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Various substituted D-hexopypyranosides units with nitrogen-containing functionalities are present in many important natural compounds and pharmaceutical substances. Since their complex structural diversity contributes to a broad spectrum of biological functions and activities, these derivatives are frequently studied. This review covers syntheses of D-hexopyranosides with vicinal nitrogen-containing functionalities since the 1960s, when the first articles emerged. The syntheses are arranged according to the positions of substitutions, to form a relative configuration of vicinal functionalities, and synthetic methodologies. [ABSTRACT FROM AUTHOR]

Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo. [ABSTRACT FROM AUTHOR]

The novel synthesis of unsymmetrical 1,1'‐bibenzimidazoles is described. The key N−N bond was introduced on 1H‐benzimidazole or 1H‐benzimidazole‐2‐sulfonic acid by N‐amination with hydroxylamine‐O‐sulfonic acid (HASA). The precursors, 1‐[(2‐nitrophenyl)amino]‐1H‐benzimidazoles, were prepared by nucleophilic aromatic substitution of 1‐fluoro‐2‐nitrobenzene with 1H‐benzimidazole‐1‐amines. The synthesis was demonstrated on 11 novel 1,1'‐bibenzimidazoles, which were prepared in the final step by one‐pot reduction/cyclization with DMF or DMA acetals under mild acidic conditions in good overall yields. [ABSTRACT FROM AUTHOR]

New screen-printed sensor with a boron-doped diamond working electrode (SP/BDDE) was fabricated using a large-area linear antenna microwave chemical deposition vapor system (LA-MWCVD) with a novel precursor composition. It combines the advantages of disposable printed sensors, such as tailored design, low cost, and easy mass production, with excellent electrochemical properties of BDDE, including a wide available potential window, low background currents, chemical resistance, and resistance to passivation. The newly prepared SP/BDDEs were characterized by scanning electron microscopy (SEM) and Raman spectroscopy. Their electrochemical properties were investigated by cyclic voltammetry and electrochemical impedance spectroscopy using inner sphere ([Fe(CN)6]4−/3−) and outer sphere ([Ru(NH3)6]2+/3+) redox probes. Moreover, the applicability of these new sensors was verified by analysis of the anti-inflammatory drug lornoxicam in model and pharmaceutical samples. Using optimized differential pulse voltammetry in Britton–Robinson buffer of pH 3, detection limits for lornoxicam were 9 × 10−8 mol L−1. The oxidation mechanism of lornoxicam was investigated using bulk electrolysis and online electrochemical cell with mass spectrometry; nine distinct reaction steps and corresponding products and intermediates were identified. [ABSTRACT FROM AUTHOR]

Prototropic tautomerism was used as a tool for the reductive dehalogenation of (hetero)aryl bromides and iodides, or dehalogenative sulfonation of (hetero)aryl chlorides and fluorides, using sodium sulfite as the sole reagent in an aqueous medium. This protocol does not require a metal or phase transfer catalyst and avoids using organic solvent as the reaction medium. This method is especially suitable for substrates that readily tautomerize (such as 2- or 4-halogenated aminophenols and 4-halogenated resorcinols), for which dehalogenation or sulfonation proceeds under mild reaction conditions (≤60 °C). As sodium sulfite is an inexpensive, safe, and environmentally less hazardous reagent, this method has at least three potential applications: (i) in the deprotection of halogens as protecting groups, using sodium sulfite as a reducing agent; (ii) in the sulfonation of aromatic halides under mild reaction conditions avoiding hazardous and corrosive reagents/solvents; and (iii) in the transformation of toxic halogenated aromatics into less harmful compounds. [ABSTRACT FROM AUTHOR]

Synthesis of [15N4] purine labeled cytokinine glycosides derived from zeatins and topolins containing a 9‐β‐d, 7‐β‐d‐glucopyranosyl, or 9‐β‐d‐ribofuranosyl group is described. These N6‐substituted adenine derivatives are intended as internal analytic standards for phytohormone analysis. All labeled compounds were prepared from 6‐chloro[15N4]purine (1). The equilibrium reaction of 1 with acetobromo‐α‐d‐glucose gave isomeric 7‐β‐d (3) and 9‐β‐d (4) chloro glucosyl precursors, which were treated with the corresponding amines to get desired labeled cytokinin 7‐β‐d (6) and 9‐β‐d (5) glucopyranosides. Cytokinins containing 9‐β‐d‐ribofuranosyl group (8) were obtained by direct enzymatic transglycosylation reaction of cytokinins (7) prepared from 6‐chloro[15N4] purine (1). Synthesis and characterization of some [15N4] purine labeled cytokinin glycosides derived from zeatins and topolins containing 9‐β‐d, 7‐β‐d‐glucopyranosyl, or 9‐β‐d‐ribofuranosyl group with using chemical and enzymatic approaches is described. [ABSTRACT FROM AUTHOR]

Electrochemical oxidation of azoxystrobin, a systemic fungicide commonly used in agriculture to protect a wide variety of crops, was investigated using cyclic voltammetry with a boron‐doped diamond electrode (BDDE) in aqueous buffer solutions. Two pH independent irreversible anodic current peaks controlled mostly by diffusion were observed in wide pH range (2 to 12) at potentials +1600 mV and +2150 mV vs. saturated silver‐silver chloride electrode. Mechanism of the electrochemical oxidation was proposed and supported with high performance liquid chromatography/mass spectrometry analysis of azoxystrobin solutions electrolyzed on carbon fiber brush electrode. The main product of the first two‐electron oxidation step was identified as methyl 2‐(2‐{[6‐(2‐cyanophenoxy)pyrimidin‐4‐yl]oxy}phenyl)‐2‐hydroxy‐3‐oxopropanoate. An analytical method for the determination of azoxystrobin in water samples and pesticide preparation by differential pulse voltammetry with BDDE was developed. The method provides a wide linear dynamic range (3.0×10−7 to 2.0×10−4 mol L−1) with limit of detection 8×10−8 mol L−1. Accuracy of the method was evaluated by the addition and recovery method with recoveries ranging from 96.0 to 105.8 %. Interference study proved sufficient selectivity of the developed voltammetric method for the azoxystrobin determination in presence of azole fungicides as well as pesticides used to prevent the same crops. [ABSTRACT FROM AUTHOR]

The cyclin-dependent kinase inhibitor, CAN508, was protected with di-tert-butyl dicarbonate to access the amino-benzoylated pyrazoles. The bromo derivatives were further arylated by Suzuki-Miyaura coupling using the XPhos Pd G2 pre-catalyst. The coupling reaction provided generally the para-substituted benzoylpyrazoles in the higher yields than the meta-substituted ones. The Boc groups were only utilized as directing functionalities for the benzoylation step and were hydrolyzed under conditions of Suzuki-Miyaura coupling, which allowed for elimination of the additional deprotection step. [ABSTRACT FROM AUTHOR]

Halogenated aminopyrazoles have rarely been utilized in metal-catalysed cross-coupling reactions mainly due to the complexation of the aminopyrazoles to the metal center, which deactivates the catalyst. In this paper we reveal that the appropriate combination of palladium source and ligand enables efficient Suzuki-Miyaura cross-coupling reactions with even challenging substrates such as halogenated aminopyrazoles. The combination of Pd(OAc)2 and XPhos allowed efficient coupling of halogenated N-acetylaminopyrazoles, whereas XPhos Pd G2 was needed when unprotected aminopyrazoles were used. Generally, the halogenated aminopyrazoles underwent facile cross-coupling reactions with a range of aryl-, heteroaryl-, and styrylboronic acids and esters. The resulting biaryl, bisheteroaryl, or arylalkenyl derivatives were obtained in good-to-high isolated yields. [ABSTRACT FROM AUTHOR]

