Day: November 21, 2022

Myrianthopoulos, Vassilios published the artcileTandem virtual screening targeting the SRA domain of UHRF1 identifies a novel chemical tool modulating DNA methylation, Name: 2-(Dimethylamino)pyrimidine-4,6-diol, the publication is European Journal of Medicinal Chemistry (2016), 390-396, database is CAplus and MEDLINE.

Ubiquitin-like protein UHRF1 that contains PHD and RING finger domain 1 is a key epigenetic protein enabling maintenance of the DNA methylation status through replication. A tandem virtual screening approach was implemented for identifying small mols. able to bind the 5-methylcytosine pocket of UHRF1 and inhibit its functionality. The NCI/DTP small mols. Repository was screened in silico by a combined protocol implementing structure-based and ligand-based methodologies. Consensus ranking was utilized to select a set of 27 top-ranked compounds that were subsequently evaluated exptl. in a stepwise manner for their ability to demethylate DNA in cellulo using PCR-MS and HPLC-MS/MS. The most active mols. were further assessed in a cell-based setting by the Proximity Ligation In Situ Assay and the ApoTome technol. Both evaluations confirmed that the DNMT1/UHRF1 interactions were significantly reduced after 4 h of incubation of U251 glioma cells with the most potent compound NSC232003, showing a 50% interaction inhibition at 15 μM as well as induction of global DNA cytosine demethylation as measured by ELISA. This is the first report of a chem. tool that targets UHRF1 and modulates DNA methylation in a cell context by potentially disrupting DNMT1/UHRF1 interactions. Compound NSC232003, a uracil derivative freely available by the NCI/DTP Repository, provides a versatile lead for developing highly potent and cell-permeable UHRF1 inhibitors that will enable dissection of DNA methylation inheritance.

European Journal of Medicinal Chemistry published new progress about 5738-14-7. 5738-14-7 belongs to pyrimidines, auxiliary class Pyrimidine,Amine,Alcohol,Pyrimidine, name is 2-(Dimethylamino)pyrimidine-4,6-diol, and the molecular formula is C6H9N3O2, Name: 2-(Dimethylamino)pyrimidine-4,6-diol.

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

Wang, Binju published the artcileComputations Reveal a Rich Mechanistic Variation of Demethylation of N-Methylated DNA/RNA Nucleotides by FTO, HPLC of Formula: 608-34-4, the publication is ACS Catalysis (2015), 5(12), 7077-7090, database is CAplus.

The fat-mass and obesity-associated (FTO) protein employs an iron(IV) oxo species to demethylate N-methylated nucleic acids. Herein, we use atomistic-theor. calculations to study the demethylation of the N-methylated DNA/RNA bases 6-methylated adenine (m⁶A), 3-methylated thymine (m³T), and 3-methylated uracil (m³U). The mechanisms involve in-enzyme hydroxylation of the Me group, followed by hydrolysis of the oxidized intermediates in aqueous solution to demethylate the bases. The in-enzyme reactions have been studied using quantum mech./mol. mech. (QM/MM) calculations, while the hydrolytic reactions occurring outside the enzyme have been explored with hybrid cluster-continuum (HCC) calculations When the results obtained with these different methods are combined, the calculated barrier for the overall transformation is consistent with the exptl. free energy barrier for the major route of m⁶A demethylation: in this pathway, adenine’s N1 site acts as an internal base catalyst in the rate-determining hydrolysis of the hydroxylated hemiaminal intermediate hm⁶A to a demethylated A and formaldehyde. This N1-catalyzed mechanism makes m⁶A the most reactive substrate in comparison to other bases we tested. In the minor, slower, route, two oxidation steps by FTO generate an amide intermediate (f⁶A) that undergoes in-water hydrolysis, producing A and formic acid, as found exptl. In contrast, since m³T and m³U lack internal basic catalytic sites, their hemiaminals decompose with high barriers. The mechanism instead involves two sequential oxidations, leading to demethylated bases and formic acid. Thus, our results, obtained using a holistic approach combining modeling the enzyme and the surrounding aqueous solution, suggest revisions of the exptl. mechanisms for m³T and m³U demethylation.

ACS Catalysis 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 C50H65O4P, HPLC of Formula: 608-34-4.

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

Ke, Shaoyong published the artcileSubstituted-nicotinyl thiourea derivatives bearing pyrimidine moiety: synthesis and biological evaluation, Safety of 2-Amino-4,6-dichloropyrimidine, the publication is Research on Chemical Intermediates (2011), 37(6), 627-633, database is CAplus.

Several substituted nicotinyl thiourea derivatives containing a pyrimidine ring were designed and the synthesis of the target compounds was achieved in good to excellent yield using PEG-400 as solid-liquid phase transfer catalyst under ultrasound irradiation conditions. The structures of the new compounds were confirmed by IR, ¹H-NMR and elemental anal. The preliminary biol. tests show that some of the target compounds present good inhibitory activities against the root and stalk of Magnoliopsida (dicotyledon plants) and are safe for Liliopsida (monocotyledon plants).

