Concurrent ultrafast twisting and proton transfer photoreactions in new pyrano[2,3-]pyrazole derivatives.

Pyrano[2,3-]pyrazole derivatives are a class of compounds exhibiting dual solvent-dependent fluorescence. This interesting and potentially useful optical property is attributed to the excited state intramolecular proton transfer (ESIPT). We have investigated excited state dynamics of these molecules in detail using femtosecond time-resolved fluorescence and transient absorption spectroscopy.

Synthesis and photo-induced anticancer activity of new 2-phenylethenyl-1H-benzo[e]indole dyes.

Herein, a series of new 1,1,2-trimethyl-1H-benzo[e]indole dyes was prepared via Knoevenagel condensation reaction between 1,1,2-trimethyl-1H-benzo[e]indole and benzaldehydes, and characterized using various spectroscopic methods. The obtained compounds showed cytotoxic properties in G361 melanoma cell line upon irradiation with 414 nm blue light at submicromolar doses. The mechanism of action of the most potent compound 15 was further investigated.

Multicomponent Synthesis of New Fluorescent Boron Complexes Derived from 3-Hydroxy-1-phenyl-1-pyrazole-4-carbaldehyde.

Novel fluorescent pyrazole-containing boron (III) complexes were synthesized employing a one-pot three-component reaction of 3-hydroxy-1-phenyl-1-pyrazole-4-carbaldehyde, 2-aminobenzenecarboxylic acids, and boronic acids. The structures of the novel heterocyclic compounds were confirmed using H-, C-, N-, F-, and B-NMR, IR spectroscopy, HRMS, and single-crystal X-ray diffraction data. The photophysical properties of the obtained iminoboronates were investigated using spectroscopic techniques, such as UV-vis and fluorescence spectroscopies.

Synthesis and photodynamic activity of new 5-[(E)-2-(3-alkoxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-2-phenyl-3H-indoles.

A series of new indole-pyrazole hybrids 8a-m were synthesized through the palladium-catalyzed ligandless Heck coupling reaction from easily accessible unsubstituted, methoxy- or fluoro-substituted 4-ethenyl-1H-pyrazoles and 5-bromo-3H-indoles. These compounds exerted cytotoxicity to melanoma G361 cells when irradiated with blue light (414 nm) and no cytotoxicity in the dark at concentrations up to 10 µM, prompting us to explore their photodynamic effects. The photodynamic properties of the example compound 8d were further investigated in breast cancer MCF-7 cells.

Assessment of the alpha 7 nicotinic acetylcholine receptor as an imaging marker of cardiac repair-associated processes using NS14490.

Background: Cardiac repair and remodeling following myocardial infarction (MI) is a multifactorial process involving pro-reparative inflammation, angiogenesis and fibrosis. Noninvasive imaging using a radiotracer targeting these processes could be used to elucidate cardiac wound healing mechanisms. The alpha7 nicotinic acetylcholine receptor (ɑ7nAChR) stimulates pro-reparative macrophage activity and angiogenesis, making it a potential imaging biomarker in this context.

Synthesis and neuroprotective activity of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives.

A library of 3-aryl-3-azetidinyl acetic acid methyl ester derivatives was prepared from N-Boc-3-azetidinone employing the Horner-Wadsworth-Emmons reaction, rhodium(I)-catalyzed conjugate addition of arylboronic acids, and subsequent elaborations to obtain N-unprotected hydrochlorides, N-alkylated and N-acylated azetidine derivatives. The compounds were evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, revealing several derivatives to possess AChE inhibition comparable to that of the AChE inhibitor rivastigmine. The binding mode of the AChE inhibitor donepezil and selected active compounds 26 and 27 within the active site of AChE was studied using molecular docking.

Synthesis and Characterization of New Pyrano[2,3-]pyrazole Derivatives as 3-Hydroxyflavone Analogues.

In this paper, an efficient synthetic route from pyrazole-chalcones to novel 6-aryl-5-hydroxy-2-phenylpyrano[2,3-]pyrazol-4(2)-ones as 3-hydroxyflavone analogues is described. The methylation of 5-hydroxy-2,6-phenylpyrano[2,3-]pyrazol-4(2)-one with methyl iodide in the presence of a base yielded a compound containing a 5-methoxy group, while the analogous reaction of 5-hydroxy-2-phenyl-6-(pyridin-4-yl)pyrano[2,3-]pyrazol-4(2)-one led to the zwitterionic 6-(-methylpyridinium)pyrano[2,3-]pyrazol derivative. The treatment of 5-hydroxy-2,6-phenylpyrano[2,3-]pyrazol-4(2)-one with triflic anhydride afforded a 5-trifloylsubstituted compound, which was further used in carbon-carbon bond forming Pd-catalyzed coupling reactions to yield 5-(hetero)aryl- and 5-carbo-functionalized pyrano[2,3-]pyrazoles.

