Crystallography and Structure–Property Relationships in 2,2′,2″,2′′′,4,4′,4″,4′′′,6,6′,6″,6′′′‐Dodecanitro‐1,1′ : 3′1″ : 3″,1′′′‐ Quaterphenyl (DODECA)

X‐ray crystallographic study of 2,2′,2″,2′′′,4,4′,4″,4′′′,6,6′,6″,6′′′‐dodecanitro‐1,1′ : 3′1″ : 3″,1′′′‐quaterphenyl (DODECA) has been carried out. Nonbonding interatomic distances of oxygen atoms inside of all the nitro groups are shorter than those corresponding to the intermolecular contact radii for oxygen. By means of the DFT B3LYP/6‐31(d, p) method a difference of 136 kJ mol⁻¹ between the X‐ray and DFT structures of DODECA was found. The bearer of the highest initiation reactivity in its molecule in solid phase should be the nitro group at 4′′′‐position, in contrast to those at 2′‐ or 2″‐positions in its isolated molecule. The most reactive nitro group in the DODECA molecule can be well specified by the relationship between net charges on nitro groups and charges on their nitrogen atoms, both of them for the X‐ray structure. The ¹⁵N chemical shift, corresponding to this nitro group for the initiation by impact and shock, correlates very well with these shifts of the reaction centers of the other six “genuine” polynitro arenes.     

Die Reaktion von α,β-Dihalogen-propionitrilen mit monosubstituierten Hydrazinen - einfache Synthese 1-substituierter 3- bzw. 5-Amino-pyrazole

The Reaction of α,β-Dihalogeno-propionitriles with Monosubstituted Hydrazines — A Simple Synthesis of 1-Substituted 3- or 5-Amino-pyrazoles In methanol hydrazines 3 , and α,β-dihalogeno-propionitriles 1, 2 even at 0°C irreversibly yield 3 · HX, and α-halogenoacrylonitriles 4, 5 (A₁). Fast addition of alkyl- and aralkyl- hydrazines 3 to 4, 5 (C) gives 1-substituted 1-(2′-halogeno-2′-cyan-ethyl)-hydrazines 6 , the addition of arylhydrazines 3 to 4, 5 (D) 1-aryl-2-(2′-halogeno-2′-cyan-ethyl)-hydrazines 8 . In methanol 6 spontaneously cyclise (E) to hydrogen halides 7 · HX of 1-alkyl- and 1-aralkyl-3-amino-pyrazoles, 8 with 2 moles of acids (F) to salts 10 · 2HY of 1-aryl-4-halogeno-5-imino-pyrazolidines, and the free 10 spontaneously (G) to hydrogen halides 9 · HX of 1-aryl-5-amino-pyrazoles. Mechanisms (A₁), (C), (D), (E), (F), and (G) are proved by t.l.c., ¹H-n.m.r., and isolation of intermediates, the structures of 7 resp. 9 , using the significant ¹H-n.m.r.-parameter Δ. Simple general syntheses are described for 3-amino-pyrazoles 7 (R = H, alkyl, aralkyl) or 5-amino-pyrazoles 9 (R = aryl) starting with α,β-dihalogeno-propionitriles 1, 2 , and for α-bromo-acrylonitrile 5 .     

Synthesis of 4,4′-aryldihydrazono-3-(3′-pyridyl)-2-pyrazolin-4,5-diones and 1-aryl-3-(3′-pyridyl)-4,4′-arylbisazo-5-aryliminopyrazoles and their application as disazo disperse dyes. Part II

3-(3′-Pyridyl)-2-pyrazoline-4,5-dione 4,4′(4,4′-biphenylenedihydrazone and p-phenylenedihydrazone) and its derivatives ( IIa-e, IIIa-e ) were obtained by the coupling reaction of tetrazotised benzidine and p-diamonobenzene with 3-(3′-pyridyl)-2-pyrazolin-5-ones ( Ia-e ). Similarly, bis-azo compounds containing pyrazole nucleous as, 1-aryl-3-(3′-pyridyl)-4,4′-arylbisazo-5-aryliminopyrazoles ( VIa-i and VIIa-i ) were prepared by the interaction of the corresponding chloro compound ( IV and V ) with aromatic amines. The compounds so obtained ( II, III, VI and VII ) are used as disazo disperse dyes for dyeing polyester fibres fast yellow-orange shades. Their fastness properties towards washing, rubbing, acid-alkaline perspiration and light were investigated.     

Synthesis and spectroelectrochemistry of dithieno(3,2‐b:2′,3′‐d)pyrrole derivatives

New π‐conjugated polymers containing dithieno(3,2‐b:2′,3′‐d)pyrrole (DTP) were successfully synthesized via electropolymerization. The effect of structural differences on the electrochemical and optoelectronic properties of the 4‐[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl]aniline (DTP–aryl–NH₂), 10‐[4H‐dithiyeno(3,2‐b:2′,3′‐d)pirol‐4‐il]dekan‐1‐amine (DTP–alkyl–NH₂), and 1,10‐bis[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl] decane (DTP–alkyl–DTP) were investigated. The corresponding polymers were characterized by cyclic voltammetry, NMR (¹H‐NMR and ¹³C‐NMR), and ultraviolet–visible spectroscopy. Changes in the electronic nature of the functional groups led to variations in the electrochemical properties of the π‐conjugated systems. The electroactive polymer films revealed redox couples and exhibited electrochromic behavior. The replacement of the DTP–alkyl–DTP unit with DTP–aryl–NH₂ and DTP–alkyl–NH₂ resulted in a lower oxidation potential. Both the poly(10‐(4H‐Dithiyeno[3,2‐b:2′,3′‐d]pirol‐4‐il)dekan‐1‐amin) (poly(DTP–alkyl–NH₂)) and poly(1,10‐bis(4H‐dithieno[3,2‐b:2′,3′‐d]pyrrol‐4‐yl) decane) (poly(DTP–alkyl–DTP)) films showed multicolor electrochromism and also fast switching times (<1 s) in the visible and near infrared regions. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40701.     

NMR-spektroskopische Untersuchungen zum Konformations-verhalten von 2′- und 3′-halogensubstituierten Pyrimidinnucleosiden

N.M.R. Spectroscopical Investigations on the Conformational Behaviour of Some 2′ - and 3′-Halogen-substituted Pyrimidine Nucleosides A series of 2′- and 3′-halogenated pyrimidine nucleosides has been synthesized and investigated by ¹H, ¹³C and ¹⁹F n.m.r. spectroscopy. The ¹H and ¹³C chemical shifts for the positions 2′ and 3′ depend linearly but oppositely on the substituent electronegativities X_R. The conformational equilibrium N ⇌ S of the nucleosides in solution is determined. An approximately linear correlation between the prefered gauche-gauche interaction of the exocyclic CH₂OH groups and the ribose N conformation has been found.     

Synthese und biochemische Aktivität perfluoralkylierter Derivate des 5′-Desoxy-5′-fluor und 2′,5′-Didesoxy-5′-fluor-uridins

Synthesis and Biochemical Activity of Perfluoroalkylated Derivatives of 5′-Deoxy-5′-fluoro-, and 2′, 5′-Dideoxy-5′-fluorouridine 5-Perfluoroalkylated 5′-deoxy-5′-fluoro-, and 2′,5′-dideoxy-5′-fluorouridine are obtained by the reaction of 5′-fluorouridine or 2′,5′-dideoxy-5′-fluorouridine, respectively, with a perfluoroalkyl-coppercomplex in DMSO under inert conditions, and at temperatures of about 100 °C. Analogously 5-perfluoroethyl, 5-perfluorobutyl, and 5-perfluorohexyl derivatives of uridine, and 5-perfluoroethyl, and 5-perfluorobutyl derivatives of 2′-deoxyuridine could be isolated. It is shown either by mass spectroscopy or by ¹H-n.m.r. spectroscopy that the substitution always takes place at the 5-position of the pyrimidine. The 5-perfluoroethyl derivatives are particularly effective as cytostatics.     

3,1′-Bridged 2-[2′-(4″-dialkylaminophenyl)ethenyl] pyrylium and 1-Benzopyrylium Dyes – Synthesis and Vis/NIR Absorption/Emission Behaviour

A series of new 3,1′-bridged 2-[2′-(4″-dialkylaminophenyl)ethenyl]-4,6-diarylpyrylium perchlorates ( 3 ), 2-[2′-(4″-dialkylaminophenyl)ethenyl]-7-diethylamino-1-benzopyrylium perchlorates 5–8 , 2-[4′-(4″-dialkylaminophenyl)butadien-1′,3″-yl]-, and 2-[2′-(7″-diethylaminocoumar-3″-yl)ethenyl]-7-diethylamino-1-benzopyrylium perchlorates 10–12 were synthesized and characterized by means of elemental analysis, m.p., Vis/NIR, and ¹H NMR spectra. Semiempirical MO calculations were performed to elucidate the essential features of the chromophores. The size of the bridging ring strongly affects the geometry of the chromophores which, in turn, determines the extent of charge transfer of the longest wavelength electronic transition. Increasing deviation from planarity causes the polymethine-like chromophore to become more polyene-like.     

O6‐Alkylguanine‐DNA Alkyltransferase‐Mediated Repair of O4‐Alkylated 2′‐Deoxyuridines

O⁶‐Alkylguanine‐DNA alkyltransferases (AGTs) are responsible for the removal of O⁶‐alkyl 2′‐deoxyguanosine (dG) and O⁴‐alkyl thymidine (dT) adducts from the genome. Unlike the E. coli OGT (O⁶‐alkylguanine‐DNA‐alkyltransferase) protein, which can repair a range of O⁴‐alkyl dT lesions, human AGT (hAGT) only removes methyl groups poorly. To uncover the influence of the C5 methyl group of dT on AGT repair, oligonucleotides containing O⁴‐alkyl 2′‐deoxyuridines (dU) were prepared. The ability of E. coli AGTs (Ada‐C and OGT), human AGT, and an OGT/hAGT chimera to remove O⁴‐methyl and larger adducts (4‐hydroxybutyl and 7‐hydroxyheptyl) from dU were examined and compared to those relating to the corresponding dT species. The absence of the C5 methyl group resulted in an increase in repair observed for the O⁴‐methyl adducts by hAGT and the chimera. The chimera was proficient at repairing larger adducts at the O⁴ atom of dU. There was no observed correlation between the binding affinities of the AGT homologues to adduct‐containing oligonucleotides and the amounts of repair measured.     

6‐Substituted 2‐Aminopurine‐2′‐deoxyribonucleoside 5′‐Triphosphates that Trace Cytosine Methylation

Gene expression is extensively regulated by the occurrence and distribution of the epigenetic marker 2′‐deoxy 5‐methylcytosine (5mC) in genomic DNA. Because of its effects on tumorigenesis there is an important link to human health. In addition, detection of 5mC can serve as an outstanding biomarker for diagnostics as well as for disease therapy. Our previous studies have already shown that, by processing O⁶‐alkylated 2′‐deoxyguanosine triphosphate (dGTP) analogues, DNA polymerases are able to sense the presence of a single 5mC unit in a template. Here we present the synthesis and evaluation of an extended toolbox of 6‐substituted 2‐aminopurine‐2′‐deoxyribonucleoside 5′‐triphosphates modified at position 6 with various functionalities. We found that sensing of 5‐methylation by this class of nucleotides is more general, not being restricted to O⁶‐alkyl modification of dGTP but also applying to other functionalities.     

