Amino Group In Position Research Articles

Structure−Function Relationships within Keppler-Type Antitumor Ruthenium(III) Complexes: the Case of 2-Aminothiazolium[trans-tetrachlorobis(2-aminothiazole)ruthenate(III)

Keppler-type ruthenium(III) complexes exhibit promising antitumor properties. We report here a study of 2-aminothiazolium[trans-tetrachlorobis(2-aminothiazole)ruthenate(III)], both in the solid state and in solution. The crystal structure has been solved and found to exhibit classical features. Important solvatochromic effects were revealed. Notably, we observed that introduction of an amino group in position 2 greatly accelerates chloride hydrolysis compared to the thiazole analogue; this latter finding may be of interest for a fine-tuning of the reactivity of these novel metallodrugs.

Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists

A series of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Conformational analysis and superimposition of energy minima conformers of the designed molecules on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity. It seems this effect is mediated through benzodiazepine receptors mechanism.

Experimental and theoretical IR, Raman, NMR spectra of 2-, 3- and 4-aminobenzoic acids

The influence of amino group position towards the carboxylic group on the vibration structure of the molecule was estimated. The calculated parameters were compared to experimental characteristic of these molecules. FT-IR, FT-Raman and NMR spectra of the title compounds were recorded and analyzed. The most important vibration bands due to amino and carboxyl groups and the benzene ring were assigned. Wavenumbers and intensities for the three studied acids were compared and discussed in terms of location of the carboxylic group. A linear correlation between proton and carbon GIAO NMR shieldings of studied compounds and experimental data was found.

Conversion of Amino Group in Position 6 of Uracil.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Photocatalytic transformations of aminopyrimidines on TiO2 in aqueous solution

The photocatalytic degradation in aqueous solution of aminopyrimidines (2-aminopyrimidine, 4-aminopyrimidine, 4-methyl-2-aminopyrimidine, 2,6-dimethoxy-4-aminopyrimidine) on TiO2 has been investigated. Their transformation pathways seem to be closely related to the position of the amino group in the heterocyclic ring; especially the fate of the organic nitrogen is deeply influenced.Both the ratio [NH4+]/[NO3−] and the extent of their formation are connected to the nature of the substituents and the amino group position in the heteroaromatic ring. When the amino group is located in C4, the transformation pathways proceed mainly through the cleavage of the CN bonds, with the formation of oxygenated structures as intermediates and the release of nitrogen mainly as ammonium ions. In this case, the stoichiometric conversion of nitrogen into inorganic ions and the complete mineralization is achieved within few hours of irradiation.On the contrary, when the amino group is held in C2, a lack in both nitrogen and carbon mineralization is observed. It is attributable to the stoichiometric conversion of the NC(NH2)N moiety into guanidine, a very stable compound for which the mineralization is obtained only at long irradiation times (>70h). Interestingly, in this latter case the nitrogen is mainly released as nitrate ions.

Conversion of Amino Group in Position 6 of Uracil

The possibility of substituting amino groups in position 6 of 5-R-uracils (R = H, NO) by hydroxylamine and phenylhydrazine has been demonstrated. The products of substitution — 6-hydroxyaminouracil, 5,6 dihydroxydiiminouracil, and 5-nitroso-6-phenylhydrazinouracil — are readily oxidized into 1,2,5 oxadiazolo- and 1,2,3-triazolo[3,4-d]pyrimidine N-oxides respectively.

Efficient and chemoselective N-acylation of 10-amino-7-ethyl camptothecin with poly(ethylene glycol)

A new poly(ethylene glycol) (PEG) conjugate of 10-amino-7-ethyl camptothecin, a potent antitumor analogue of camptothecin, has been synthesized and preliminary in vivo tests have been performed. Successful chemoselective N-acylation of 10-amino-7-ethyl camptothecin was accomplished using phenyl dichlorophosphate, a coupling reagent used in esterification of alcohols, while other coupling methods failed, due to the low nucleophilicity of the amino group in position 10. The conjugate was tested against P388 murine leukemia cell lines and resulted equipotent to CPT-11, a camptothecin analogue already in clinical use.

Multistate properties of 7-(N,N-diethylamino)-4'-hydroxyflavylium. An example of an unidirectional reaction cycle driven by pH.