The synthesis of 1 H-benzimidazol-2-yl-1 H-pyrazole-3,5-diamines has been developed. Synthesized bisheteroaryls contain two privileged medicinal scaffolds, aminopyrazole and benzimidazole, with two diversity positions at N1 of benzimidazole and C3 of pyrazole, respectively. The three-step synthesis includes the Mitsunobu of benzimidazole and subsequent one-pot formation of aminopyrazole involving substitution of methylthio groups with amine and hydrazine followed with final ring closure. Inhibitory activity toward cyclin-dependent kinase 2/cyclin E and cytotoxicity against two cancer cell lines were evaluated for all novel pyrazoles. Two compounds showed modest cyclin-dependent kinase inhibition activity and cytotoxicity against cancer cell lines K562 and MCF7. [ABSTRACT FROM AUTHOR]

Inhibitors of cyclin-dependent kinases 9 have been developed as potential anticancer drugs for the treatment of multiple myeloma. We have previously prepared a library of arylazo-3,5-diaminopyrazole inhibitors of CDKs. Here, we describe a novel member, AAP1742 (CDK9 inhibition with IC50 = 0.28 μ m), that reduces the viability of multiple myeloma cell lines in low micromolar concentrations. Consistent with inhibition of CDK9, AAP1742 decreases the phosphorylation of RNA polymerase II and inhibits mRNA synthesis of anti-apoptotic proteins Mcl-1, Bcl-2, and XIAP, followed by apoptosis in the RPMI-8226 cell line in a dose- and a time-dependent manner. These results are consistent with the biochemical profile of AAP1742 and further suggest cellular inhibition of CDK9 as a possible target for anticancer drugs. [ABSTRACT FROM AUTHOR]

The fluorescence properties of selected benzo[c]phenanthridines (BPs) were examined. The effect of structure, pH and solvent on the fluorescence properties has been investigated. It was found out that the presence of charged iminium nitrogen significantly decreased the fluorescence of the compounds. The fluorescence (intensity as well as emission spectra shape) of the investigated compounds was significantly dependent on pH as well as used solvent. The utilization in epigenetic modification mechanisms studies as demethylase probe and as possible pH indicator was suggested. [ABSTRACT FROM AUTHOR]

The first nitration of codeine by using bismuth nitrate pentahydrate under mild reaction conditions is described. The resulting 1-nitrocodeine was reduced to 1-aminocodeine, a key precursor for the synthesis of the azo derivative and several hydrazones. Structures of both 1-nitrocodeine and 1-aminocodeine were unequivocally determined by single-crystal X-ray analysis. The reported preliminary synthetic study lays the groundwork for the synthesis of modified codeine derivatives with potential biological activity. [ABSTRACT FROM AUTHOR]

The electrochemical behavior of tolterodine, an antimuscarinic drug used to treat urge incontinence and overactive bladder, was investigated using cyclic and differential pulse voltammetry at glassy carbon electrode. Electrooxidation of tolterodine proceeds as a complex two-step pH-dependent process. Controlled potential electrolysis of tolterodine solutions was performed at platinum gauze electrode in methanolic, aqueous-methanolic and acetonitrile media. Electrolyzed solutions were analyzed using liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry. 5-Hydroxymethyl tolterodine, the main biologically active metabolite of tolterodine, was identified among monomeric oxidation products. Dimeric products, formed by oxidative coupling of phenoxy radicals, were found in all electrolyzed solutions. The mechanism of the electrochemical oxidation of tolterodine has been proposed. [ABSTRACT FROM AUTHOR]

Several variously substituted 1 H-pyrazol-5-yl hydrazones were prepared in order to study their cyclisation reactions. It has been found that the pathway of the cyclisation depends on the nature of the cyclisation medium and the position of substitution in the pyrazole ring. Graphical abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]