Day: November 21, 2022

Scheibe, Christian published the artcileDNA-programmed spatial screening of carbohydrate-lectin interactions, Computed Properties of 169396-92-3, the publication is Chemical Science (2011), 2(4), 770-775, database is CAplus.

A wide range of multivalent scaffolds was assembled by using only five different PNA oligomers and various DNA templates. The flexibility of the PNA-DNA duplexes could be increased by introducing nick-sites and partially unpaired regions, as confirmed by MD simulations. The self-organized glyco-assemblies were used in a spatial screening of accessible carbohydrate binding sites in the Erythrina cristagalli lectin (ECL). This systematic investigation revealed a distance dependence which is in agreement with the crystal structure anal.

Chemical Science published new progress about 169396-92-3. 169396-92-3 belongs to pyrimidines, auxiliary class Pyrimidine,Carboxylic acid,Amine,Amide,Others,PNA, name is 2-(N-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)acetic acid, and the molecular formula is C26H26N4O7, Computed Properties of 169396-92-3.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Nyeki, A. published the artcileNAT2 and CYP1A2 phenotyping with caffeine: head-to-head comparison of AFMU vs. AAMU in the urine metabolite ratios, HPLC of Formula: 608-34-4, the publication is British Journal of Clinical Pharmacology (2003), 55(1), 62-67, database is CAplus and MEDLINE.

Aims. (i) To compare the phenotyping of healthy subjects for NAT2 (N-acetyltransferase) and CYP1A2 activities with caffeine, by the simultaneous assay of the urinary metabolites AFMU and AAMU, and (ii) to ascertain whether NAT2 and CYP1A2 phenotyping is influenced by the use of AFMU or AAMU in the metabolite ratio. Methods. Thirty-five healthy subjects (16 men, 19 women) participated to the study. Caffeine metabolite concentrations were measured in urine collected 8 h after 2.5 mg kg^-1 caffeine intake using a new validated h.p.l.c. method. The metabolite ratios AFMU/1X, AFMU/(AFMU+1X+1U), AAMU/1X, AAMU/(AAMU+1X+1 U), and (AFMU+1U+1X)/17U, (AAMU+1U+1X)/17U were determined as indexes of NAT2 and CYP1A2 activity, resp. Results. Slow and rapid acetylators were similarly identified using the four NAT2 metabolite ratios in 139 out of 1.40 measurements. An appreciable amount of AAMU was present in urine that was immediately acidified and analyzed. Consequently, the ratio using AFMU was lower than that using total AAMU following transformation of AFMU in basic conditions. The proportion of AFMU in urine analyzed immediately expressed as AFMU/(AFMU+AAMU) ratio did not correlate with urine pH, but was a function of the acetylation phenotype, with a low intergroup variability (64±3% and 32±5%, for rapid and slow acetylators, resp.; P < 0.00001, ANOVA). Regarding CYP1A2 activity, a good correlation (r = 0.99) was observed between the metabolite ratios calculated from AFMU and AAMU, although the ratios calculated from AFMU were proportionately and systematically lower (P < 0.00001, paired t-test, slope 1.2). Conclusions. This study demonstrates that both AFMU and AAMU can be used for NAT2 and CYP1A2 metabolite ratio determinations The reported conversion of AFMU into AAMU is unlikely to explain the large amount of AAMU in urine that was acidified and analyzed immediately after voiding. The results suggest that AAMU is formed not solely through a nonenzymic hydrolysis in urine, but in vivo by a NAT2 phenotype-dependent pathway.

British Journal of Clinical Pharmacology published new progress about 608-34-4. 608-34-4 belongs to pyrimidines, auxiliary class Pyrimidine,Amide, name is 3-Methylpyrimidine-2,4(1H,3H)-dione, and the molecular formula is C5H6N2O2, HPLC of Formula: 608-34-4.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Mahe, Yann published the artcileA minoxidil-related compound lacking a C6 substitution still exhibits strong anti-lysyl hydroxylase activity in vitro, Related Products of pyrimidines, the publication is Skin Pharmacology (1996), 9(3), 177-183, database is CAplus.

It has been previously reported that minoxidil inhibits the activity of lysyl hydroxylase (LH), an enzyme which catalyzes the formation of hydroxylysine, which is necessary for proper maturation of collagen at the transcriptional and enzymic levels. Using the reverse transcriptase-polymerase chain reaction, we confirmed that this inhibition occurred at least at the transcriptional level. Furthermore, we took advantage of this sensitive and rapid method to perform a quant. structure activity relation study using several compounds structurally related to minoxidil. We found that when the C6 of the pyrimidinyl moiety was substituted, it had to be by a tertiary nitrogen, i.e. an N-piperidin ring for the inhibition of LH mRNA synthesis to be observed Surprisingly, however, we found that 2,4-diamino-pyrimidin-3-oxide, a new compound lacking an organic moiety para to the nitroxide oxygen, also retained a high inhibitory effect on LH mRNA expression, comparable to that of minoxidil. We thus conclude that the presence of a substituent para to the nitroxide oxygen is dispensable for inhibition of LH mRNA to be observed in vitro. This brings new insights into the design of therapeutic agents useful in any condition where an overproduction of mature collagen is unwanted, i.e. accelerated wound healing, keloids and localized scleroderma.

