Amino Imidazole Research Articles

The reactions of [Au(dien)Cl]2+ with L-histidine-containing dipeptides. Dependence of complex formation on the dipeptide structure

Reactions between the monofunctional [Au(dien)Cl]2+ complex with L-histidine-containing dipeptides, L-histidyl-glycine (L-His-Gly), and glycyl-L-histidine (Gly-L-His) were studied by 1H NMR spectroscopy. All reactions were performed in aqueous solution at 3.50 pD 5.50 at ambient temperature. In reaction of [Au(dien)Cl]2+ with L-His-Gly, only 1 with N3-monodentate coordinated dipeptide was formed. The reaction was completed within 3 min and the complex was very stable during several days with no release of dien from Au(III). However, in the reaction of [Au(dien)Cl]2+ with Gly-L-His, depending on the pD, different Au(III)-dipeptide complexes were observed. When this reaction was carried out at 3.50 pD 4.50, only 4 with tridentate coordination of the dipeptide via the amino, deprotonated amide, and N3 imidazole nitrogen were observed after 4 days. However, during this time, at 4.50 < pD 5.50, two Au(III)-dipeptide products, 5 which represents an imidazole-bridged species along with the already described 4, were observed. The formation of these complexes proceeds through intermediates, 2 and 3 with N3-monodentate and NP,N3-bidentate coordinated dipeptide, respectively, and with complete loss of dien.

ChemInform Abstract: Design, Synthesis, and in vivo Characterization of a Novel Series of Tetralin Amino Imidazoles as γ‐Secretase Inhibitors: Discovery of PF‐3084014 (I).

ChemInform Abstract: Design, Synthesis, and in vivo Characterization of a Novel Series of Tetralin Amino Imidazoles as γ‐Secretase Inhibitors: Discovery of PF‐3084014 (I).

A Quinoliene-Containing Conjugated Polymer-Based Sensing Platform for Amino Acids

A Quinoliene-Containing Conjugated Polymer-Based Sensing Platform for Amino Acids

Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014

A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.

ChemInform Abstract: Enzyme Action: The Delineation of Novel Strategies Based on Reaction Mechanisms and Transition States

Novel synthetic strategies based on the chemical models designed to simulate the enzyme action in some important biological processes have been developed. Successful chemical simulation of some vital cyclic operations of Nature, for example, ATP-Imidazole cycle - wherein a daughter imidazole is grown on a parent imidazole template via a cyclic pathway that is linked to the biosynthesis of the purine code bases ATP and GTP as well as to the imidazole amino acid histidine - and urea cycle wherein ornithine, a non-coded amino acid is used as a carrier molecule for urea via cyclic pathway that is linked to the biosynthesis of arginine - has provided a novel concept of the use of templates and carrier molecules in organic synthesis. A practical methodology for the synthesis of C-terminal amides from serine and threonine extended polypeptide precursors has been designed, patterned on the mechanism of action of pituitary enzymes for the generation of bioactive C-terminal polypeptide hormones from their glycine extended precursors. An aspect of enzyme action that has hitherto received scant attention is that in a large number of cases the reaction so mediated brings about changes remarkably close to those carried out with model systems under the laboratory conditions. Our endeavours at the chemical simulation of highly evolved and vital biological processes envisaged, inter alia, a correlation of processes 'mediated by enzymes on the one hand and those by using purely chemical means on the other. The long range objective of such study is to bring about a symbiosis of both enzymes and chemically mediated reactions to make the synthesis of complex target molecules effective. The work reported here would show that it is possible to bring about enzyme mediated changes effectively by chemical methodologies. The importance of this lies in the fact that chemically mediated processes are flexible in terms of substrates, reaction conditions and isolation procedures. We have also successfully demonstrated that the proper delineation of chemical means to bring about the enzyme mediated processes can be taken advantage of to generate novel strategies in organic synthesis for the preparation of substrates of biological importance. From this vantage, we have examined three carefully chosen key biological transformations, namely, the chemical simulation of the ATP-Imidazole cycle, the Urea cycle and a-amidating action of pituitary enzymes.

Synthesis of chiral threefold and sixfold functionalized macrocyclic imidazole peptides

Starting from 4-oxa- or 4-azasubstituted 2-amino-3-oxoesters and ( S)-valine, chiral imidazole diamino monocarboxylic acids as well as diamino dicarboxylic acids were prepared in a few synthetic steps. Macrolactamization of the side chain protected imidazole amino acids yields the corresponding 18- and 24-membered ring analogues of the naturally occurring cyclic peptide Westiellamide with various anchoring sites. The threefold functionalized scaffolds 2b– 4b and the sixfold functionalized scaffold 5 are versatile central modules for artificial receptors and ligands. Structural investigations of threefold functionalized scaffolds based on oxazole and N-methylimidazole units by DFT modeling are provided.

