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In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a–g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e). Two novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. 5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM). 5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM). In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment. [ABSTRACT FROM AUTHOR]

The [1,2,4]triazolo[4,3-a]pyridine derivative 3-(4-(benzyloxy)-3-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine was prepared in a 73% isolated yield by means of an oxidative ring closure of a hydrazine intermediate. Sodium hypochlorite was used as the oxidant and ethanol as a solvent, making the process a clean, green approach. The reaction was performed at room temperature for 3 h, and then the heterocycle was isolated in an analytically pure form by extraction, followed by passing the crude product mixture through a small plug of alumina. [ABSTRACT FROM AUTHOR]

5-Alkenyl hydantoins and alkenyl spirohydantoins are converted into bicyclic and tricyclic hydantoins, under indirect electrochemical conditions, generating the phenylselenyl cation in situ. The reactions proceeded in good to exelent yields. The influence of electrochemical conditions on regioand diastereoselectivity of the selenocyclization reactions is investigated. [ABSTRACT FROM AUTHOR]

1,2,5-Chalcogenadiazoles fused with electron-withdrawing heterocycles have been actively investigated for the preparation of organic photovoltaic materials. [1,2,5]Oxadiazolo[3,4-d]pyridazines are much less studied than other chalcogenadiazolopyridazines due to their low availability. In this communication, we report our study showing that 5,6-dihydro-[1,2,5]oxadiazolo[3,4-d]pyridazine-4,7-dione, a key precursor for the synthesis of 4,7-dihalo-[1,2,5]oxadiazolo[3,4-d]pyridazines, is formed via the cyclization of 1,2,5-oxadiazole-3,4-dicarbohydrazide in hydrochloric acid. The structure of the newly synthesized compound was established by means of elemental analysis; high-resolution mass spectrometry; 1H and 13C NMR; IR spectroscopy, and mass spectrometry. [ABSTRACT FROM AUTHOR]

The intramolecular Heck reaction is a well-established strategy for natural product total synthesis. When constructing large rings, this reaction is also referred to as Heck macrocyclization, which has proved a viable avenue to access diverse naturally occurring macrocycles. Less noticed but likewise valuable, it has created novel macrocycles of non-natural origin that neither serve as nor derive from natural products. This review presents a systematic account of the title reaction in forging this non-natural subset of large rings, thereby addressing a topic rarely covered in the literature. Walking through two complementary sections, namely (1) drug discovery research and (2) synthetic methodology development, it demonstrates that beyond the well-known domain of natural product synthesis, Heck macrocyclization also plays a remarkable role in forming synthetic macrocycles, in particular macrocyclic drugs. [ABSTRACT FROM AUTHOR]

Density functional theory is used to study ring closure HSCH2CH2S- and HSCH2CH2CH2S-. The transition state for ring closure of HSCH2CH2S- is predicted to be three-membered and for HSCH2CH2CH2S- is four-membered. Geometries are optimized using a 3-21G basis set. Calculated charges using B3LYP density functional shows that TS1 has more ionic character than TS2. The reactions are found to be endothermic. The activation energy for HSCH2CH2S- is smaller than HSCH2CH2CH2S.- [ABSTRACT FROM AUTHOR]

Functionally substituted 1,2-benzisoxazoles are very important and promising heterocycles with various pharmacological activities. Benzoxazoles containing reactive 3-chloromethyl and 5-amino groups are practically unexplored derivatives in this series. In this communication, the simple method for the synthesis of N-[3-(chloromethyl)-1,2-benzisoxazol-5-yl]acetamide which is an interesting precursor for the preparation of a series of 3,5-disubstituted benzoxazoles was described. The structure of the synthesized compound was established by elemental analysis, high-resolution mass spectrometry, 1H, 13C NMR and IR spectroscopy, and mass spectrometry.

A new and unexpected Rh(I)-catalyzed cycloisomerization of 1,6-enynes is reported. Several different alkyne substitution patterns were evaluated under the reaction conditions, including a deuterated derivative that provides some insight into the reaction mechanism.