Research on Chemical Intermediates 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 C4H3Cl2N3, Safety of 2-Amino-4,6-dichloropyrimidine.

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

D’Attoma, Joseph published the artcileEfficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process, Computed Properties of 56-05-3, the publication is Organic Process Research & Development (2017), 21(1), 44-51, database is CAplus.

The transposition of Sandmeyer chlorination from a batch to a safe continuous flow process was investigated. Our initial approach was to develop a cascade method using flow chem. which involved the generation of diazonium salt and its quenching with copper chloride. To achieve this safe diazotation continuous process, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorines. Validation and scale-up of the process were also performed. A higher productivity was obtained under increasingly tight security.

Organic Process Research & Development 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 C4H3Cl2N3, Computed Properties of 56-05-3.

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

Kaczanowska, Katarzyna published the artcileSubstituted 2-Aminopyrimidines Selective for α7-Nicotinic Acetylcholine Receptor Activation and Association with Acetylcholine Binding Proteins, Name: 2-Amino-4,6-dichloropyrimidine, the publication is Journal of the American Chemical Society (2017), 139(10), 3676-3684, database is CAplus and MEDLINE.

Through studies with ligand binding to the acetylcholine binding protein (AChBP), the authors previously identified a series of 4,6 substituted 2-aminopyrimidines that associate with this soluble surrogate of the nicotinic acetylcholine receptor (nAChR) in a cooperative fashion, not seen for classical nicotinic agonists and antagonists. To examine receptor interactions of this structural family on ligand-gated ion channels, the authors employed HEK cells transfected with cDNA’s encoding three requisite receptor subtypes: α7-nAChR, α4β2-nAChR and a serotonin receptor (5-HT3AR), along with a fluorescent reporter. Initial screening of a series of over 50 newly characterized 2-aminopyrimidines with affinity for AChBP showed only two to be agonists on the α7-nAChR below 10 μM concentration Their unique structural features were incorporated into design of a second subset of 2-aminopyrimidines yielding several congeners that elicited α7 activation with EC₅₀‘s of 70 nM and Kd’s for AChBP in a similar range. Several compounds within this series exhibit specificity for the α7-nAChR, showing no activation or antagonism of α4β2-nAChR or 5-HT3AR at concentrations up to 10 μM, while others were weaker antagonists (or partial agonists) on these receptors. Anal. following cocrystn. of four ligand complexes with AChBP show binding at the subunit interface, but with an orientation or binding pose that differs from classical nicotinic agonists and antagonists and from the previously analyzed set of 2-aminopyrimidines that displayed distinct cooperative interactions with AChBP. Orientations of aromatic side chains of these complexes are distinctive, suggesting new modes of binding at the agonist-antagonist site and perhaps an allosteric action for heteromeric nAChRs.

Journal of the American Chemical Society 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 C4H3Cl2N3, Name: 2-Amino-4,6-dichloropyrimidine.

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

Li, Chengxi published the artcileAutomated Flow Synthesis of Peptide-PNA Conjugates, HPLC of Formula: 186046-81-1, the publication is ACS Central Science (2022), 8(2), 205-213, database is CAplus and MEDLINE.

Antisense peptide nucleic acids (PNAs) have yet to translate to the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached to PNAs may facilitate clin. development by improving uptake into cells. We report an efficient technol. that utilizes a fully automated fast-flow instrument to manufacture CPP-conjugated PNAs (PPNAs) in a single shot. The machine is rapid, with each amide bond being formed in 10 s. Anti-IVS2-654 PPNA synthesized with this instrument presented threefold activity compared to transfected PNA in a splice-correction assay. We demonstrated the utility of this approach by chem. synthesizing eight anti-SARS-CoV-2 PPNAs in 1 day. A PPNA targeting the 5′ untranslated region of SARS-CoV-2 genomic RNA reduced the viral titer by over 95% in a live virus infection assay (IC₅₀ = 0.8 μM). Our technol. can deliver PPNA candidates to further investigate their potential as antiviral agents.

ACS Central Science published new progress about 186046-81-1. 186046-81-1 belongs to pyrimidines, auxiliary class Pyrimidine,Carboxylic acid,Amine,Benzene,Amide,Others,PNA,, name is 2-(N-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(4-(((benzhydryloxy)carbonyl)amino)-2-oxopyrimidin-1(2H)-yl)acetamido)acetic acid, and the molecular formula is C39H35N5O8, HPLC of Formula: 186046-81-1.

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

Li, Chengxi published the artcileAutomated Flow Synthesis of Peptide-PNA Conjugates, HPLC of Formula: 169396-92-3, the publication is ACS Central Science (2022), 8(2), 205-213, database is CAplus and MEDLINE.