Synthetic Receptors for the Differentiation of Phosphorylated Peptides with Nanomolar Affinities

Artificial ditopic receptors for the differentiation of phosphorylated peptides varying in i+3 amino acid side chains were synthesized, and their binding affinities and selectivities were determined. The synthetic receptors show the highest binding affinities to phosphorylated peptides under physiological conditions (HEPES, pH 7.5, 154 mM NaCl) reported thus far for artificial systems. The tight and selective binding was achieved by high cooperativity of the two binding moieties in the receptor molecules. All receptors interact with phosphorylated serine by bis(ZnII-cyclen) complex coordination and a second binding site recognizing a carboxylate or imidazole amino acid side chain functionality.

The Diverse Chemistry of Oxazol‐5‐(4H)‐ones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Nagelamide J, a Novel Dimeric Bromopyrrole Alkaloid from a Sponge Agelas Species

A novel dimeric bromopyrrole alkaloid, nagelamide J (1), with antimicrobial activity has been isolated from an Okinawan marine sponge Agelas species, and the structure and stereochemistry were elucidated from spectroscopic data. Nagelamide J (1) is the first bromopyrrole alkaloid possessing a cyclopentane ring fused to an amino imidazole ring.

Displacement of D1, HP1 and topoisomerase II from satellite heterochromatin by a specific polyamide

The functions of DNA satellites of centric heterochromatin are difficult to assess with classical molecular biology tools. Using a chemical approach, we demonstrate that synthetic polyamides that specifically target AT-rich satellite repeats of Drosophila melanogaster can be used to study the function of these sequences. The P9 polyamide, which binds the X-chromosome 1.688 g/cm3 satellite III (SAT III), displaces the D1 protein. This displacement in turn results in a selective loss of HP1 and topoisomerase II from SAT III, while these proteins remain bound to the adjacent rDNA repeats and to other regions not targeted by P9. Conversely, targeting of (AAGAG)n satellite V repeats by the P31 polyamide results in the displacement of HP1 from these sequences, indicating that HP1 interactions with chromatin are sensitive to DNA-binding ligands. P9 fed to larvae suppresses the position-effect variegation phenotype of white-mottled adult flies. We propose that this effect is due to displacement of the heterochromatin proteins D1, HP1 and topoisomerase II from SAT III, hence resulting in stochastic chromatin opening and desilencing of the nearby white gene.

Risk genotypes in folate‐dependent enzymes and their association with methotrexate‐related side effects in rheumatoid arthritis

Methotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folate-dependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA). Blood was collected for analysis in a muticenter, cross-sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low-penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clustered-center effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs). Among 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an approximately 7-fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01). These data suggest that a composite index of the cumulative risk genotypes in folate-dependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.

Straightforward Synthesis of a Novel Class of Rigid Bicyclic Dipeptidomimetics from Simple Dipeptides: Fused Imidazole Amino Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Alternative heterocycles for DNA recognition: the benzimidazole/imidazole pair.

Boc-protected benzimidazole-pyrrole, benzimidazole-imidazole, and benzimidazole-methoxypyrrole amino acids were synthesized and incorporated into DNA binding polyamides, comprised of N-methyl pyrrole and N-methyl imidazole amino acids, by means of solid-phase synthesis on an oxime resin. These hairpin polyamides were designed to determine the DNA recognition profile of a side-by-side benzimidazole/imidazole pair for the designated six base pair recognition sequence. Equilibrium association constants of the polyamide-DNA complexes were determined at two of the six base pair positions of the recognition sequence by quantitative DNase I footprinting titrations on DNA fragments each containing matched and single base pair mismatched binding sites. The results indicate that the benzimidazole-heterocycle building blocks can replace pyrrole-pyrrole, pyrrole-imidazole, and pyrrole-hydroxypyrrole constructs while retaining relative site specifities and subnanomolar match site affinities. The benzimidazole-containing hairpin polyamides represent a novel class of DNA binding ligands featuring tunable target recognition sequences combined with the favorable properties of the benzimidazole type DNA minor groove binders.

Straightforward Synthesis ofa Novel Class of Rigid Bicyclic Dipeptidomimetics fromSimple Dipeptides: Fused Imidazole Amino Acids

A novel class of rigid bicyclic dipeptidomimetics consisting of fused imidazole amino acids is presented. Their straight-forward synthesis was realized by using simple dipeptides consisting of a diamino acid and threonine as starting material.

Variation in the alkaloids among indo-pacific Leucetta sponges.

Nine different Indo-Pacific collections of calcareous Leucetta sp. sponges were investigated for variation in their alkaloid constituents. These alkaloids consisted of 2-amino imidazoles such as dorimidazole A (1) and a polyunsaturated fatty amino alcohol (PUFAA), leucettamol A (3). The nine Leucetta species were divided into five different groups based on taxonomy. Significantly, six specimens contained leucettamol A (3), while the other three contained imidazoles, and these two classes of alkaloids did not occur in the same sponge sample. We recently found a Fijian Leucetta sponge that was a source of spirocyclopentimidazolidins, including spirocalcaridine A (4). We now show that another Fijian collection affords three amino imidazoles consisting of the known alkaloid naamine A (6) plus two new structures, N,N-dimethyl naamine D (5) and leucettamine C (7).