New heterocyclic systems containing 1,2,5-chalcogenadiazoles are of great interest for the creation of organic photovoltaic materials and biologically active compounds. In this communication, 3,6-dibromopyridazine-4,5-diamine was investigated in reaction with selenium dioxide in order to obtain 4,7-dibromo-[1,2,5]selenadiazolo[3,4-d]pyridazine. We found that 7-bromo-[1,2,5]selenadiazolo[3,4-d]pyridazin-4(5H)-one, the first representative of the new heterocyclic system, was isolated as a hydrolysis product of the corresponding 4,7-dibromoderivative. The structure of the newly synthesized compound was established by means of elemental analysis, high-resolution mass spectrometry, 1H, 13C NMR, IR and UV spectroscopy, and mass spectrometry.

Functionally substituted 1,2-benzisoxazoles are very important and promising heterocycles with various pharmacological activities. Benzoxazoles containing reactive 3-chloromethyl and 5-amino groups are practically unexplored derivatives in this series. In this communication, the simple method for the synthesis of N-[3-(chloromethyl)-1,2-benzisoxazol-5-yl]acetamide which is an interesting precursor for the preparation of a series of 3,5-disubstituted benzoxazoles was described. The structure of the synthesized compound was established by elemental analysis, high-resolution mass spectrometry, 1H, 13C NMR and IR spectroscopy, and mass spectrometry. [ABSTRACT FROM AUTHOR]

Abstract Biologically attractive azaspiro[4.5]trienones have been prepared via Ugi four-component reaction (Ugi-4CR) followed by bromine-mediated ipso-cyclization. This allows a straightforward synthetic route to a diverse collection of fully functionalized 3-bromoaza­spiro[4,5]trienones in moderate to good yields that can be used as templates for further modifications.

A novel stereocontrolled approach has been developed for the syntheses of tashiromine and epitashiromine alkaloids from cyclooctene β-amino acids. The synthetic concept is based on the azetidinone opening of a bicyclic β-lactam, followed by oxidative ring opening through ring C–C double bond and reductive ring-closure reactions of the cis- or trans-cyclooctene β-amino acids.

Abstract Heterocyclic nucleus plays a fundamental role in the medicinal chemistry and serves as a key template for the development of various therapeutic agents including broad spectrum antibacterial drugs. In an effort to develop new antibacterial agents, a bicyclic twelve-membered heterocyclic nucleus derived from coumarin was prepared by an uncomplicated method. The rate of ring closure for this nucleus, which was given the name coumacine, in addition to two of its derivatives was monitored spectroscopically and this rate followed zero order kinetics. The chemical structures of the synthesized products were established by detecting their physicochemical properties and analyzing their IR, 1H NMR and 13C NMR spectra. The in vitro antibacterial activity of coumacines was evaluated via agar dilution method against different standard aerobic and anaerobic bacterial strains using ciprofloxacin and metronidazole as positive controls, respectively; the results indicated that coumacine I has an excellent broad spectrum antibacterial activity against the tested bacterial strains with percentage of growth inhibition approximating to those of positive controls. [ABSTRACT FROM AUTHOR]

In the present paper, we report an expedient total synthesis of triciribine, a tricyclic 7-deazapurine nucleoside and protein kinase B (AKT) inhibitor, in 35% overall yield. Our synthesis route features a highly regioselective substitution of 1-N-Boc-2-methylhydrazine and a trifluoroacetic acid catalyzed one-pot transformation which combined the deprotection of the tert-butylcarbonyl (Boc) group and ring closure reaction together to give a tricyclic nucleobase motif. [ABSTRACT FROM AUTHOR]

A concise enantioselective synthesis of the advanced intermediate 5 for the synthesis of pumiliotoxins (Gallagher’s intermediate) is described. The synthesis started from the regio- and trans-diastereoselective (dr = 98:2) reductive 3-butenylation of (R)-3-(tert-butyldimethylsilyloxy)glutarimide 14. After O-desilylation and Dess–Martin oxidation, the resulting keto-lactam 10 was subjected to a highly trans-stereoselective addition of the methylmagnesium iodide to give carbinol 11 as sole diastereomer. An efficient ring closure procedure consisting of ozonolysis and reductive dehydroxylation provided the indolizidine derivative 5, which completed the formal enantioselective total synthesis of pumiliotoxins 251D and 237A.