Substituierte N,N′-Bis(thiazol-2-yl)-diaminoalkane aus α-Thiocyanato-acetophenonen und N,N′-Dialkyl-diamino-alkanen

Substituted N,N′-Bis(thiazol-2-yl)-diaminoalkanes from α-Thiocyanato-acetophenones and N,N′-Dialkyl-diaminoalkanes α-Thiocyanato-acetophenones 1 react with N,N′-dialkyl-diaminoalkanes 2 in the presence of an appropriate weak acid (acetic acid, propionic acid, benzoic acid) to give the hitherto unknown N,N′-dialkyl-N,N′-bis(4-aryl-thiazol-2-yl)-diaminoalkanes 3 . As reaction medium aliphatic alcohols (ethanol, methanol), halogenated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride) or dipolar-aprotic solvents (acetonitrile, dimethylformamide) can be used. - I.r., u.v., n.m.r. and mass spectroscopic data of the novel bisthiazoles 3 are reported.     

Spiegelsymmetrische Hexahydro-1,2,4,5-tetrazine aus Pyrazolidon-(3)-N,N-betainen – ein Beitrag zur „thermischen Dimerisierung”︁ von 1,3-Dipolen

Mirror-symmetric Hexahydro-1,2,4,5-tetrazines from Pyrazolidine-3-one-N,N-betaines—a Contribution to the „Thermal Dimerization”︁ of 1,3-Dipoles Chemical reactions, i.r., ¹H-n.m.r., and ¹³C-n.m.r. data show that the “thermal dimers” of pyrazolidine-3-one azomethinimines 2 , which till now accidentally formed during the synthesis of 2 from pyrazolidine-3-ones 5 and aldehydes 6 , are 5,11-diaryl-perhydro-dipyrazolo[1,2-a; 1′,2′-d][1,2,4,5]-tetrazine-1,9-diones 3 , i.e. mirror-symmetric hexahydro-1,2,4,5-tetrazines with (C-5) and (C-11) placed on the mirror plane. From DREIDING models and from the nonequivalence, concerning ¹³C-n.m.r., of the pairs of carbon atoms in the o- resp. m-positions of the aryl substituent I at (C-5) of the “dimers” 3 is derived that the rotation of I is sterically hindered (ΔG = 16,3 kcal/mole for 3b ), and that the preferred arrangement of I is perpendicular to the plane of the hexahydrotetrazine ring. The “thermal dimerization” of the 1,3-dipoles 2 is a complex series of two addition and elimination steps proceeding in the presence of catalytical amounts of pyrazolidine-3-one 5 and of H^⊕. The mechanism is rationalized, consequences are suggested concerning known “dimerizations” of 1,3-dipoles.     

β-Fur-2-yl-α-halogenacrylonitrile. VII. Reaktionen von β-(5-Brom-fur-2-yl)-α-bromacrylonitril mit Mercaptan,Thioharnstoff und Thioharnstoffderivaten

β-Fur-2-yl-α-halogenacrylonitriles. VII. Reactions of β-(5-Bromo-fur-2-yl)-α-bromoacrylonitriles with Mercaptans, Thiourea and Thiourea Derivatives β-(5-Bromo-fur-2-yl)-α-bromoacrylonitrile 1 reacts with ethylmercaptan to yield β-(5-bromo-fur-2-yl) β-ethylthioacrylonitrile 3 . With thiourea β,β′-thio-bis[β-(5-bromo-fur-2-yl)]-acrylonitrile 2 is formed. The pyrimidines 4 and 5 have been prepared by the reaction of 1 with s-methylthiourea and 2-aminothiazole, respectively. The structure of the new compounds were determined by means of x-ray analysis, ¹H-n.m.r., ¹³C-n.m.r. and mass-spectroscopy.     

Solution NMR study of the post-polymerization crosslinking agent N,N′-(2-propyloximino)-4,4′-methylenebis(phenylcarbamate). I

Because of its possible use as a blocked “post-polymerization crosslinking agent” for polymers containing labile hydrogen, the structure of the acetone oxime adduct of 4,4′-methylenebis-(phenylisocyanate) has been determined. ¹³C and ¹H nuclear magnetic resonance (NMR) spectroscopy has identified this product to be N,N′-(2-propyloximino)-4,4′-methylenebis(phenylcarbamate). Chemical shift assignments were based on information obtained by proton decoupled, off-resonance decoupled, and gated decoupled ¹³C-NMR, proton-NMR, and semiemperical substituent chemical shift (SCS) parameters.     

Synthese eines neuen Thienospirans: 6,7-Dihydro-1′-methyl-spiro[benzo[b]thiophen-4(5H),2′-piperidin]

Synthesis of a New Thienospiran: 6,7-Dihylro-1′-methyl-spiro[benzo[j]thioxhen-4(5H),2′-piperidine] The title spiro compound 6 – a N-methyl derivative of a new parent system - has been synthesized from nitrile 8 via 4-phenoxybutylation, followed by modified Schmidt degradation, ensuing O-deprotection and final cyclization. The constitution of the target compound and of all intermediates is established by ¹H-n.m.r. and ¹³C-n.m.r.-spectroscopy and by microelementary analysis.     

Folgeprodukte aus Sulfonamiden. VI. Darstellung und Cyclisierung von N-Allyl-N′-arylsulfonyl-thioharnstoffen

Consecutive Products of Sulphonamides. VI. Synthesis and Cyclization of N-Allyl-N′-arylsulphonyl-thioureas N-Allyl-N′-arylsulphonyl-thioureas 3a–e are synthesized by addition reaction of substituted arensulphonamides 2a–e and allylisothiocyanate 1 . The thioureas 3a–e react with hydrogen bromide in acetic acid or bromine in chloroform to 2-(arylsulphonylimino)-5-methyl-(or bromomethyl)thiazolidines 8a-j . The mechanism of reaction and the structures are discussed by means of i.r., m.s. and ¹H-n.m.r. data.     

O4‐Alkylated‐2‐Deoxyuridine Repair by O6‐Alkylguanine DNA Alkyltransferase is Augmented by a C5‐Fluorine Modification

Oligonucleotides containing various adducts, including ethyl, benzyl, 4‐hydroxybutyl and 7‐hydroxyheptyl groups, at the O⁴ atom of 5‐fluoro‐O⁴‐alkyl‐2′‐deoxyuridine were prepared by solid‐phase synthesis. UV thermal denaturation studies demonstrated that these modifications destabilised the duplex by approximately 10 °C, relative to the control containing 5‐fluoro‐2′‐deoxyuridine. Circular dichroism spectroscopy revealed that these modified duplexes all adopted a B‐form DNA structure. O⁶‐Alkylguanine DNA alkyltransferase (AGT) from humans (hAGT) was most efficient at repair of the 5‐fluoro‐O⁴‐benzyl‐2′‐deoxyuridine adduct, whereas the thymidine analogue was refractory to repair. The Escherichia coli AGT variant (OGT) was also efficient at removing O⁴‐ethyl and benzyl adducts of 5‐fluoro‐2‐deoxyuridine. Computational assessment of N1‐methyl analogues of the O⁴‐alkylated nucleobases revealed that the C5‐fluorine modification had an influence on reducing the electron density of the O⁴?C_α bond, relative to thymine (C5‐methyl) and uracil (C5‐hydrogen). These results reveal the positive influence of the C5‐fluorine atom on the repair of larger O⁴‐alkyl adducts to expand knowledge of the range of substrates able to be repaired by AGT.     

An Efficient Lanthanide‐Dependent DNAzyme Cleaving 2′–5′‐Linked RNA

RNA can form two types of linkage. In addition to the predominant 3′–5′ linkage, 2′–5′‐linked RNA is also important in biology, medicine, and prebiotic studies. Here, in vitro selection was used to isolate a DNAzyme that specifically cleaves 2′–5′ RNA by using Ce³⁺ as the metal cofactor, but leaves the 3′–5′ counterpart intact. This Ce5 DNAzyme requires trivalent light lanthanide ions and shows a rate of 0.16 min^?1 in the presence of 10 μm Ce³⁺; the activity decreases with heavier lanthanide ions. This is the fastest DNAzyme reported for this reaction, and it might enable applications in chemical biology. As a proof‐of‐concept, using this DNAzyme, the reactions between phosphorothioate‐modified RNA and strongly thiophilic metals (Hg²⁺ and Tl³⁺) were studied as a function of pH.     

Studies on the Vilsmeier-haack reaction. Part XIII: Novel heterocyclo-substituted 4,4′-bi-pyrazolyl dithiocarbamate derivatives

5-Imino-3-methyl-l-phenyl-2-pyrazoline-4-dithiocarbamic acid (I) underwent simultaneous formylation and dimerization reactions with the Vilsmeier reagent giving 4-[5′-imino-3-(1″-formyl-2″-dimethylaminoethenyl)-3′-methyl-1′-phenyl-1′H-pyrazolo-4′-dithiocarbamyl-2,4-dihydro-3-imino-5-methyl-2-phenyl-1-pyrazoline]dithiocarbamate (II) which hydrolysed with sodium hydroxide to give 4-[3′-(1″-formyl-2″-hydroxyethenyl)-3′-methyl-1-phenyl-1′-H-pyrazolo-4′-dithiocarbamyl-1′-pyrazoline]dithiocarbamate-5,5′-dione (IV). Treatment of II and/or IV with morpholine, piperidine, piperazine, hydroxylamine, hydrazine hydrate or phenylhydrazine afforded the corresponding dipyrazolo-4,4′-dithiocarbamate derivatives with different heterocyclic systems at the 3-position. The structures of these compounds were confirmed by microanalysis data, IR and ¹H-NMR spectrometry. All synthesized compounds have been screened in vitro against Gram-positive and Gram-negative bacteria, and fungi.     

Crystallography and Structure–Property Relationships of 2,2″,4,4′,4″,6,6′,6″‐Octanitro‐1,1′ : 3′,1″‐Terphenyl (ONT)

An X‐ray crystallographic study of 2,2″,4,4′,4″,6,6′,6″‐octanitro‐1,1′ : 3′,1″‐terphenyl (ONT) has been carried out. The dihedral angles between benzene rings vary from 84.9° to 89.4°. Nonbinding interatomic distances of oxygen atoms inside all the nitro groups are shorter than the intermolecular contact radii for oxygen. On the basis of the DFT B3LYP/6‐31(d, p) method it was found that the difference between the X‐ray structure in the solid phase and DFT result for the gas phase is 98 kJ mol⁻¹, and the bearer of the highest initiation reactivity of the ONT molecule in the solid phase should be the nitro group at 4″‐position, in contrast to those at 4′‐ or 6′‐position that play this role in the isolated molecule. It has been stated that the nitro groups at the reaction centers of the ONT molecule are relatively well specified by their ¹⁵N NMR chemical shifts.     

Syntheses and Biological Activities of Polymers Containing 3′-Azido-3′-deoxythymidine

The new monomer, 5′-O-methacryloyl-3′-azido-3′-deoxythymidine (MAZT), was synthesized by the reaction of methacryloyl chloride and 3′-azido-3′-deoxythymidine (AZT). Poly(MAZT) and copolymers of MAZT with vinyl acetate (VAc) and maleic anhydride (MAH) were synthesized by radical polymerizations. The synthesized MAZT and polymers were identified by ¹H nuclear magnetic resonance (NMR), ¹³C NMR, elemental analysis and gel permeation chromatography. The quantities of MAZT units in poly(MAZT-co-VAc) and poly(MAZT-co-MAH) were 45 and 27 mol%, respectively. The weight average molecular weights of the polymers synthesized were in the range from 8800 to 17600. The in vitro cytotoxicities of samples against K562 human leukaemia cell line at 100 μg ml^-1 decreased in the following order: poly(MAZT-co-MAH) > poly(MAZT-co-VAc) > poly(MAZT) > MAZT > AZT. The in vivo anti-tumour activities of the polymers synthesized against Balb/C mice bearing sarcoma 180 tumour cells were greater than those of 5-fluorouracil at all concentrations.