Unusual methylene transfer in reactions of Simmons–Smith reagent with 1,3-diazabuta-1,3-dienes: synthesis of functionalised imidazole derivatives

The reactions of Simmons–Smith reagent with 1-aryl-2-phenyl-4-methylthio-4-secondary amino 1,3-diazabuta-1,3-dienes 1 underwent an unusual 1,4-methylene transfer resulting in the formation of 1-aryl-2-phenyl-4-secondary amino imidazoles 4 . Whereas, its reactions with 1-aryl-2-phenyl-4-secondary amino-1,3-diazabuta-1,3-dienes 8 underwent an initial 1,2-methylene transfer leading to an aziridine intermediate which rearranges to 1-aryl-4-phenyl-imidazoles 11 .

Chromatin Opening of DNA Satellites by Targeted Sequence-Specific Drugs

There are few tools available for dissecting and elucidating the functions of DNA satellites and other nongenic DNA. To address this, we have explored the experimental potential of DNA sequence-specific drugs containing pyrrole and imidazole amino acids (polyamides). Compounds were synthesized that target different Drosophila melanogaster satellites. Dimeric oligopyrroles were shown to target the AT-rich satellites I, III, and SARs (scaffold associated regions). One polyamide (P31) specifically binds the GAGAA satellite V. Specificity of targeting was established by footprinting, epifluorescence of nuclei, and polytene chromosomes stained with fluorescent derivatives. These polyamides were shown to mediate satellite-specific chromatin opening of the chromatin fiber. Remarkably, certain polyamides induced defined gain or loss-of-function phenotypes when fed to Drosophila melanogaster.

Synthesis of polyamide containing pyrrole and imidazole amino acids

AbstractA polyamide containing N‐methylpyrrole (Py) and N‐methylimidazole (Im) amino acids was synthesized by coupling two of the four‐ring oligopeptide chains using DCC/ HOBT as promoting additives. The structure of the polyamide was confirmed by IR, NMR and MS spectra.

New Biologically Active N-(Tetrahydrobenzothienopyrimidin-4-YL)-Amino Acids, Thiourethane, Sulfonamides and Related Compounds

Some derivatives of thieno[2,3-d]pyrimidine containing amino acids 3a-i, imidazoles 4a-f, isothiocyanate 5, thiourethane 6, triazine 8, pyrimidine 10, sulphonamides 13a-d, 14, pyrazole 16 and pyrazolone 17 were synthesized. The structural assignments of the new compounds were based on analytical, spectroscopic measurements and chemical reactions. Some of the obtained compounds showed interesting antimicrobial activities.

Influence of different classes of NO synthase inhibitors in the pig gastric fundus.

The inhibitory potency of different classes of nitric oxide synthase (NOS) inhibitors (amino acid-based substances, guanidines, isothioureas, imidazoles and indazoles) versus peripheral neuronal NOS in the pig gastric fundus was investigated by studying their influence on electrically induced relaxations in non-adrenergic noncholinergic conditions. Circular muscle strips were mounted for isotonic registration in the presence of atropine and guanethidine, and tone was raised with 5-hydroxytryptamine. Electrical field stimulation (40 V, 0.1 ms, 4 Hz, 10 s) induced short-lasting relaxations. The inhibitory effect of 1-phenylimidazole could not be evaluated because it nearly abolished the 5-hydroxytryptamine-induced tone of the tissues. 7-Nitroindazole, imidazole, 2-iminobiotin and aminoguanidine did not inhibit the electrically induced relaxations, while the other 9 substances tested were able to do so. The influence of the incubation period was tested by studying the inhibitory effect after incubation for 10 up to 60 min. For N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-nitro-L-arginine (L-NNA), L-N5-(1-iminoethyl)-ornithine (L-NIO), L-N6-(1-iminoethyl)-lysine (L-NIL), S-methyl-L-thiocitrulline and S-isopropyl isothiourea there was a moderate increase in the inhibitory effect up to 30 min of incubation so that they were incubated for 30 min to study their inhibitory potency. For L-thiocitrulline, S-methyl isothiourea and S-ethyl isothiourea, an incubation period of 60 min was used. The 9 substances concentration-dependently inhibited the electrically induced relaxations with a maximal inhibitory effect of approximately 80% except for S-methyl isothiourea (Emax of 53%). The overall order of potency was: S-isopropyl isothiourea > S-ethyl isothiourea > or = S-methylL-thiocitrulline > or = L-NNA > L-NIO > L-NAME > S-methyl isothiourea > L-thiocitrulline > L-NIL. While the potency for S-isopropyl isothiourea (EC50: 3.1 x 10(-5) M, n = 6) to S-methyl isothiourea (EC50: 11.5 x 10(-5) M, n = 5) was in the same range, the potency of L-thiocitrulline and L-NIL was clearly lower. This study showed several compounds to be potent inhibitors of peripheral neuronal NOS in the pig gastric fundus while some compounds, that were reported to inhibit brain neuronal NOS were not effective. The EC50 values found for the effective substrates in this functional study may be a guideline for the concentrations required to evaluate the role of NO in NANC neurotransmission in gastrointestinal smooth muscle preparations.