Thiomaltol‐Based Organometallic Complexes with 1‐Methylimidazole as Leaving Group: Synthesis,Stability, and Biological Behavior

Thiomaltol, a potential S,O‐coordinating molecule, has been utilized for the complexation of four different organometallic fragments, yielding the desired Ru^II, Os^II, Rh^III, and Ir^III complexes having a “piano‐stool” configuration. In addition to the synthesis of these compounds with a chlorido leaving group, the analogous 1‐methylimidazole derivatives have been prepared, giving rise to thiomaltol‐based organometallics with enhanced stability under physiological conditions. The organometallic compounds have been characterized by NMR spectroscopy, elemental analysis, and X‐ray diffraction analysis. Their behavior in aqueous solution and their interactions with certain amino acids have been studied by ESI mass spectrometry. Their pH‐dependent stability has been investigated by ¹H NMR in aqueous solution, and their cytotoxicity against three different cancer cell lines has been investigated. Furthermore, their capacity as topoisomerase IIα inhibitors as well as their effect on the cell cycle distribution and reactive oxygen species (ROS) generation have been elucidated.     

Development and validation of a liquid chromatography–tandem mass spectrometry method for topotecan determination in beagle dog plasma and its application in a bioequivalence study

Topotecan (TPT) is an important anti‐cancer drug that inhibits topoisomerase I. A sensitive and robust liquid chromatography–tandem mass spectrometry (LC‐MS/MS) method that potentially determines TPT in beagle dog plasma is needed for a bioequivalence study of TPT formulations. We developed and validated LC‐MS/MS to evaluate TPT in beagle dog plasma in terms of specificity, linearity, precision, accuracy, stability, extraction recovery and matrix effect. Plasma samples were treated with an Ostro^TM sorbent plate (a robust and effective tool) to eliminate phospholipids and proteins before analysis. TPT and camptothecin (internal standard) were separated on an Acquity UPLC BEH C₁₈ column (1.7 µm, 2.1 × 50 mm) with 0.1% formic acid and methanol as the mobile phase at a flow rate of 0.25 mL/min. TPT was analyzed using positive ion electrospray ionization in multiple‐reaction monitoring mode. The obtained lower limit of quantitation was 1 ng/mL (signal‐to‐noise ratio > 10). The standard calibration curve for TPT was linear (correlation coefficient > 0.99) at the concentration range of 1–400 ng/mL. The intra‐day and inter‐day precision, accuracy, stability, extraction recovery and matrix effect of TPT were within the acceptable limits. The validated method was successfully applied in a bioequivalence study of TPT in healthy beagle dogs. Copyright © 2013 John Wiley & Sons, Ltd.     

Identification of 2‐chloropyrazine oxidation products and several derivatives by multinuclear magnetic resonance

¹H, ¹³C, ¹⁴N and ¹⁵N NMR chemical shifts were used to prove the structures of the products of 2‐chloropyrazine oxidation. It was shown that oxidation by hydrogen peroxide in acetic acid or m‐chloroperbenzoic acid leads to the N4‐oxide, whereas potassium persulfate in sulfuric acid gives the N1‐oxide as the main product. Additionally, the results of NMR measurements of products from the nucleophilic substitution of the chlorine atom by azide anion, yielding the respective azides, and ethylation reactions of both 2‐chloropyrazine N‐oxides leading to the N‐ethyl salts confirm the structures of both isomeric N‐oxides. Protonation studies of the compounds obtained are also reported. The favoured protonation site is found to be the N atom that is not hindered by any substituents, and in some cases probably the oxygen atom of the N‐oxide function. Copyright © 2003 John Wiley & Sons, Ltd.     

A Greener Approach Synthesis and Docking Studies of Perimidine Derivatives as Potential Anticancer Agents

Microwave solvent‐free technique was employed to the synthesis of series of 2‐(1H‐perimidin‐2(3H)‐ylidene) derivatives, 4‐(1H‐perimidin‐2‐yl)‐1H‐pyrazole‐3‐carboxamides, pyrrolo[1,2‐a]perimidin‐10‐ones, and 8H‐[1,2,4]triazolo[4,3‐a]perimidine. Compared with conventional method, the obvious feature of microwave method is higher in chemical yield, faster reaction rate, and cleaner reaction condition. The structures of the synthesized compounds were confirmed based on their elemental analyses and spectroscopic data (FT‐IR, ¹H‐NMR, ¹⁹F‐NMR, ¹³C‐NMR, and LC‐MS/MS). Some of the synthesized compounds exhibit anticancer potential against the growth of both the human breast (MCF‐7) and the liver carcinoma (HepG2) tumor cells. The most active cytotoxic perimidine derivatives were docked against topoisomerase II to investigate their binding and DNA intercalating activity against the protein crystal structure.     