Skin Pharmacology published new progress about 74638-76-9. 74638-76-9 belongs to pyrimidines, auxiliary class Pyrimidine, name is 2,4-Diaminopyrimidine-3-oxide, and the molecular formula is C4H6N4O, Related Products of pyrimidines.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Panchaud, Philippe published the artcileDiscovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents, Computed Properties of 1187931-22-1, the publication is Journal of Medicinal Chemistry (2017), 60(9), 3755-3775, database is CAplus and MEDLINE.

Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal Et urea binding motif led to the identification of isoquinoline Et urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an i.v.-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chem. series, and efforts toward its minimization are reported.

Journal of Medicinal Chemistry published new progress about 1187931-22-1. 1187931-22-1 belongs to pyrimidines, auxiliary class Pyrimidine,Bromide,Salt, name is 4-Bromopyrimidine hydrobromide, and the molecular formula is C4H4Br2N2, Computed Properties of 1187931-22-1.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Riand, J. published the artcileMass spectrometry. Induced fragmentation by electron impact of amino and dimethylaminopyrimidines, Recommanded Product: N,N-Dimethylpyrimidin-4-amine, the publication is Journal of Heterocyclic Chemistry (1983), 20(5), 1187-90, database is CAplus.

Fragmentation patterns for I (R = R² = H, R¹ = NH₂; R = R¹ = NH₂, R² = H; R = R¹ = R² = NH₂; R= Me₂N, R¹ = R² = H; R = R² = H, R¹ = Me₂N; R = R¹ = Me₂N, R² = H; R = R¹ = R² = Me₂N) were determined and discussed.

Journal of Heterocyclic Chemistry published new progress about 31401-45-3. 31401-45-3 belongs to pyrimidines, auxiliary class Pyrimidine,Amine, name is N,N-Dimethylpyrimidin-4-amine, and the molecular formula is C6H9N3, Recommanded Product: N,N-Dimethylpyrimidin-4-amine.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Volkov, Oleg A. published the artcileSpecies-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase, Computed Properties of 56-05-3, the publication is Journal of Medicinal Chemistry (2018), 61(3), 1182-1203, database is CAplus and MEDLINE.

New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, the authors describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that the authors identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chem. program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the x-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.

Journal of Medicinal Chemistry published new progress about 56-05-3. 56-05-3 belongs to pyrimidines, auxiliary class Pyrimidine,Chloride,Amine,API, name is 2-Amino-4,6-dichloropyrimidine, and the molecular formula is C8H7NO4, Computed Properties of 56-05-3.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Lomoth, R. published the artcileSpectral and kinetic identification of radical cations of pyrimidine bases by stepwise electron transfer, Formula: C5H6N2O2, the publication is Chemical Physics Letters (1998), 288(1), 47-51, database is CAplus.

Radical cations of methylated derivatives of uracil and thymine were generated by electron transfer to the parent radical cation, generated in acetone by nanosecond pulse radiolysis. The resulting transient absorption peaking around 400 and 550 nm is assigned to the radical cations of the pyrimidine bases. Direct kinetic and spectroscopic evidence for this assignment has been given by a subsequent electron transfer from triphenylamine to the pyrimidine radical cations yielding the characteristic absorption spectrum of the triphenylamine radical cation.

Chemical Physics Letters published new progress about 608-34-4. 608-34-4 belongs to pyrimidines, auxiliary class Pyrimidine,Amide, name is 3-Methylpyrimidine-2,4(1H,3H)-dione, and the molecular formula is C5H6N2O2, Formula: C5H6N2O2.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Kosevich, M. V. published the artcileInteraction of calcium and copper ions with pyrimidine bases in frozen water solutions, COA of Formula: C5H6N2O2, the publication is Visnik Kharkivs’kogo Natsional’nogo Universitetu im. V. N. Karazina (2003), 29-39, database is CAplus.

Interaction of nucleic acid pyrimidine bases m₁³Ura, m₁¹Thy, Cyt with calcium and copper ions in frozen water solutions was studied using low temperature fast atom bombardment mass spectrometric technique. Inspection of systems with varied concentrations of bases and chlorides of the metals have shown that base-metal associates recorded in the mass spectra are connected with finely dispersed structure of the eutectic of the frozen samples. It was revealed that the rate of the interactions and types of the associates formed are dependent on the divalent metal type. Calcium ions showed higher yields of associates with the bases in the solid-frozen systems in comparison with dilute water solutions Calcium ions produced along with electrostatically bound complexes covalent ones by substitution of a proton of a base while copper ions produced only non-covalent low-abundant associates In the case of thymine base which is prone to self-association, the distinctions between calcium and copper interactions were preserved at the level of the base dimers.