The synthetic flavylium salt 7-(N,N-diethylamino)-4'-hydroxyflavylium tetrafluoroborate gives rise in aqueous solution to a complex network of chemical reactions driven by pH. The system was studied by 1H NMR, single crystal X-ray diffraction, steady state and transient UV-Vis spectrophotometry as well as stopped flow. The crystal structure shows a high degree of coplanarity between the pyrylium system and the phenyl group in position 2. Thermodynamic and kinetic constants for the pH dependent network of chemical reactions were obtained. The introduction of an amino group in position 7 allows formation of protonated species leading, in particular, to a tautomeric form of the protonated cis-chalcone, H+, whose absorption spectra is rather red shifted, in comparison with the correspondent protonated trans-chalcone, H+. The H+ species can be rapidly converted into the flavylium cation through a first order process with lifetime of 0.2 s at pH = 2.35. This new reaction channel confers this compound a peculiar behaviour in acidic media, allowing to define an unidirectional pH driven reaction cycle.

Reaction of 1-alkyl/aryl-3-amino-1 H,3 H-quinoline-2,4-diones with urea. Synthetic route to novel 3-(3-acylureido)-2,3-dihydro-1 H-indol-2-ones, 4-alkylidene-1′ H-spiro[imidazolidine-5,3′-indole]-2,2′-diones, and 3,3a-dihydro-5 H-imidazo[4,5- c]quinoline-2,4-diones

1-Substituted 3-alkyl/aryl-3-amino-1 H,3 H-quinoline-2,4-diones react with urea in boiling acetic acid to give products depending on the type of substitution in position 3 and at the nitrogen atom of the 3-amino group. Starting compounds bearing a primary amino group in position 3 give 3-(3-acylureido)-2,3-dihydro-1 H-indol-2-ones. Starting compounds bearing a secondary amino group in position 3 react according to the character of the other substituent in position 3. If there is a hydrogen atom α to the carbon atom C(3), 4-alkylidene-1′ H-spiro[imidazolidine-5,3′-indole]-2,2′-diones arise. If a hydrogen atom is not present in this position, the reaction leads to 3,3a-dihydro-5 H-imidazo[4,5- c]quinoline-2,4-diones. Reaction mechanisms for these transformations are proposed. All compounds were characterized by their 1H, 13C, IR and atmospheric pressure chemical ionization mass spectra and some of them also by 15N NMR data.

Design and synthesis of 4H-3-(2-Phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists

A series of new 5-substituted analogues of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole and its chlorinated derivatives was designed and prepared. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Rotarod and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 5 of 1,2,4-triazole ring especially in chlorinated derivatives had the best effect which was comparable with diazepam.

A primordial tRNA modification required for the evolution of life?

The evolution of reading frame maintenance must have been an early event, and presumably preceded the emergence of the three domains Archaea, Bacteria and Eukarya. Features evolved early in reading frame maintenance may still exist in present-day organisms. We show that one such feature may be the modified nucleoside 1-methylguanosine (m(1)G37), which prevents frameshifting and is present adjacent to and 3' of the anticodon (position 37) in the same subset of tRNAs from all organisms, including that with the smallest sequenced genome (Mycoplasma genitalium), and organelles. We have identified the genes encoding the enzyme tRNA(m(1)G37)methyltransferase from all three domains. We also show that they are orthologues, and suggest that they originated from a primordial gene. Lack of m(1)G37 severely impairs the growth of a bacterium and a eukaryote to a similar degree. Yeast tRNA(m(1)G37)methyltransferase also synthesizes 1-methylinosine and participates in the formation of the Y-base (yW). Our results suggest that m(1)G37 existed in tRNA before the divergence of the three domains, and that a tRNA(m(1)G37)methyltrans ferase is part of the minimal set of gene products required for life.

2-Amidinylindole-3-carbaldehydes: Versatile Synthons for the Preparation of α-Carboline Derivatives

The 2-amidinylindole-3-carbaldehydes 1 are the key starting materials for the preparation of three classes of carbolines 2, 6 and 7 in which the pyridine ring is characterised by a different substitution patterns. The carbolines 2 which are functionalized with an amino group in position 2, were obtained directly by heating 1 in presence of SiO 2. The condensation of amidines 1 with arylmethylketones afforded unsaturated ketones 5 which on heating were transformed into 2,9-dialkyl-3-aroyl-9 H-pyrido[2,3- b]indoles 7. Instead, prolonged reaction of amidines 1 with arylmethylketones in t-BuOH/ t-BuOK gave 2-aryl-9 H-pyrido[2,3- b]indoles 6.