Facile synthesis of new -(aminocycloalkylene)amino acid compounds using chiral triflate esters with -Boc-aminopyrrolidines and -Boc-aminopiperidines.

In this study, we prepared a series of new -(aminocycloalkylene)amino acid derivatives for use in chiral building blocks. The method was based on the conversion of enantiopure α-hydroxy acid esters into the corresponding chiral triflate esters, which were displaced by a nucleophilic substitution S2 reaction with aminopyrrolidine and aminopiperidine derivatives, and the inversion of the configuration to give methyl 2-[(Boc-amino)cycloamin-1-yl]alkanoates with good yield and high enantiomeric and diastereomeric purity. Synthesized 2-[(Boc-amino)piperidin-1-yl]propanoates combined with ethyl l-phenylalaninate gave new chiral -Boc- and -nosyl-dipeptides containing a piperidine moiety.

Total synthesis of lamellarin G trimethyl ether through enaminone cyclocondensation.

A synthesis of pyrrolo[2,1-]isoquinolines based on intramolecular condensation of an enaminone intermediate obtained by -acylation of an -alkylated 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolinium salt was developed. This methodology was further applied to the total synthesis of lamellarin G trimethyl ether from commercially available starting materials compatible with xylochemistry with an overall yield of 26% in 7 steps based on homoveratrylamine.

Pyrazole-based lamellarin O analogues: synthesis, biological evaluation and structure-activity relationships.

A library of pyrazole-based lamellarin O analogues was synthesized from easily accessible 3(5)-aryl-1-pyrazole-5(3)-carboxylates which were subsequently modified by bromination, -alkylation and Pd-catalysed Suzuki cross-coupling reactions. Synthesized ethyl and methyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1-pyrazole-5-carboxylates were evaluated for their physicochemical property profiles and cytotoxicity against three human colorectal cancer cell lines HCT116, HT29, and SW480. The most active compounds inhibited cell proliferation in a low micromolar range.

Synthesis of New Azetidine and Oxetane Amino Acid Derivatives through Aza-Michael Addition of NH-Heterocycles with Methyl 2-(Azetidin- or Oxetan-3-Ylidene)Acetates.

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (-Boc-azetidin-3-ylidene)acetate was obtained from (-Boc)azetidin-3-one by the DBU-catalysed Horner-Wadsworth-Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds.

Convenient Synthesis of -Heterocycle-Fused Tetrahydro-1,4-diazepinones.

A general approach towards the synthesis of tetrahydro-4-pyrazolo[1,5-][1,4]diazepin-4-one, tetrahydro[1,4]diazepino[1,2-]indol-1-one and tetrahydro-1-benzo[4,5]imidazo[1,2-][1,4]diazepin-1-one derivatives was introduced. A regioselective strategy was developed for synthesizing ethyl 1-(oxiran-2-ylmethyl)-1-pyrazole-5-carboxylates from easily accessible 3(5)-aryl- or methyl-1-pyrazole-5(3)-carboxylates. Obtained intermediates were further treated with amines resulting in oxirane ring-opening and direct cyclisation-yielding target pyrazolo[1,5-][1,4]diazepin-4-ones.

Copper-catalyzed -arylation of Furanose-Fused Oxazolidine-2-thiones.

The 1,3-oxazolidine-2-thiones (OZTs) are important chiral molecules, especially in asymmetric synthesis. These compounds serve as important active units in biologically active compounds. Herein, carbohydrate anchored OZTs were explored to develop a copper-catalyzed C-S bond formation with aryl iodides.

Synthesis and Characterization of Novel Heterocyclic Chalcones from 1-Phenyl-1-pyrazol-3-ol.

An efficient synthetic route to construct diverse pyrazole-based chalcones from 1-phenyl-1-pyrazol-3-ols bearing a formyl or acetyl group on the C4 position of pyrazole ring, employing a base-catalysed Claisen-Schmidt condensation reaction, is described. Isomeric chalcones were further reacted with -hydroxy-4-toluenesulfonamide and regioselective formation of 3,5-disubstituted 1,2-oxazoles was established. The novel pyrazole-chalcones and 1,2-oxazoles were characterized by an in-depth analysis of NMR spectral data, which were obtained through a combination of standard and advanced NMR spectroscopy techniques.

Regioselective synthesis of methyl 5-(-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks.

A convenient and efficient synthesis of novel achiral and chiral heterocyclic amino acid-like building blocks was developed. Regioisomeric methyl 5-(-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates were prepared by the reaction of β-enamino ketoesters (including azetidine, pyrrolidine or piperidine enamines) with hydroxylamine hydrochloride. Unambiguous structural assignments were based on chiral HPLC analysis, H, C, and N NMR spectroscopy, HRMS, and single-crystal X-ray diffraction data.

Synthesis of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines and their photodynamic properties in the human skin melanoma cell line G361.

A small series of N-aryl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridin-7-amines was synthesized from easily accessible 1-phenyl-1H-pyrazol-3-ol via 7-iodo-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine and 7-iodo-4-methyl-2,6-diphenyl-2H-pyrazolo[4,3-c]pyridine intermediates and their subsequent use in palladium catalyzed Buchwald-Hartwig cross-coupling reaction with various anilines. Majority of the compounds were not significantly cytotoxic to melanoma G361 cells in the dark up to 10 µM concentration, but their activity could be increased by irradiation with visible blue light (414 nm). The most active compound 10 possessed EC values of 3.

Mild Copper-Catalyzed, l-Proline-Promoted Cross-Coupling of Methyl 3-Amino-1-benzothiophene-2-carboxylate.

Cu-catalyzed -arylation is a useful tool for the chemical modification of aromatic heterocycles. Herein, an efficient carbon-nitrogen cross-coupling of methyl 3-amino-1-benzothiophene-2-carboxylate with a range of (hetero)aryl iodides using CuI, l-proline and CsCO in dioxane at moderate temperature is described. The procedure is an extremely general, relatively cheap, and experimentally simple way to afford the -substituted products in moderate to high yields.

Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2-pyrazolo[4,3-]pyridines.

A library of 2,4,6,7-tetrasubstituted-2-pyrazolo[4,3-]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1-pyrazoles to 7-iodo-2,6-diphenyl-2-pyrazolo[4,3-]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI values.

Convenient Synthesis of Pyrazolo[4',3':5,6]pyrano[4,3-][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition.

A simple and efficient synthetic route to the novel 3a,4-dihydro-3,7- and 4,7-pyrazolo[4',3':5,6]pyrano[4,3-][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant isomer. The structures of the obtained heterocyclic products were confirmed by detailed H, C and N NMR spectroscopic experiments and HRMS measurements.

Synthesis and Characterization of Novel Methyl (3)5-(-Boc-piperidinyl)-1-pyrazole-4-carboxylates.

Series of methyl 3- and 5-(-Boc-piperidinyl)-1-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their -Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and ()- and ()-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with ,-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various -mono-substituted hydrazines afforded the target 5-(-Boc-piperidinyl)-1-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further -alkylated with alkyl halides to give 3-(-Boc-piperidinyl)-1-pyrazole-4-carboxylates.

Synthesis of 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones and their protective activity against oxidative stress.

A small library of 2-[(1H-indol-3-yl)methyl]-5-(alkylthio)-1,3,4-oxadiazoles was prepared, starting from indole-3-acetic acid methyl ester and its 5-methyl-substituted derivative. The synthetic route involved the formation of intermediate hydrazides, their condensation with carbon disulfide, and intramolecular cyclization to corresponding 5-[(1H-indol-3-yl)methyl]-1,3,4-oxadiazole-2(3H)-thiones. The latter were then S-alkylated, and in case of ester derivatives, they were further hydrolyzed into corresponding carboxylic acids.

A community-built calibration system: The case study of quantification of metabolites in grape juice by qNMR spectroscopy.

Nuclear Magnetic Resonance (NMR) is an analytical technique extensively used in almost every chemical laboratory for structural identification. This technique provides statistically equivalent signals in spite of using spectrometer with different hardware features and is successfully used for the traceability and quantification of analytes in food samples. Nevertheless, to date only a few internationally agreed guidelines have been reported on the use of NMR for quantitative analysis.

Synthesis and anthelmintic activity of benzopyrano[2,3-c]pyrazol-4(2H)-one derivatives.

A series of benzopyrano[2,3-c]pyrazol-4(2H)-one derivatives were synthesized from readily available 1-phenyl- and 1-methyl-1H-pyrazol-3-ols by sequentially employing O-acylation, Fries rearrangement and potassium carbonate-induced cyclization. The anthelmintic properties of the obtained compounds were investigated in vivo in a model nematode, Caenorhabditis elegans. Five compounds, namely 2-phenyl[1]benzopyrano[2,3-c]pyrazol-4(2H)-one 33 and its 7-fluoro, 7-chloro-, 7-bromo- and 8-fluoro-analogues, 36, 38, 40 and 43, respectively, altered the development of C.

Facile synthesis of novel amino acid-like building blocks by N-alkylation of heterocyclic carboxylates with N-Boc-3-iodoazetidine.

An efficient protocol providing easy access to highly functionalized heterocyclic compounds as novel organic building blocks was developed by coupling alkyl pyrazole-, indazole- and indolecarboxylates with N-Boc-3-iodoazetidine. The synthesized compounds are representatives of constrained non-chiral synthetic azole carboxylates in their N-Boc protected ester forms. Diversification of the prepared heterocyclic building blocks was achieved via application of palladium-catalyzed Suzuki-Miyaura cross-coupling reactions.

Development and radiosynthesis of the first F-labeled inhibitor of monocarboxylate transporters (MCTs).

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers.