Exocyclic Nitrogen Atom Research Articles

Syntheses and characterizations of the in vivo replicative bypass and mutagenic properties of the minor-groove O2-alkylthymidine lesions.

Endogenous metabolism, environmental exposure, and treatment with some chemotherapeutic agents can all give rise to DNA alkylation, which can occur on the phosphate backbone as well as the ring nitrogen or exocyclic nitrogen and oxygen atoms of nucleobases. Previous studies showed that the minor-groove O2-alkylated thymidine (O2-alkyldT) lesions are poorly repaired and persist in mammalian tissues. In the present study, we synthesized oligodeoxyribonucleotides harboring seven O2-alkyldT lesions, with the alkyl group being a Me, Et, nPr, iPr, nBu, iBu or sBu, at a defined site and examined the impact of these lesions on DNA replication in Escherichia coli cells. Our results demonstrated that the replication bypass efficiencies of the O2-alkyldT lesions decreased with the chain length of the alkyl group, and these lesions directed promiscuous nucleotide misincorporation in E. coli cells. We also found that deficiency in Pol V, but not Pol II or Pol IV, led to a marked drop in bypass efficiencies for most O2-alkyldT lesions. We further showed that both Pol IV and Pol V were essential for the misincorporation of dCMP opposite these minor-groove DNA lesions, whereas only Pol V was indispensable for the T→A transversion introduced by these lesions. Depletion of Pol II, however, did not lead to any detectable alterations in mutation frequencies for any of the O2-alkyldT lesions. Thus, our study provided important new knowledge about the cytotoxic and mutagenic properties of the O2-alkyldT lesions and revealed the roles of the SOS-induced DNA polymerases in bypassing these lesions in E. coli cells.

Two stable phosphorus-containing four-membered ring radical cations with inverse spin density distributions.

Two phosphorus-containing four-membered ring radical cations 1(•+) and 2(•+) have been isolated and characterized by UV-vis absorption spectroscopy, electron paramagnetic resonance (EPR), and single-crystal X-ray diffraction. Compared with neutral molecules 1 and 2, radical 1(•+) has elongated P-P bonds and more pyramidalized phosphorus atoms, while shortened P-Nring distances and larger angles around phosphorus centers are observed for 2(•+). EPR studies indicate that for 1(•+) spin density mainly resides on the exocyclic nitrogen atoms with very minor contribution from endocyclic phosphorus atoms, while the situation is opposite for 2(•+). Such an inverse spin density distribution is controlled by the exocyclic substituents, which is supported by DFT calculations.

Synthesis and Properties of Alkylnitramino-1,2,4,5-Tetrazines

The peculiarities of the nitration reaction under acidic conditions were studied for a series of alkylamino-1,2,4,5-tetrazines. It was found that the extent of N,N'-dialkyl-1,2,4,5-tetrazine-3,6-diamine nitration was determined by the concentration of nitric acid and the selection of alkyl substituents at the exocyclic nitrogen atom. A new method was developed for the preparation of unsymmetrically substituted N,N'-dialkyl-1,2,4,5-tetrazine-3,6-diamines from N-nitro derivatives of N-alkyl-1,2,4,5-tetrazin-3-amines.

Synthesis, biological activity, distribution and membrane permeability of novel spiro-thiazines as potent neuroprotectors

New spiro-derivatives of 1,3-thiazine – potential neuroprotectors have been synthesized. It has been determined that the obtained compounds are biologically active and capable of blocking the glutamate-induced calcium ion uptake into synaptosomes of rat brain cortex. The inhibitory activity of the test substances was shown to depend on the chemical nature and structure of the substituents bound with an exocyclic nitrogen atom. Non-polar alkyl and polar radicals with halogen, oxygen and nitrogen atoms were used as substituents. It is typical of the active spiro-thiazines to have alkyl substituents in ortho- and para-position of the benzene ring. Among the investigated spiro-thiazines it is the derivatives with ethyl- and isopropyl-groups in the aril part of the molecules that are the lead-compounds with a high inhibitory ability. We measured the distribution coefficients of the substances in octanol/buffer and hexane/buffer systems and made conclusions about the ability of the investigated drug-like compounds to penetrate the biological membranes. By using the parabolic model we derived a quadratic equation that allowed us to evaluate quantitatively the inhibitory activity of spiro-thiazines with hydrophobic substituents based on lipophilicity data. We also studied the permeability through the phospholipidic membrane and introduced a correlation equation describing the dependence of the investigated spiro-thiazines activity on the descriptors characterizing the donor–acceptor properties.

SYNTHESIS AND PROPERTIES OF ALKYLNITROAMINO-1,2,4,5-TETRAZINES

Using a series of 1,2,4,5-tetrazine alkylamino derivatives the peculiarities of their reactivity under acidic nitration conditions were demonstrated. It was found that the degree of nitration of N , N '-dialkyl-1,2,4,5-tetrazine-3,6-diamines is determined by nitric acid concentration and the alkyl substituent at the exocyclic nitrogen atom. A new method of the synthesis of unsymmetrically substituted N , N '-dialkyl-1,2,4,5-tetrazine-3,6-diamines from N -alkyl-1,2,4,5-tetrazine-3-amine N -nitro derivatives was developed. How to Cite Rudakov, G. F.; Ustinova, T. V.; Kozlov, I. B.; Zhilin, V. F. Chem. Heterocycl. Compd. 2014 , 50 , 53. [ Khim. Geterotsikl. Soedin. 2014 , 59.] For this article in the English edition see DOI 10.1007/s10593-014-1448-9

Quaternization and oxidation reactions of cyclodiphosphazane derivatives and their copper(I) and gold(I) complexes.

The reactions of cyclodiphosphazane derivatives cis-{(t)BuN(H)P(μ-N(t)Bu)2PN(H)(t)Bu} (1), cis-{MeN(C4H8N)P(μ-N(t)Bu)2P(NC4H8Me)} (2) and {(Me2NCH2CH2O)P(μ-N(t)Bu)2P(OCH2CH2NMe2)} (3) with methyl iodide and methyl triflate and their subsequent reactions with elemental sulfur and selenium are reported. Interestingly, the reactions of 1-3 with an excess of methyl iodide resulted in quaternising only one phosphorus atom in cis-[{(t)BuNHP(μ-N(t)Bu)2P(CH3)NH(t)Bu}](I) (4), two exocyclic nitrogen atoms and one of the phosphorus atoms in cis-{(Me2NC4H8N)P(μ-N(t)Bu)2P(CH3)(NC4H8NMe2)}](I)3 (7) and only two exocyclic nitrogen atoms in cis-[{(Me3NCH2CH2O)P(μ-N(t)Bu)2P(OCH2CH2NMe3)}](I)2 (8). The reaction of 1 with one equiv. of methyl triflate produced cis-[{(t)BuN(H)P(μ-N(t)Bu)2P(CH3)N(H)(t)Bu}]OTf (5), whereas the same reaction in a 1 : 2 molar ratio afforded cis-{(t)BuN(H)P(CH3)(μ-N(t)Bu)2P(CH3)N(H)(t)Bu}(OTf)2 (6). Compounds 4 and 5 showed poor solubility in water, whereas 7 and 8 were high melting crystalline solids with moderate to good water solubility. Treatment of 4 with either elemental sulfur or selenium gave both cis- and trans-chalcogenide derivatives. Similar reactions of 7 and 8 produced both mono- and bischalcogenides. Reactions between 4 or 7 and CuI yielded dinuclear complexes, cis-[{Cu2(μ-I)3((t)BuN(H)P)(μ-N(t)Bu)2(P(CH3)N(H)(t)Bu)]2}(I)] (15) and cis-[{Cu2(μ-I)3[(Me2NC4H8N)P(μ-N(t)Bu)2P(CH3)(NC4H8NMe2)]2}(I)5] (16), while the reaction of 8 with CuI produced a coordination polymer [{Cu2(μ-I)3(μ-N(t)BuP)2(OCH2CH2NMe3)2}I]∞ (17), containing triiodo-bridged [Cu2(μ-I)3] linkers. The molecular structures of several of these compounds were confirmed by single crystal X-ray diffraction studies. The Cu(I)···Cu(I) distance of 2.55 Å in 15 is quite short and is the same as that found in copper metal and also in complexes containing [Cu2(μ-I)3] linkers. All the metal complexes exhibit strong intra-, inter- or both intra- and inter-molecular hydrogen bonding interactions.

Synthesis of Novel 2-Amino-(2-thioxo-3-alkyl-4-methyl-3H-thiazol-5-yl)-[1,3,4]thiadiazole Derivatives and Their Growth Stimulant Activity

On the base of synthesized 2-amino and 2-ethylamino-(2-thioxo-3-alkyl-4-methyl-3H-thiazol-5-yl)-[1,3,4]thiadiazoles, their alkyl, acetyl, and alkylacetylamino derivatives are obtained. The alkylation of 2-ethylamino derivatives can occur at both exo and endo nitrogen atoms of amidine group, and the acetylation takes place exclusively at the exocyclic nitrogen atom. At acetylation of 2-amino-[1,3,4]thiadiazoles, only exo substitution is observed. At the further alkylation of these products, a mixture of exo- and endo-substituted forms is obtained. At preliminary screening, the synthesized compounds have shown expressed growth stimulant properties. The activity of the most active derivatives was in the range of 65–100%, compared with that of heteroauxin.

Structure and properties of tetrakis[3(4)-chlorophthalocyaninato]copper(II) protonated forms in the isolated state and in the sulfuric acid solutions

Results of the quantum-chemical PM3 and experimental spectrophotometric studies of the stepwise protonation of tetrakis[3(4)-chlorophthalocyaninato]copper(II) are presented. The number, structure, and energy characteristics of consecutively protonated isolated molecules of the substituted complexes have been determined; the stability and electron absorption spectra of the complexes protonated forms in concentrated sulfuric acid solution have been studied. The special effect of substitution with halogen on the electronic structure of the exocyclic nitrogen atoms of (phthalocyaninato)copper(II) has been examined.

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate.

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl 2-cyano-3-methoxyprop-2-enoate (ethyl ethoxymethylenecyanoacetate) is investigated. At −10 °C reaction takes place on the exocyclic nitrogen atom, giving exclusively ethyl esters of 2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)amino]prop-2-enoic acid. The formation of isomeric enamines which may be a theoretical product of the reaction on N3 ring nitrogen atom is not observed. The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles. Heating of the enamines to the temperature of 120–140 °C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates. The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.Graphical

Design, synthesis and transformation of some heteroannulated 3-aminopyridines—purine isosteres with exocyclic nitrogen atom

The synthesis of 1-deazapurines and isosteres bearing the exocyclic nitrogen atom at position-1 was developed basing on the formal [3+3]-cyclization reaction of nitro-malonaldehyde with the set of electron-excessive aminoheterocycles. Through the functionalization of the purine-like scaffolds synthesized the diversity of compounds furnished in the possition-1 with aryl, alkinyl, and vinyl rests, were obtained.

INTERACTION OF 2-(R-AMINO)-BENZOTHIAZOLES WITH 3-FURFURYLOXY-1,2-EPOXYPROPANE

3-Furfuryloxy-1,2-epoxypropane reacts with 2-aminobenzothiazole at the endo- and exocyclic nitrogen atoms but its R-amino derivatives – only at the nitrogen atom of the thiazole ring. Compounds isomeric with the obtained products were prepared by interaction of the same oxirane with 2-imino-3-methylbenzothiazolines and also with methylamine with subsequent treatment with 2-chlorobenzothiazole. Authors: R. F. Ambartsumova and L. P. Kosmacheva. English Translation in Chemistry of Heterocyclic Compounds , 2000, 36 (1), pp 77-81 http://link.springer.com/article/10.1007/BF02256850

Flexible Mono‐ and Bis‐tetraazamacrocyclic Complexes of Copper and Nickel Stabilizing Different Oxidation States

AbstractThe synthesis and structural properties of new mono‐ and bis‐macrocyclic cyclidene complexes of copper(II) andnickel(II) are presented. The compounds with aliphatic ligands are flexible enough to stabilize metal centers in the three oxidation states +1, +2, and +3. All the electron‐transfer processes in the 16‐membered mono‐ and binuclear macrocyclic complexes of copper(II) and nickel(II) were fast and reversible. Two polymorphic forms of the 16‐membered mononuclear complex of nickel(II) were isolated in the solid state and characterized. The 16‐membered macrocyclic complexes show both U‐ and Z‐shape conformations. The deviation of the macrocyclic ligand from planarity affects the electrochemical properties of the complexes and leads to stabilization of different oxidation states of the Cu and Ni metal centers. Substitution of the exocyclic nitrogen atoms with a second alkyl group increases the deviation from planarity and induces rotation of the functional groups at the meso position relative to the macrocyclic ring. In the bis‐macrocyclic complexes, the electron‐donating properties are improved and the formal potential of the metal(II)/metal(III) system is less positive with increasing linker length between the macrocyclic units. The acceptor properties of the metal(II) complexes are weaker, the formal potential of the metal(II)/metal(I) couple being shifted to more negative values.

ChemInform Abstract: Transition Metal‐Catalyzed N‐Arylations of Amidines and Guanidines

AbstractReview: 200 refs.

Asymmetric Chemoenzymatic Synthesis of Ramatroban Using Lipases and Oxidoreductases

A chemoenzymatic asymmetric route for the preparation of enantiopure (R)-ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (±)-2,3,4,9-tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S)-2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms.

Synthesis of 4-aminopyrazolo[3,4-d]pyrimidine derivatives from 5-acetyl-6-amino-4-methylsulfanyl- or 5-acetyl-6-amino-4-methylsulfonylpyrimidines

Diacetyl ketene N,S-acetal was used for the synthesis of 5-acetyl-6-amino-4-methylsulfanylpyrimidines substituted at the exocyclic nitrogen atom, which were further oxidized with m-chloroperbenzoic acid to the corresponding methylsulfonylpyrimidines. Reactions of hydrazines with these pyrimidines containing vicinal Ac and MeS (or MeSO2) groups were used for the preparation of new 4-aminopyrazolo[3,4-d]pyrimidine derivatives.

Transition metal-catalyzed N-arylations of amidines and guanidines

Although several recent reviews dealt with transition metal catalyzed N-arylation of amines (all classes), to date no specific review covering the N-arylation of amidines and guanidines appeared. Amidines and guanidines are considered as fundamental entities in medicinal chemistry. The appearance of these functional groups in drugs, agrochemicals and natural products justifies a separate description of the current status of the literature on the N-arylation of the amidine and guanidine functionalities. Both acyclic and cyclic derivatives are taken into account. For cyclic amidines/guanidines only systems which possess an exocyclic nitrogen atom are considered. This critical review is largely organized by the type of amidine/guanidine and transition metal used and covers literature up to May 2011 (200 references).

Theoretical Investigations into the Role of Aryl Nitrenium Ions' Stability on Their Mutagenic Potential

By using Mulliken and Natural Bond Orbital (NBO) methods based on the density functional theory (DFT), partial charges of exocyclic nitrogen atoms were calculated for nitrenium ions formed from 201 known drugs and 50 Ames positive (mutagenic) compounds containing aryl amine and nitro moieties. The statistical difference of the partial charges was analysed based on the hypothesis that the mutagens have a more negative charge on their exocyclic nitrogen atom resulting in stable nitrenium ions, and thus a longer lifetime to react selectively with DNA; whereas known drugs are not in general mutagenic and therefore have a relatively more positive partial charge. The nitrenium ions with 1° amine parent compounds did not show a statistical difference between drugs and mutagens based on the Mulliken charges. A slight difference was observed in the NBO data where the drugs have more negative partial charge on their exocyclic nitrogen atoms compared with the mutagens. Interestingly, nitrenium ions with aryl nitro drugs as their parent compounds have more negative charge on the exocyclic nitrogen compared with the other drug classes. Aryl nitro drugs are relatively scarce and are often linked to genotoxicity, which fits with the hypotheses proposed. These results indicate that other physical properties besides the stability of the nitrenium ions are important to determine the mutagenic potential of aryl amine and nitro containing compounds.

Tris-(hydroxyamino)triazines: high-affinity chelating tridentate O,N,O-hydroxylamine ligand for the cis-VVO2+ cation

The treatment of the trichloro-1,3,5-triazine with N-methylhydroxylamine hydrochloride results in the replacement of the three chlorine atoms of the triazine ring with the function -N(OH)CH(3) yielding the symmetrical tris-(hydroxyamino)triazine ligand H(3)trihyat. Reaction of the ligand H(3)trihyat with NaV(V)O(3) in aqueous solution followed by addition of Ph(4)PCl gave the mononuclear vanadium(V) compound Ph(4)P[V(V)O(2)(Htrihyat)] (1). The structure of compound 1 was determined by X-ray crystallography and indicates that this compound has a distorted square-pyramidal arrangement around vanadium. The ligand Htrihyat(2-) is bonded to vanadium atom in a tridentate fashion at the triazine ring nitrogen atom and the two deprotonated hydroxylamido oxygen atoms. The high electron density of the triazine ring nitrogen atoms, which results from the resonative contribution of electrons of exocyclic nitrogen atoms, leads to a very strong V-N bond. The cis-[V(V)O(2)(Htrihyat)](-) species exhibits high hydrolytic stability in aqueous solution over a wide pH range, 2.5-11.5, as was evidenced by potentiometry.

Synthesis, Coordination Chemistry and Bonding of Strong N‐Donor Ligands Incorporating the 1H‐Pyridin‐(2E)‐Ylidene (PYE) Motif

A range of N-donor ligands based on the 1H-pyridin-(2E)-ylidene (PYE) motif have been prepared, including achiral and chiral examples. The ligands incorporate one to three PYE groups that coordinate to a metal through the exocyclic nitrogen atom of each PYE moiety, and the resulting metal complexes have been characterised by methods including single-crystal X-ray diffraction and NMR spectroscopy to examine metal-ligand bonding and ligand dynamics. Upon coordination of a PYE ligand to a proton or metal-complex fragment, the solid-state structures, NMR spectroscopy and DFT studies indicate that charge redistribution occurs within the PYE heterocyclic ring to give a contribution from a pyridinium-amido-type resonance structure. Additional IR spectroscopy and computational studies suggest that PYE ligands are strong donor ligands. NMR spectroscopy shows that for metal complexes there is restricted motion about the exocyclic C-N bond, which projects the heterocyclic N-substituent in the vicinity of the metal atom causing restricted motion in chelating-ligand derivatives. Solid-state structures and DFT calculations also show significant steric congestion and secondary metal-ligand interactions between the metal and ligand C-H bonds.

Novel diazadienes based on 1,3,4-oxadiazines: Ligands in iron carbonyl complexes and substrates in catalytic [2+2+1] cycloaddition reactions

N, N′-(4-methyl-4 H-1,3,4-oxadiazine-5,6-diylidene)-bis-aniline derivatives react with Fe 2(CO) 9 to give dinuclear iron carbonyl complexes. One of the iron atoms is bonded symmetrically to both exocyclic imine nitrogen atoms. The second iron atom shows a side-on coordination towards the C N bond next to the oxadiazine oxygen atom. In addition, the iron atoms are connected via a metal metal bond. The same oxadiazine derivatives produce chiral spiro-lactams in a ruthenium catalyzed formal [2+2+1] cycloaddition reaction with carbon monoxide and ethylene.