Visnik Kharkivs’kogo Natsional’nogo Universitetu im. V. N. Karazina published new progress about 608-34-4. 608-34-4 belongs to pyrimidines, auxiliary class Pyrimidine,Amide, name is 3-Methylpyrimidine-2,4(1H,3H)-dione, and the molecular formula is C5H6N2O2, COA of Formula: C5H6N2O2.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Hansen, Anna Mette published the artcileMicrowave-assisted solid-phase synthesis of antisense acpP peptide nucleic acid-peptide conjugates active against colistin- and tigecycline-resistant E. coli and K. pneumoniae, SDS of cas: 172405-16-2, the publication is European Journal of Medicinal Chemistry (2019), 134-145, database is CAplus and MEDLINE.

Recent discovery of potent antibacterial antisense PNA-peptide conjugates encouraged development of a fast and efficient synthesis protocol that facilitates structure-activity studies. The use of an Fmoc/Boc protection scheme for both PNA monomers and amino acid building blocks in combination with microwave-assisted solid-phase synthesis proved to be a convenient procedure for continuous assembly of antisense PNA-peptide conjugates. A validated antisense PNA oligomer (CTCATACTCT; targeting mRNA of the acpP gene) was linked to N-terminally modified drosocin (i.e., RXR-PRPYSPRPTSHPRPIRV; X = aminohexanoic acid) or to a truncated Pip1 peptide (i.e., RXRRXR-IKILFQNRRMKWKK; X = aminohexanoic acid), and determination of the antibacterial effects of the resulting conjugates allowed assessment of the influence of different linkers as well as differences between the L– and D-forms of the peptides. The drosocin-derived compound without a linker moiety exhibited highest antibacterial activity against both wild-type Escherichia coli and Klebsiella pneumoniae (MICs in the range 2-4 μg/mL ∼ 0.3-0.7 μM), while analogs displaying an ethylene glycol (eg1) moiety or a polar maleimide linker also possessed activity toward wild-type K. pneumoniae (MICs of 4-8 μg/mL ∼ 0.6-1.3 μM). Against two colistin-resistant E. coli strains the linker-deficient compound proved most potent (with MICs in the range 2-4 μg/mL ∼ 0.3-0.7 μM). The truncated all-L Pip1 peptide had moderate inherent activity against E. coli, and this was unaltered or reduced upon conjugation to the antisense PNA oligomer. By contrast, this peptide was 8-fold less potent against K. pneumoniae, but in this case some PNA-peptide conjugates exhibited potent antisense activity (MICs of 2-8 μg/mL ∼ 0.3-1.2 μM). Most interestingly, the antibacterial activity of the D-form peptide itself was 2- to 16-fold higher than that of the L-form, even for the colistin- and tigecycline-resistant E. coli strains (MIC of 1-2 μg/mL ∼ 0.25-0.5 μM). Low activity was found for conjugates with a two-mismatch PNA sequence corroborating an antisense mode of action. Conjugates containing D-peptide were also significantly less active. In conclusion, we have designed and synthesized antisense PNA-drosocin conjugates with potent antibacterial activity against colistin- and tigecycline-resistant E. coli and K. pneumonia without concomitant hemolytic properties. In addition, a truncated D-form of Pip1 was identified as a peptide exhibiting potent activity against both wild-type and multidrug-resistant E. coli, P. aeruginosa, and A. baumannii (MICs within the range 1-4 μg/mL ∼ 0.25-1 μM) as well as toward wild-type Staphylococcus aureus (MIC of 2-4 μg/mL ∼ 0.5-1.0 μM).

European Journal of Medicinal Chemistry published new progress about 172405-16-2. 172405-16-2 belongs to pyrimidines, auxiliary class Pyrimidine,Carboxylic acid,Amine,Amide, name is 2-(4-((tert-Butoxycarbonyl)amino)-2-oxopyrimidin-1(2H)-yl)acetic acid, and the molecular formula is C11H15N3O5, SDS of cas: 172405-16-2.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia

Rageot, Denise published the artcile(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase, Safety of 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine, the publication is Journal of Medicinal Chemistry (2019), 62(13), 6241-6261, database is CAplus and MEDLINE.

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like ATP-site PI3K/mTOR kinase inhibitor: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound 6), which qualifies as a clin. candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound 6 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound 6 prevented cell growth in a cancer cell line panel. The preclin. in vivo characterization of compound 6 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify 6 for further development as a therapeutic agent in oncol.

Journal of Medicinal Chemistry published new progress about 944401-58-5. 944401-58-5 belongs to pyrimidines, auxiliary class Trifluoromethyl,Pyrimidine,Fluoride,Boronic acid and ester,Amine,Boronate Esters,Boronic acid and ester,, name is 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine, and the molecular formula is C11H15BF3N3O2, Safety of 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia