4433-40-3Relevant academic research and scientific papers
Phosphate-triggered self-assembly of N-[(uracil-5-yl)methyl]urea: A minimalistic urea-derived hydrogelator
Kleinsmann, Alexander J.,Weckenmann, Nicole M.,Nachtsheim, Boris J.
, p. 9753 - 9761 (2014)
N-[(Uracil-5-yl)methyl]urea is reported as a minimalistic low-molecular-weight hydrogelator (LMWHG). The unusual phosphate-induced assembly of this compound has been thoroughly investigated by IR, UV/Vis, and NMR spectroscopy, electron microscopy, and rheological experiments. This rare example of an anion-triggered urea-based LMWHG is the first example of a pyrimidine- and urea-containing molecule that can be forced into self-assembly in aqueous solution without additional aromatic or lipophilic groups. The gelator/phosphate ratio within the hydrogel was successfully determined by 31P MAS NMR spectroscopy. The hydrogel exhibits a very fast and repeatable self-healing property, and remarkable G' values. The viscoelastic properties of the hydrogel can easily be tuned by variation of the phosphate ratio. Minimalistic hydrogel: N-[(Uracil-5-yl)methyl]urea is reported as a minimalist low-molecular-weight hydrogelator (LMWHG), its assembly being induced by phosphate anions (see scheme). It is the first example of a pyrimidine- and urea-containing molecule that can be forced into self-assembly in aqueous solution without additional aromatic or lipophilic groups. The viscoelastic properties of the hydrogel can easily be tuned by variation of the phosphate ratio.
Bioorthogonal Chemical Signature Enabling Amplified Visualization of Cellular Oxidative Thymines
Bai, Min,Cao, Xiaowen,Chen, Feng,Xue, Jing,Zhao, Yue,Zhao, Yongxi
, p. 10495 - 10501 (2021)
Cellular oxidative thymines, 5-hydroxymethyluracil (5hmU) and 5-formyluracil (5fU), are found in the genomes of a diverse range of organisms, the distribution of which profoundly influence biological processes and living systems. However, the distribution of cellular oxidative thymines has not been explored because of lacking both specific bioorthogonal labeling and sensitivity methods for single-cell analysis. Herein, we report a bioorthogonal chemical signature enabling amplified visualization of cellular oxidative thymines in single cells. The synthesized ATP-γ-alkyne, an ATP analogue with bioorthogonal tag modified on γ-phosphate can be specifically linked to cellular 5hmU by chemoenzymatic labeling. DNA with 5-alkynephosphomethyluracil were then clicked with azide (N3)-modified 5hmU-primer. Identification of 5fU is based on selective reduction from 5fU to 5hmU, subsequent chemoenzymatic labeling of the newly generated 5hmU, and cross-linking with N3-modified 5fU-primer via click chemistry. Then, all of the 5hmU and 5fU sites are encoded with respective circularized barcodes. These barcodes are simultaneously amplified for multiplexed single-molecule imaging. The above two kinds of barcodes can be simultaneously amplified for differentiated visualization of 5hmU and 5fU in single cells. We find these two kinds of cellular oxidative thymines are spatially organized in a cell-type-dependent style with cell-to-cell heterogeneity. We also investigate their multilevel subcellular information and explore their dynamic changes during cell cycles. Further, using DNA sequencing instead of fluorescence imaging, our proposed bioorthogonal chemical signature holds great potential to offer the sequence information of these oxidative thymines in cells and may provide a reliable chemical biology approach for studying the whole-genome oxidative thymines profiles and insights into their functional role and dynamics in biology.
BICYCLIC KINASE INHIBITORS AND USES THEREOF
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Paragraph 613; 618, (2021/11/06)
The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the SIK-family, CSF1R, HCK, TEK-family, BRK, ABL, KIT and/or their mutants. Although structurally similar to other bicyclic kinase inhibitors, the kinase inhibitors of the invention are distinctive; possessing a particular class of heterocyclic moiety. Such kinase inhibitors can display one or more certain properties distinct to their structurally similar kinase inhibitors. The kinase inhibitors of the invention or pharmaceutical compositions comprising them may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. In particular, these and other structurally related kinase inhibitors may be used in the treatment of a proliferative disorder - such as a mixed phenotype acute leukaemia (MPAL) - characterised by (inter-alia) the presence of MEF2C protein, a human chromosomal translocation at 11q23, and/or a KMT2A fusion oncoprotein. The kinase inhibitors or pharmaceutical compositions of the invention may be used topically to modulate skin pigmentation in a subject, for example to impart UV protection and reduce skin cancer risk.
FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
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Paragraph 0308, (2021/04/02)
The present disclosure relates to a class of fused pyrimidine compounds of Formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to a process of preparation of these fused pyrimidine compounds, and to pharmaceutical compositions containing them.
FGFR4 Inhibitor. Compositions and their use in pharmaceutical preparations
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Paragraph 0057-0060, (2021/10/27)
The invention provides 3 inhibitor which takes 4 - 4 dihydropyrimidine [5 - d,2] pyrimidine - (1H) FGFR4 ketone as a mother nucleus and has a covalent structure. The examples give 9 specific compounds and kinase inhibitory activity testing of these 9 compounds, wherein LX08 for FGFR4 kinase inhibitory activity is only 7 nm, lower than FIIN - 2 of the active control, and potential application prospects. In addition, by subjecting the synthesized compound to MALDI-TOF mass spectrometry, we found that compounds of LX01, LX05, LX06, LX07, LX08 are covalently bound to FGFR4 of Cys552, cannot covalently bind FGFR4 of Cys477, and LX09 are FGFR4 inhibitors which can be covalently bound to the two cysteines Cys552 and Cys477 in FGFR4.
Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors
Fugger, Kasper,Bajrami, Ilirjana,Dos Santos, Mariana Silva,Young, Sarah Jane,Kunzelmann, Simone,Kelly, Geoff,Hewitt, Graeme,Patel, Harshil,Goldstone, Robert,Carell, Thomas,Boulton, Simon J.,MacRae, James,Taylor, Ian A.,West, Stephen C.
, p. 156 - 165 (2021/05/03)
Mutations in the BRCA1 or BRCA2 tumor suppressor genes predispose individuals to breast and ovarian cancer. In the clinic, these cancers are treated with inhibitors that target poly(ADP-ribose) polymerase (PARP). We show that inhibition of DNPH1, a protein that eliminates cytotoxic nucleotide 5-hydroxymethyl-deoxyuridine (hmdU) monophosphate, potentiates the sensitivity of BRCA-deficient cells to PARP inhibitors (PARPi). Synthetic lethality was mediated by the action of SMUG1 glycosylase on genomic hmdU, leading to PARP trapping, replication fork collapse, DNA break formation, and apoptosis. BRCA1-deficient cells that acquired resistance to PARPi were resensitized by treatment with hmdU and DNPH1 inhibition. Because genomic hmdU is a key determinant of PARPi sensitivity, targeting DNPH1 provides a promising strategy for the hypersensitization of BRCA-deficient cancers to PARPi therapy.
New Metal-Free Route towards Imidazole-Substituted Uridine
Dehaen, Wim,Herdewijn, Piet,Mattelaer, Henri-Philippe,Van Hool, Anne-Sophie,Van Meervelt, Luc,Van der Auweraer, Mark,de Jong, Flip
supporting information, (2020/07/02)
Nucleosides with a bi(hetero)aryl nucleobase have unique potential applications as antiviral drugs and molecular probes. The need for transition metal catalysis to synthesize these nucleosides from pre-functionalized building blocks and the use of nucleobase protection groups results in expensive and tedious syntheses. Herein we report that 5-imidazolyl-uracil can be obtained by scalable Van Leusen imidazole synthesis and regioselectively introduced on ribose to obtain the desired nucleoside in a 5 step synthesis (total yield 55 percent). The 5-imidazolyl moiety leads to improved fluorescence properties. The only side-product formed was characterized by 2D-NMR and X-ray crystallography and could be suppressed during synthesis in favor of the desired product.
ESI-CID spectral characterization and differentiation of the cross links of thymine formed by one electron oxidation with SO4 ●-
Chandran, Jisha,Vishnu,Aravind, Usha K.,Aravindakumar
, p. 53 - 60 (2019/06/18)
The analysis of urinary nucleosides is becoming a very good tool in the diagnosis of diseases like AIDS and cancer and consequently the identification of modified nucleosides using mass spectrometry is an area of utmost importance. In this context, there is a high relevance in the understanding of the mechanism of collisionally induced dissociation (CID) of these heterocyclics. The present work characterizes and differentiates the cross-linked products formed by one electron oxidation of thymine (T). Three dimers A, B and C, were analyzed, out of which the dimer A is a C5–C5’ cross link of two T molecules containing a fused tetrahydrofuran ring, while B and C are N–C cross linked products. B and C showed very similar fragmentation pattern but that of A was different. The differentiation between these three were made by monitoring two characteristic peaks, the water loss peak ([M+H]+) and the protonated T fragment ([T + H]+). The probable mechanism of formation of these fragments and their CID mechanism in both positive and negative ionization modes are also explained. The neutral losses of NH3, H2O and NHCO were the prominent mechanism in the positive mode, while in the negative mode, only NHCO and CO losses were observed.
BICYCLIC UREA KINASE INHIBITORS AND USES THEREOF
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Paragraph 00260; 00261, (2018/09/25)
The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.
PYRIMIDINE DERIVATIVES AND THEIR USE IN TREATING OR PREVENTING A RESPIRATORY SYNCYTIAL VIRUS INFECTION
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Page/Page column 23, (2018/03/28)
Pyrimidine derivatives of formula (I) wherein: Z is a direct bond or -(CH2)n- wherein n is 1 or 2; one of X and Y is N, CH or CF, and the other of X and Y is CH; one of R1 and R2 is selected from -NHR, -NR2, -OR, -SR, -S(O)R, -S(O)2R and a group of the following formula (A) and the other of R1 and R2 is selected from -NHR', -OH, -OR' and a group of the above formula (A); R is unsubstituted C1-C6 alkyl; R' is a group selected from C1-C6 alkyl, 5- to 12-membered aryl and C3-C6 cycloalkyl, which group is unsubstituted or substituted; W is -(CH2)m-, -CH2-O-CH2-, -CH2-S-CH2- or -CH2-S(O)2-CH2-; p is 1, q is an integer of 1 - 6 and V is N; or p is 1, q is 0 and V is CH; or p is 0, q is 0 and V is N; r is 0 or 1; and R3 is -(CH2)s-NH2 or -(CH2)s-OH wherein s is 0 or an integer of 1 to 4; and the pharmaceutically acceptable salts thereof are inhibitors of RSV and can therefore be used to treat or prevent an RSV infection.