Antisense peptide nucleic acids (PNAs) have yet to translate to the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached to PNAs may facilitate clin. development by improving uptake into cells. We report an efficient technol. that utilizes a fully automated fast-flow instrument to manufacture CPP-conjugated PNAs (PPNAs) in a single shot. The machine is rapid, with each amide bond being formed in 10 s. Anti-IVS2-654 PPNA synthesized with this instrument presented threefold activity compared to transfected PNA in a splice-correction assay. We demonstrated the utility of this approach by chem. synthesizing eight anti-SARS-CoV-2 PPNAs in 1 day. A PPNA targeting the 5′ untranslated region of SARS-CoV-2 genomic RNA reduced the viral titer by over 95% in a live virus infection assay (IC₅₀ = 0.8 μM). Our technol. can deliver PPNA candidates to further investigate their potential as antiviral agents.

ACS Central 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, HPLC of Formula: 169396-92-3.

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

Rapp, Magdalena published the artcileReactions of trimethylsilyl fluorosulfonyldifluoroacetate with purine and pyrimidine nucleosides, Application of 3-Methylpyrimidine-2,4(1H,3H)-dione, the publication is Journal of Fluorine Chemistry (2009), 130(3), 321-328, database is CAplus and MEDLINE.

Difluorocarbene, generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), reacts with the uridine and adenosine substrates preferentially at the enolizable amide moiety of the uracil ring and the 6-amino group of the purine ring. 2′,3′-Di-O-benzoyl-3′-deoxy-3′-methyleneuridine reacts with TFDA to produce 4-O-difluoromethyl product derived from an insertion of difluorocarbene into the 4-hydroxyl group of the enolizable uracil ring. Reaction of the difluorocarbene with the adenosine substrates having the unprotected 6-amino group in the purine ring produced the 6-N-difluoromethyl derivative, while reaction with 6-N-benzoyl protected adenosine analogs gave the difluoromethyl ether product derived from the insertion of difluorocarbene into the enol form of the 6-benzamido group. Treatment of the 6-N-phthaloyl protected adenosine analogs with TFDA resulted in the unexpected one-pot conversion of the imidazole ring of the purine into the corresponding N-difluoromethylthiourea derivatives Treatment of the suitably protected pyrimidine and purine nucleosides bearing an exo-methylene group at carbons 2′, 3′ or 4′ of the sugar rings with TFDA afforded the corresponding spiro-difluorocyclopropyl analogs but in low yields.

Journal of Fluorine Chemistry 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, Application of 3-Methylpyrimidine-2,4(1H,3H)-dione.

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

Tang, Qi published the artcileCharacterization of Byproducts from Chemical Syntheses of Oligonucleotides Containing 1-Methyladenine and 3-Methylcytosine, Category: pyrimidines, the publication is ACS Omega (2017), 2(11), 8205-8212, database is CAplus and MEDLINE.

Oligonucleotides serve as important tools for biol., chem., and medical research. The preparation of oligonucleotides through automated solid-phase synthesis is well established. However, identification of byproducts generated from DNA synthesis, especially from oligonucleotides containing site-specific modifications, is sometimes challenging. Typical HPLC, Mass Spectrometry (MS), and gel electrophoresis methods alone are not sufficient for characterizing unexpected byproducts, especially for those having identical or very similar mol. weight (MW) to the products. The authors used a rigorous quality control procedure to characterize byproducts generated during oligonucleotide syntheses: (1) purify oligonucleotide by different HPLC systems; (2) determine the exact MW by high resolution MS; (3) locate modification position by MS/MS or exonuclease digestion with MALDI-TOF anal.; and (4) conduct, where applicable, enzymic assays. The authors applied these steps to characterize byproducts in the syntheses of oligonucleotides containing important Me DNA adducts 1-methyladenine (m1A) and 3-methylcytosine (m3C). In m1A synthesis, the authors differentiated a regioisomeric byproduct 6-methyladenine, which possesses identical MW to m1A. As for m3C, the authors identified a deamination byproduct 3-methyluracil, which is only 1 Da greater than m3C in the ∼ 4900 Da context. The detection of these byproducts would be very challenging if the abovementioned procedure were not adopted.

ACS Omega 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 C14H12N2S, Category: pyrimidines.

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

Scheibe, Christian published the artcileDNA-programmed spatial screening of carbohydrate-lectin interactions, Name: 2-(N-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(4-(((benzhydryloxy)carbonyl)amino)-2-oxopyrimidin-1(2H)-yl)acetamido)acetic acid, 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 186046-81-1. 186046-81-1 belongs to pyrimidines, auxiliary class Pyrimidine,Carboxylic acid,Amine,Benzene,Amide,Others,PNA,, name is 2-(N-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(4-(((benzhydryloxy)carbonyl)amino)-2-oxopyrimidin-1(2H)-yl)acetamido)acetic acid, and the molecular formula is C39H35N5O8, Name: 2-(N-(2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2-(4-(((benzhydryloxy)carbonyl)amino)-2-oxopyrimidin-1(2H)-yl)acetamido)acetic acid.

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