An Efficient,One‐Pot,Green Synthesis of Tetracyclic Imidazo[2,1‐b]Thiazoles via Electrochemically Induced Tandem Heteroannulation Reactions

A series of novel catechol‐fused tetracyclic compounds, with an imidazo[2,1‐b]thiazole central core, were successfully synthesized through the anodic oxidation of catechols in the presence of 2‐mercaptobenzimidazole in aqueous solution. The cyclic voltammetric results indicate that a one‐pot four‐step sequential reaction occurs between 2‐mercaptobenzimidazole and the electrochemically derived o‐benzoquinones affording fused polyheterocyclic compounds. The mechanism of this catalyst‐free, domino reaction is proved as an ECEC pathway using controlled‐potential coulometry. In addition, the electrosyntheses of fused compounds have been successfully performed in ambient conditions in an undivided cell using an environmentally friendly method with high atom economy. The structures of products were characterized by FT‐IR, ¹H NMR, ¹³C NMR, and HRMS spectrometric methods.     

Synthesis and properties of two novel silicon‐containing cycloaliphatic epoxy resins for electronic packaging application

In this paper, two silicon‐containing cycloaliphatic olefins were synthesized through the nucleophilic substitution reactions of cyclohex‐3‐enyl‐1‐methanol with di‐ or tri‐chlorosilane compounds. Then, after epoxidation, two new cycloaliphatic epoxy resins with different epoxy groups were successfully prepared. Their chemical structures were confirmed by ²⁹Si NMR, ¹H NMR, and Fourier‐transform infrared spectra (FTIR). The properties of cured products, including viscoelasticity, glass transition temperature (T_g), coefficient of thermal expansion, thermal stability and water absorption, were investigated. Compared to the difunctional epoxy resin, the trifunctional one exhibited a remarkably increased cross‐linking density from 0.82 to 4.08 × 10^?3 mol/cm³ and T_g from 157 to 228°C. More importantly, prior to curing, they had viscosities of only 240–290 mPa sec at 25°C, which were much lower than that of ERL‐4221 (409 mPa sec), providing the possibility of easy processing. The high glass transition temperatures, good thermal stabilities, and mechanical properties as well as excellent flowability endow the silicon‐containing epoxy resins with promising potential in microelectronic packaging application. Copyright © 2011 John Wiley & Sons, Ltd.     

Reaction of Tertiary 2-Chloroketones with Cyanide Ions: Application to 3-Chloroquinolinediones

3-Chloroquinoline-2,4-diones react with cyanide ions in dimethyl formamide to give 3-cyanoquinoline-2,4-diones in small yields due to the strong hindrance of the substituent at the C-3 atom. Good yields can be achieved if the substituent at this position is the methyl group. In the methanol solution, the reaction proceeds by an addition mechanism to form 2-oxo-1a,2,3,7b-tetrahydrooxireno[2,3-c]quinoline-7b-carbonitriles, from which 4-hydroxy-3-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonitriles are subsequently formed by opening of the epoxide ring with methanol. Some minor products of these reactions have also been isolated. The ¹H, ¹³C and ¹⁵N NMR spectra of the prepared compounds were measured, and all resonances were assigned using appropriate two-dimensional spectra.     