Activation and cross-reactivity pattern of a new allergen in adhesive plaster.

N,N'-disalicylidene-1,2-diaminopropane is a copper inhibitor present in some adhesive plasters, rubber products and gasoline. Upon contact with water it is hydrolyzed to salicylaldehyde and 1,2-diaminopropane. All patients in this study showed positive patch-test reactions to N,N'-disalicylidene-1,2-diaminopropane, and also to 1,2-diaminopropane and ethylenediamine. None reacted to salicylaldehyde. Patch testing with different N,N'-disalicylidene-derivatives showed localization of the amino groups in positions 1 and 2 to be a prerequisite of cross-reactivity to 1,2-diaminopropane and ethylenediamine. An extraction procedure and a high-performance liquid chromatography (HPLC) method for the analysis of adhesive plasters is described. Studies of the hydrolysis of the copper inhibitor at physiological pH showed rapid formation of 1,2-diaminopropane under biomimetic conditions.

Design and Synthesis of New Aminoglycoside Antibiotics Containing Neamine as an Optimal Core Structure: Correlation of Antibiotic Activity with in Vitro Inhibition of Translation

The structure and activity of the pseudodisaccharide core found in aminoglycoside antibiotics was probed with a series of synthetic analogues in which the position of amino groups was varied around the glucopyranose ring. The naturally occurring structure neamine was the best in the series according to assays for in vitro RNA binding and antibiotic activity. With this result in hand, neamine was used as a common core structure for the synthesis of new antibiotics, which were evaluated for binding to models of the Escherichia coli 16S A-site ribosomal RNA, in vitro protein synthesis inhibition, and antibiotic activity. Analysis of RNA binding revealed some correlation between the relative affinity and specificity of RNA binding and antibacterial efficacy. However, the correlation was not linear. This result led us to develop the in vitro translation assay in an effort to better understand aminoglycoside−RNA interactions. A linear correlation between in vitro translation inhibition and antibiotic activity w...

Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives.

Tryptophan is mainly metabolized in the brain through methoxyindole and kynurenine pathways. The methoxyindole pathway produces (among other compounds) melatonin, which displays inhibitory effects on human and animal central nervous systems, including a significant attenuation of excitatory, glutamate-mediated responses. The kynurenine pathway produces kynurenines that interact with brain glutamate-mediated responses. Nitric oxide (NO) increases glutamate release, and melatonin and kynurenines may act via modification of NO synthesis. In the present study, the effects of melatonin and four synthetic kynurenines were studied on the activity of rat striatal nitric oxide synthase (NOS) and on the response of rat striatal neurons to sensorimotor cortex (SMCx) stimulation, a glutamate-mediated response. Melatonin inhibited both NOS activity and the striatal glutamate response, and these effects were dose-related. Compound A (2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid) did not inhibit NOS activity but inhibited the striatal response similarly to melatonin. Compound B (2-acetamide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) was more potent than melatonin in inhibiting both NOS activity and the striatal response. Compound C (2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid) did not change NOS activity, but increased the striatal response. Compound D (2-butyramide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) showed potent inhibitory effects on both NOS activity and striatal glutamate-mediated response. A structure-related effect of the kynurenine derivatives was observed, and those with an amino group in position 2 of the benzenic ring had more potent effects than melatonin itself in inhibiting striatal NOS activity and the response of striatal neurons to SMCx.

[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands.

A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT1A over the alpha 1-adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the best selectivity, with a ratio of 74, while its affinity IC50 for 5-HT1A was 6.8 nM. These results, compared to those for compounds 46 (IC50 24 nM; selectivity 2) and 49 (IC50 226 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thienopyrimidine system for the interaction with 5-HT1A receptor binding sites, although this fragment can affect the affinity and selectivity only if linked to the (arylpiperazinyl)alkyl moiety. The better selectivity of piperidine 74 (IC50 0.8; selectivity 45) compared to the analogous piperazine 70 is also noteworthy. Twenty of the 30 molecules used for determining the binding affinity to 5-HT1A and alpha 1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.

