of two order magnitude. Both LPO and PCO inhibition potency data were found primarily related to the OH-scavenging activities, whereas lipophilicity plays a role in improving the LPO (but not PCO) inhibition, as a statistically valuable two-parameter equation proved.

A series of ester derivatives of annulated tetrahydroazocines, namely 2,3,6,11-tetrahydro-1H-azocino[4,5-b]indoles (5-10), 2,3,6,7-tetrahydro-1H-azocino[5,4-b]indoles (11-14), and 4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocines (15-18), synthesized through an efficient 6-->8 membered ring expansion procedure, were investigated for their acetylcholinesterase (AChE) inhibitory activities. Most of the compounds acted as AChE inhibitors in vitro, with IC(50) values ranging from 5 to 40 microM. The most potent compounds 11 and 15, both as racemic mixtures, proved selective toward AChE, exhibiting selectivity ratios versus butyrylcholinesterase (BuChE) of ca. 15 and more than 20, respectively. Structure-activity studies highlighted, among other factors, lipophilicity as a property modulating the AChE inhibition potency, as shown by a reasonable parabolic correlation between pIC(50) and experimental 1-octanol/water partition coefficient (logP), which described the prevailing behavior of the examined compounds (r(2)=0.665). Molecular docking simulations using the X-ray crystal structure of AChE from Torpedo californica suggested possible binding modes of the tetrahydroazocine ester derivatives 11 and 15.

The reactions of 3-acetyl-3-aza-11-oxatricyclo[6.2.1.0(1,6)]undec-9-ene and its 9,10-epoxy derivative with bromine and Ac(2)O/BF(3).OEt(2) under different conditions were studied. Unusual products of Wagner-Meerwein rearrangement bearing the olefin fragment (5-aza-2-oxatricyclo[6.2.1.0(3,9)]undecen-3-enes) were isolated and characterized by X-ray analysis.

A series of 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines (THPPs), mostly C(2)-substituted derivatives, and some 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles (THPIs) were synthesized and tested in-vitro for their ability to inhibit aggregation of human platelet-rich plasma (PRP) induced by adenosine 5'-diphosphate (ADP) and adrenaline (epinephrine). 5-Benzyl THPP (3), 2-(benzylamino)methyl THPP (5f) and 2-ethyl THPI (6) moderately and dose-dependently inhibited platelet aggregation induced by adrenaline and, to a lesser extent, by ADP. These compounds inhibited the second phase of the PRP aggregation triggered by adrenaline, which largely depends upon thromboxane A(2) production and ADP release. In the adrenaline stimulated aggregation, the THPI derivative 6 was found to be nearly equipotent with aspirin, their IC50 values (concentration effecting 50% inhibition of aggregation) being 90 and 60 microM, respectively. A relation between activity and calculated octanol-water partition coefficient suggested that a log P value around 2.5 should be the optimal lipophilicity value for the activity of THPP-containing compounds.