A high-yielding general synthesis of imidazophosphor ester based tetrazolo[1,5-b]pyridazines is described. A conjugated reaction between 3,6-diazidopyridazine and different types of phosphonyl carbanion reagents followed by intramolecular cyclization afforded the target products, by using sodium ethanolate solution as a reaction medium. Among the products, five compounds, at a dose of 50 mg per kilogram body weight, showed a notable antinociceptive and anti-inflammatory activity without toxic side-effects.

Benzo-condensed four-ring heterocycles, such as benzoxetes 1 and benzothietes 3 represent multi-purpose starting compounds for the preparation of various higher heterocyclic ring systems. The thermal or photochemical valence isomerizations between the benzenoid forms 1,3 and the higher reactive o-quinoid structures 2,4 provide the basis for the synthetic applications. On the other hand, this valence isomerization impedes in particular the generation and storage of 1 because the thermal equilibrium 1 2 is completely on the side of 2. Thus, the number of erroneous or questionable benzoxete structures published to date is surprisingly high. On the contrary, the thermal equilibrium 3 4 is on the side of the benzothietes 3, which makes them easily accessible, especially by different flash vacuum pyrolysis techniques. The present article gives a survey of the preparations of 1 and 2, and tries to stimulate their use in synthetic projects. Naphtho-condensed and higher condensed compounds and compounds with an exocyclic C=O or S=O double bond (lactones, thiolactones, sulfoxides and sulfones) are not covered in this article.

A number of conceptually new synthetic approaches to the elaboration of constitutionally diverse isoindolinones have been disclosed. The main objective was to develop synthetic tactics for the creation of the lactam unit that would allow for incorporation of appropriate functionalities liable to give access to an array of synthetic, natural and/or bioactive compounds through rather simple chemical manipulation. The flexibility and potentiality of these new processes have been further exemplified by the total synthesis of exemplary representatives in both series, i.e. alkaloids and compounds endowed with chemotherapeutic properties.

The reaction of anthranilic acid with ethyl acetoacetate gives rise directly to 4-methylpyrano[3,2-c]quinoline- 2,5-dione. The mechanism is assumed to involve condensation of the initial product with a second molecule of the β-ketoester. None of the expected compound (2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) is formed in the reaction. [ABSTRACT FROM AUTHOR]

3,5-Disubstituted isoxazoles have been designed and synthesized to be used as central units for bent-core mesogens. The substituents at position 3 of the isoxazole ring are either hydroxymethyl or carboxyl, while alkenylterminated substituents have been inserted at position 5. A multi-step reaction sequence comprising the O-alkylation of 4-hydroxyacetophenone with the suitable alkenyl halide, the Claisen-type condensation with diethyl oxalate and the cyclization to isoxazole led to the isoxazole esters as key intermediates, which were subsequently reduced and hydrolyzed to the corresponding isoxazol-3-ylmethanols and isoxazole-3-carboxilic acids, respectively. [ABSTRACT FROM AUTHOR]

The nucleophilic substitution of substituted o-nitrochlorobenzenes with substituted methanethiolates, catalysed with triethylamine or pyridine, has been used to prepare a series of appropriately substituted methyl-o-nitrophenylsulfides. The prepared compounds were identified by their 1H- and 13C-NMR spectra. The base catalysed ring closure of methyl 2-(methoxycarbonylmethylsulfanyl)-3,5-dinitrobenzenecarboxylate only results in an attack of carbanion on the ester group, not on a nitro group as with the other compounds prepared. The cyclisation product is methyl 3-hydroxy-5,7-dinitrobenzo[b]thiophene-2-carboxylate (11).

Acylation of 2-aminothiobenzamide or 2-methylaminothiobenzamide with substituted benzoyl chlorides has been used to synthesise the corresponding 2-benzoylaminothiobenzamides whose subsequent sodium methoxide-catalysed ring closure gives the corresponding quinazoline-4-thiones. These compounds were characterised by means of their 1H- and 13C-NMR spectra. The preferred tautomeric form of selected compounds has been discussed on the basis of their 13C-NMR, IR and Raman spectra. It has been found that in the given medium 1-methyl-quinazoline-4-thiones undergo a replacement of the sulphur substituent by oxygen giving 1-methyl-quinazoline-4-ones. In strong acid media, 2-benzoylaminothiobenzamide is cyclised through its sulphur atom to give 2-phenylbenzo[d-1,3]thiazin-4-one.

Abstract: A series of carbamate melatonin derivatives was treated with performic acid, providing tricyclic products with a 3-hydroxytetrahydropyrrolo[2,3-b]indole skeleton. An unusual migration of carbamate groups was observed in some cases, and the reaction appeared to be strongly dependent on the type of substituent in the phenyl ring of the phenylcarbamate group. Theoretical calculations suggest that the reaction is kinetically controlled. [Copyright &y& Elsevier]

An efficient,general, and atom-economic procedure for the synthesis of 2-amino-6 methyl-4-aryl-8-[(E)-arylmethylidene]-5, 6, 7, 8-4H-pyrano [3, 2-c]pyridine-3-carbonitriles has been developed by reaction of 3,5-bis[(E)-arylmethylidene]-tetrahydro-4(1H)-pyridinones with malononitrile. The reaction proceeds under green media (EtOH/H2O, 1:1) and in the presence of diammonium hydrogen phosphate (10%) or piperidine (10%) to afford pyranopyridines at room temperature with good high yields. [ABSTRACT FROM PUBLISHER]

Benzo-condensed four-ring heterocycles, such as benzoxetes 1 and benzothietes 3 represent multi-purpose starting compounds for the preparation of various higher heterocyclic ring systems. The thermal or photochemical valence isomerizations between the benzenoid forms 1,3 and the higher reactive o-quinoid structures 2,4 provide the basis for the synthetic applications. On the other hand, this valence isomerization impedes in particular the generation and storage of 1 because the thermal equilibrium 1⇆ 2 is completely on the side of 2. Thus, the number of erroneous or questionable benzoxete structures published to date is surprisingly high. On the contrary, the thermal equilibrium 3⇆4 is on the side of the benzothietes 3, which makes them easily accessible, especially by different flash vacuum pyrolysis techniques. The present article gives a survey of the preparations of 1 and 2, and tries to stimulate their use in synthetic projects. Naphtho-condensed and higher condensed compounds and compounds with an exocyclic C=O or S=O double bond (lactones, thiolactones, sulfoxides and sulfones) are not covered in this article. [ABSTRACT FROM AUTHOR]

The N-alkylated 2,2,6,6-tetramethylpiperidin-4-ones 3c-f were prepared from the acetal 6a of triacetonamine (3a) by alkylation followed by hydrolysis of the acetal functionality or alternatively from the corresponding secondary alcohol 2,2,6,6-tetramethylpiperidin-4-ol (7a) by N-alkylation and subsequent oxidation to introduce the ketone unit. Direct alkylation of 3a was only possible by using highly reactive halides such as allyl or benzyl bromide with low yields. Treatment of phorone (5) with primary amines 2c-f with an alkyl group greater than methyl did not lead to the desired heterocycles 3c-f since open-chain addition products 8 and 9 were formed instead. Consequently, the reactions of acetone (1) with benzyl- or n-butylamine (2e,f) in the presence of calcium chloride did not generate the corresponding N-alkylated derivatives of 3a. [ABSTRACT FROM AUTHOR]

Novel azabicyclic β-amino acid derivatives were readily prepared from diexo or diendo norbornene β-amino acids. The 3-azabicyclo[3.2.1]octane skeleton was obtained by NaIO4-mediated cleavage of the dihydroxylated β-amino ester intermediates, followed by reductive amination. Lipase-catalyzed enantioselective ring opening of racemic exo-norbornene β-lactam allowed preparation of the corresponding azabicyclic exo β-amino acid in enantiopure form. [ABSTRACT FROM AUTHOR]

Oxazepines, which were synthesized in literature by means a variety of methods, are of great importance in heterocyclic chemistry along with biology and pharmacology. In this work we tried to synthesize naphthoxazepines by using a number of Schiff bases, which were synthesized from 2-hydroxy-1-napthaldehyde and anilines. The obtained imines were reduced to amines, acylated with chloroacetyl chloride and cyclised to give naphthoxazepinones in an overall yield of 20-49%. The identifications of the isolated and purified compounds were determined by IR, UV, ¹H-NMR, 13C-NMR, mass spectra and elemental analysis. [ABSTRACT FROM AUTHOR]

The synthesis of novel chiral monoaza-15-crown-5 compounds (1-4) with pyridine-ring starting from methyl-4,6-O-benzylidene-α-D-glucopyranoside and methyl-4,6-O-benzylidene-α-Dmannopyranoside by different methods are reported. These crown ethers showed significant asymmetric induction in a Michael addition (up to 80% ee). [ABSTRACT FROM AUTHOR]

Starting from the of bicyclic proline ester, ethyl exo-2-azabicyclo[2.2.1]heptane-3-carboxylate (+)-5 several hydantoines and thiohydantoines were prepared by acidic ring closure of the corresponding urea or thiourea derivatives. Enantiomer (-)-5 was reduced to 2-azanorbornylmethanol 12, which was transformed to 5,8-methanooxazolo- and thiazolo[3,4-a]pyridine derivatives. The structures, stereochemistry and relative configurations of the synthesized compounds were proved by NMR. [ABSTRACT FROM AUTHOR]

Reinvestigation of an old experimental finding - the formation of linearly fused tetrazoloisoquinolines from 2,3-diamino-isoquinolinium salts, by using 15N-labeling and 15N-NMR spectroscopy, revealed that the ring closure pathway - unlike a recently observed cyclization of the same diamino salt - does not proceed via a rearrangement route. By comparison of this reaction with the entirely different reactivities of other related 1,2-diamino-azinium salts, a general mechanism is suggested, revealing an ambident reactivity of these diamino compounds. [ABSTRACT FROM AUTHOR]

Abstract: One approach to designing RNA nanoscale structures is to use known RNA structural motifs such as junctions, kissing loops or bulges and to construct a molecular model by connecting these building blocks with helical struts. We previously developed an algorithm for detecting internal loops, junctions and kissing loops in RNA structures. Here we present algorithms for automating or assisting many of the steps that are involved in creating RNA structures from building blocks: (1) assembling building blocks into nanostructures using either a combinatorial search or constraint satisfaction; (2) optimizing RNA 3D ring structures to improve ring closure; (3) sequence optimisation; (4) creating a unique non-degenerate RNA topology descriptor. This effectively creates a computational pipeline for generating molecular models of RNA nanostructures and more specifically RNA ring structures with optimized sequences from RNA building blocks. We show several examples of how the algorithms can be utilized to generate RNA tecto-shapes. [Copyright &y& Elsevier]

New heterocyclic systems containing 1,2,5-chalcogenadiazoles are of great interest for the creation of organic photovoltaic materials and biologically active compounds. In this communication, 3,6-dibromopyridazine-4,5-diamine was investigated in reaction with selenium dioxide in order to obtain 4,7-dibromo-[1,2,5]selenadiazolo[3,4-d]pyridazine. We found that 7-bromo-[1,2,5]selenadiazolo[3,4-d]pyridazin-4(5H)-one, the first representative of the new heterocyclic system, was isolated as a hydrolysis product of the corresponding 4,7-dibromoderivative. The structure of the newly synthesized compound was established by means of elemental analysis, high-resolution mass spectrometry, 1H, 13C NMR, IR and UV spectroscopy, and mass spectrometry. [ABSTRACT FROM AUTHOR]

The first synthesis of 2,3,6,7-tetrabromoanthracene is presented, starting from benzene in a straightforward four step synthesis.