Identification of competitive antagonists of the rod photoreceptor cGMP-gated cation channel: beta-phenyl-1,N2-etheno-substituted cGMP analogues as probes of the cGMP-binding site.

cGMP is the natural activator of the cyclic nucleotide-gated channel originally isolated from rod photoreceptors but now known to be expressed in a wide variety of neural and non-neural cells. To identify antagonists of cGMP action and to better understand the interaction between cGMP and the channel protein, experimental studies were undertaken using four synthetic cGMP analogues, PET-cGMP, 8-Br-PET-cGMP, Rp-8-Br-PET-cGMPS, and Sp-8-Br-PET-cGMPS. With excised patches from either Xenopus oocytes expressing a cloned rat rod channel alpha-subunit or from native Xenopus rod photoreceptors, Rp-8-Br-PET-cGMPS competitively suppressed the cGMP-induced current with an IC50 of 25 microM and Sp-8-Br-PET-cGMPS inhibited this current with an IC50 of 105 microM. On the expressed rat rod channel, 8-Br-PET-cGMP behaved as a very weak partial agonist at high concentrations and an antagonist (IC50 = 64 microM) at lower concentrations when coapplied with cGMP. PET-cGMP did not activate channel currents alone but showed a synergism when coapplied with subsaturating concentrations of cGMP. Because Sp-8-Br-PET-cGMPS is a potent activator of type I cGMP-dependent protein kinase, but a competitive antagonist of channel activation, it will be a useful reagent for discriminating between those effects of cGMP that are mediated by a protein kinase and those mediated by channel activation. Because the PET derivatives all contain a phenyl-substituted 5-membered ring system fused to the amino group in position 2 and the nitrogen in position 1 of the guanine ring, the results support the idea that N1 and N2 are important for channel activation. They also suggest a minor role for the cyclic phosphate group in binding or activation.

Is cysteine residue important in FITC-sensitive ATP-binding site of P-type ATPases? A commentary to the state of the art.

Treatment of P-type ATPases (from mammalian sources) by fluorescein isothiocyanate (ITC) revealed the ITC label on a lysine residue that was than considered as essential for binding of ATP in the ATP-binding site of these enzymes. On the other hand, experiments with site directed mutagenesis excluded the presence of an essential Iysine residue that would be localized in the ATP binding sites of ATPases. Other previous studies, including those of ourselves, indicated that the primary site of isothiocyanate interaction may be the sulfhydryl group of a cysteine residue and this may be essential for binding of ATP. In addition considerable knowledge accumulated since yet also about the differences in stability of reaction product of isothiocyanates with SH- or NH2- groups. Based upon evaluation of the data available up to now, in present paper the following tentative roles for lysine and cysteine residues located in the ATP-binding site of P-type ATPases are proposed: The positively charged micro-domain of the lysine residue may probably attract the negatively charged phosphate moiety of the ATP molecule whereas the cysteine residue may probably be responsible for recognition and binding of ATP by creation of a proton bridge with the amino group in position 6 on the adenosine ring of ATP.

Naphthalimido derivatives as antifolate thymidylate synthase inhibitors

Summary A new series of N -(substituted)benzyl-1,8-naphthalimides 4 , structurally related to the previously reported thymidylate synthase (TS) inhibitor naphthaleins 3 , were synthesized and compounds tested for their inhibition of several species of TS. Moreover, their in vitro cytotoxicity together with antimycotic and antibacterial properties were assayed. While no activity was detected in the antibacterial tests, the m -nitro ( 4ae ) and the p -nitro ( 4af ) derivatives were found able to partially inhibit TS at low micromolar concentrations. Introduction of nitro or (substituted)-amino groups in position 4 of the naphthalic ring always led to less active compounds.

Synthesis, hydrolysis reactions and conformational study of 2-substituted 3,5-diamino-4-nitroso-2H-1,2,6-thiadiazine 1,1-dioxides

The 2-substituted 3,5-diamino-4-nitroso-2H-1,2,6-thiadiazine 1,1-dioxides are present in solution as a mixture of two rotational conformers of the nitroso group that are stabilized by hydrogen bonds with the amino groups in positions 3 and 5. The stability of these conformations has been studied using 1H, 13C and 15N NMR spectroscopy, as well as molecular orbital ab initio calculations. In addition, hydrolysis reactions of these compounds have been carried out affording 5-amino-4-hydroxyimino-3-oxo-3,4-dihydro-2H-1,2,6-thiadiazine 1,1-dioxides and 4-amino-3-oxo-2,3-dihydro-1,2,5-thiadiazole 1,1-dioxides.