New Biphenyl‐Based Bispyrazolines: Synthesis,Antimicrobial, and Docking Studies

In this study, a series of new bispyrazolines 8 ( a – f ) have been prepared from the cyclization reactions of bischalcones 7 ( a – f ) with phenyl hydrazine by refluxing under the alkaline alcoholic (KOH/EtOH) conditions. The O‐alkylation reactions of hydroxyl substituted chalcone 6 with different 1,ω‐dibromoalkanes in the presence of anhydrous potassium carbonate, tetrabutylammonium iodide, and dry acetone afforded the symmetrical new bischalcones 7 ( a – f ) in good yields. Chalcone 6 was realized by using the Claisen–Schmidt reaction of m‐hydroxyacetophenone with bipheny‐4‐carboxaldehyde. The various spectroscopic parameters such as IR, ¹H‐NMR, ¹³C‐NMR, and ESI‐MS have been thoroughly used for the structural interpretations of the newly prepared products. The in vitro antibacterial and antifungal activities of these compounds have been examined with the help of serial tube dilution method, and many of the tested products were found to be revealing the promising antimicrobial properties, which were evident from their minimum inhibitory concentration values. The molecular docking simulations of the synthesized substances have also been achieved to observe the structural association into the active site of the Escherichia coli FabH (PdB: 3IL9). Docking results of these compounds suggested that bispyrazoline 8b demonstrated the lowest binding energy that describes its higher stability into the pocket of E. coli. The excellent inhibitory activity of this bisheterocycle against E. coli FabH may be ascribed on the basis of hydrophobic and van der Waals interactions.     

On the photochemical dimerization of some 5‐substituted 2‐styryl‐4‐pyrones. The effect of 5‐hydroxy‐/ 5‐methoxy‐substitution

Irradiation of styryl‐4‐pyrones 1a‐1d or 2a‐2e (6‐9 × 10^?3 M, methanol solution) with filtered (RAYONET photochemical reactor, 300 nm) or unfiltered uv‐light (high‐pressure mercury arc lamp) under aerobic conditions led mainly to dimeric products. Parent 5‐hydroxy‐substituted compounds 1a‐1d yielded exclusively “half‐cage” dimers 3a‐d characteristic for 4‐pyrone dimerization. 5‐Methoxy‐analogues 2a‐2e behave like typical stilbene structures and the mixture of tetrasubstituted cyclobutanes 4 and 5 accompanied with minor amount of phenanthrene‐like compound 6 were the only isolable products of the irradiation. The structure elucidation of products is based on spectral data obtained from MS, IR, ¹H NMR and ¹³C NMR spectra applying COSY, APT, HETCOR, HMBC and NOESY techniques.     

Initial DNA Interactions of the Binuclear Threading Intercalator Λ,Λ‐[μ‐bidppz(bipy)4Ru2]4+: An NMR Study with [d(CGCGAATTCGCG)]2

Binuclear polypyridine ruthenium compounds have been shown to slowly intercalate into DNA, following a fast initial binding on the DNA surface. For these compounds, intercalation requires threading of a bulky substituent, containing one Ru^II, through the DNA base‐pair stack, and the accompanying DNA duplex distortions are much more severe than with intercalation of mononuclear compounds. Structural understanding of the process of intercalation may greatly gain from a characterisation of the initial interactions between binuclear Ru^II compounds and DNA. We report a structural NMR study on the binuclear Ru^II intercalator Λ,Λ‐B (Λ,Λ‐[μ‐bidppz(bipy)₄Ru₂]⁴⁺; bidppz=11,11′‐bis(dipyrido[3,2‐a:2′,3′‐c]phenazinyl, bipy = 2,2′‐bipyridine) mixed with the palindromic DNA [d(CGCGAATTCGCG)]₂. Threading of Λ,Λ‐B depends on the presence and length of AT stretches in the DNA. Therefore, the latter was selected to promote initial binding, but due to the short stretch of AT base pairs, final intercalation is prevented. Structural calculations provide a model for the interaction: Λ,Λ‐B is trapped in a well‐defined surface‐bound state consisting of an eccentric minor‐groove binding. Most of the interaction enthalpy originates from electrostatic and van der Waals contacts, whereas intermolecular hydrogen bonds may help to define a unique position of Λ,Λ‐B. Molecular dynamics simulations show that this minor‐groove binding mode is stable on a nanosecond scale. To the best of our knowledge, this is the first structural study by NMR spectroscopy on a binuclear Ru compound bound to DNA. In the calculated structure, one of the positively charged Ru²⁺ moieties is near the central AATT region; this is favourable in view of potential intercalation as observed by optical methods for DNA with longer AT stretches. Circular dichroism (CD) spectroscopy suggests that a similar binding geometry is formed in mixtures of Λ,Λ‐B with natural calf thymus DNA. The present minor‐groove binding mode is proposed to represent the initial surface interactions of binuclear Ru^II compounds prior to intercalation into AT‐rich DNA.     

A new approach to the synthesis of 2‐aryl‐substituted benzimidazoles,quinazolines, and other related compounds and their antibacterial activity

A new synthesis method of benzimidazoles, dihydroquinazolines, and other related compounds containing a 2,4‐dihydroxyphenyl moiety was elaborated. Their structures were identified from elemental, infrared, ¹H NMR, ¹³C NMR, and mass spectra analyses. The minimal inhibitory concentration values of the compounds toward eight reference bacterial strains were determined by the two‐fold serial microdilution broth method. The compounds exhibited substantial inhibitory effects against the Gram‐positive strains tested contrary to Gram‐negative ones. The compounds of imidazopyridine, N‐methylbenzimidazole, and dihydroquinazoline structures exhibited the largest activity. The magnification of covering a two‐nitrogen atom heterocyclic ring fused to a benzene one decreases the biological effect. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:265–275, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21012     

Synthesis and Halogen Bonding in the Crystal Structures of the New 2,3‐Diiodo Indenone and 1‐Ethoxy‐2,3‐diiodo Indene

The CuI‐catalyzed addition of iodine to the C≡C triple bond of 3,3‐diethoxy‐1‐phenyl propyne ( 1 ) unexpectedly leads to the new cyclization products 2,3‐diiodo‐1H‐inden‐1‐one ( 2 ) and 1‐ethoxy‐2,3‐diiodo‐1H‐indene ( 3 ). Both compounds were isolated and characterized via ¹H, ¹³C NMR (Nuclear Magnetic Resonance) spectroscopy and HRMS (High Resolution Mass Spectrometry). The molecular and crystal structures of compounds 2 and 3 were determined by single crystal X‐ray diffraction. Their crystal structures are governed by extensive halogen bonding, involving I·I and I·O interactions.     

Methylated Azoles, 2‐Tetrazenes,and Hydrazines

This report is a summary of our work on energetic materials. Herein, triazole‐, tetrazole‐, 2‐tetrazene‐ and hydrazine‐based energetic compounds are described. An overview of the synthetic methods and of the problematic around the quest of new explosives is given. Hydrogen‐bonding formation and alkylation (methylation) reactions were studied as a mean to decrease the sensitivities towards classical stimuli and increase their thermal and chemical stability. ¹⁵N NMR spectroscopy is a valuable tool for the assignment of the methylation site in keeping with the results of the crystal structure analysis. Lastly, the thermal/chemical stability, sensitivity data and energetic performance of the compounds is described.     

Synthesis and biological activities of new 1H‐1,2,4‐triazole alcohol derivatives containing a ferrocenyl moiety

Fourteen new 1H‐1,2,4‐triazole alcohol derivatives containing a ferrocenyl moiety were synthesized. In addition, six unexpected compounds, the hydroxyls of the title compounds, methylated by methanol, were obtained. The structures of all these new compounds were confirmed using ¹H NMR spectra, ¹³C NMR, MS and elemental analyses. Some compounds were also confirmed with IR spectra. The antifungal and plant growth regulatory activities of the title compounds are discussed. Copyright © 2008 John Wiley & Sons, Ltd.     

F···HO intramolecular hydrogen bond as the main transmission mechanism for 1hJF,H(O) coupling constant in 2′‐fluoroflavonol

Flavonoids are useful compounds in medicinal chemistry and exhibit conformational isomerism, which is ruled by intramolecular interactions. One of the main intramolecular forces governing the stability of conformations is the hydrogen bond. Hydrogen bond involving fluorine covalently bonded to carbon has been found to be rare, but it appears in 2′‐fluoroflavonol, although the F···HO hydrogen bond cannot be considered the main effect governing the conformational stability of this compound. Because ¹⁹F is magnetically active and suitable for NMR studies, the ^1hJ_F,H(O) coupling constant can be used as a probe for such an interaction in 2′‐fluoroflavonol. In fact, the ^1hJ_F,H(O) coupling was computationally analyzed in this work, and the F···HO hydrogen bond was found to be its main transmission mechanism, which modulates this coupling in 2′‐fluoroflavonol, rather than overlap of proximate electronic clouds, such as in 2‐fluorophenol. Copyright © 2012 John Wiley & Sons, Ltd.     

1H and 13C NMR spectral assignments of pyridinium salts linked to a N‐9 or N‐3 adenine moiety

¹H and ¹³ C NMR spectral data of 13 new compounds containing a 4‐(dimethylamino)‐ or 4‐(pyrrolidin‐1‐yl)pyridinium moiety linked to the N‐9 or N‐3 nitrogen atom of an adenine moiety were assigned. 1D and 2D NMR experiments (DEPT, HSQC and HMBC) allowed the unequivocal identification of N‐9 and N‐3 isomers. Copyright © 2012 John Wiley & Sons, Ltd.     

Functionalization of 5-(4-alkoxybenzyl)-4-R-4<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazole-3-thiols. Synthesis of novel DNA methylation inhibitors

Aminomethylation and cyanoethylation reactions of 5-(4-alkoxybenzyl)-4-methyl(phenyl, allyl)-4H-1,2,4-triazole-3-thiols have been investigated. According to NMR spectroscopy data, the reactions occur at the nitrogen atom Ν². The effect of the synthesized compounds on cancer DNA methylation has been evaluated.     

Unequivocal total assignment of 13C and 1H NMR spectra of some pyrido[1,2‐a]pyrimidine derivatives by 2D‐NMR

We report the total assignments of the ¹³C and ¹H NMR spectra of some 4‐methyl‐2‐oxo‐(2H)‐pyrido[1,2‐a]pyrimidine and 2‐methyl‐4‐oxo‐(4H)‐pyrido[1,2‐a]pyrimidine derivatives. The products were characterized by ¹H and ¹³C NMR and reported data for similar compounds. No comparative data for the two sets of isomeric compounds with respect to ¹³C and ¹H NMR have been reported to date. We made some detailed studies of the 2D NMR spectra of these compounds and observed that assignments made for non‐protonated carbon atoms by us and those reported in the literature for similar compounds need correction. The revised assignments were made on the basis of heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) techniques. Copyright © 2003 John Wiley & Sons, Ltd.     

Hypervalent Silicon Compounds by Coordination of Diphosphine–Silanes to Gold

Coordination of ambiphilic diphosphine–silane ligands [o‐(iPr₂P)C₆H₄]₂Si(R)F (R=F, Ph, Me) to AuCl affords pentacoordinate neutral silicon compounds in which the metal atom acts as a Lewis base. X‐ray diffraction analyses, NMR spectroscopy, and DFT calculations substantiate the presence of Au→Si interactions in these complexes, which result in trigonal‐bipyramidal geometries around silicon. The presence of a single electron‐withdrawing fluorine atom is sufficient to observe coordination of the silane as a σ‐acceptor ligand, provided it is positioned trans to gold. The nature of the second substituent at silicon (R=F, Ph, Me) has very little influence on the magnitude of the Au→Si interaction, in marked contrast to N→Si adducts. According to variable‐temperature and 2D EXSY NMR experiments, the apical/equatorial positions around silicon exchange in the slow regime of the NMR timescale. The two forms, with the fluorine atom in trans or cis position to gold, were characterized spectroscopically and the activation barrier for their interconversion was estimated. The bonding and relative stability of the two isomeric structures were assessed by DFT calculations.     

Synthesis,Structure, and Solution Study of a Mercury(II) Complex with the Ligand [1‐(2‐Methoxyphenyl)‐3‐(4‐chlorophenyl)]triazene

The title ligand, [1‐(2‐methoxyphenyl)‐3‐(4‐chlorophenyl)]triazene, H L ( 1 ), was prepared. In a reaction with Hg(NO₃)₂ it forms the complex [Hg(C₂₆H₂₂Cl₂N₆O₂)], [Hg L ₂] ( 2 ). Both compounds were characterized by means of X‐ray crystallography, CHN analysis, FT‐IR, ¹H NMR, and ¹³C NMR spectroscopy. In the structure of compound 1 , two independent fragments are present in the unit cell. They exhibit trans arrangement about the –N=N– double bond. The dihedral angles between two benzene rings in both fragments are 4.36 and 18.79 Å, respectively. Non‐classic C–H ··· N hydrogen bonding and C–H ··· π interactions form a layer structure along the crystallographic ab plane [110]. In compound 2 , the Hg^II atom is hexacoordinated by two tridentate [1‐(2‐methoxyphenyl)‐3‐(4‐chlorophenyl)]triazenide ligands through a N₂O₂ set. In addition, in the structure of 2 , monomeric complexes are connected to each other by C–H ··· π stacking interactions, resulting in a 2D architecture. These C–H ··· π edge‐to‐face interactions are present with H ··· π distances of 3.156 and 3.027 Å. The results of studies of the stoichiometry and formation of complex 2 in methanol solution were found to support its solid state stoichiometry.