1195-08-0Relevant articles and documents
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)
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.
Synthesis and mass spectrometry analysis of oligonucleotides bearing 5- formyl-2'-deoxyuridine in their structure
Berthod,Petillot,Guy,Cadet,Forest,Molko
, p. 1287 - 1305 (1996)
Two oligonucleotides containing FdU (1) have been synthesized. The use of the 'Pac-amidites' for the natural nucleosides has allowed the incorporation of the oxidized thymine residue without protection of the aldehydic function. The oligonucleotide composition was confirmed by enzymatic digestion and electrospray mass spectrometry.
Molecular basis for the substrate specificity and catalytic mechanism of thymine-7-hydroxylase in fungi
Li, Wenjing,Zhang, Tianlong,Ding, Jianping
, p. 10026 - 10038 (2015)
TET proteins play a vital role in active DNA demethylation in mammals and thus have important functions in many essential cellular processes. The chemistry for the conversion of 5mC to 5hmC, 5fC and 5caC catalysed by TET proteins is similar to that of T to 5hmU, 5fU and 5caU catalysed by thymine-7-hydroxylase (T7H) in the nucleotide anabolism in fungi. Here, we report the crystal structures and biochemical properties of Neurospora crassa T7H. T7H can bind the substrates only in the presence of cosubstrate, and binding of different substrates does not induce notable conformational changes. T7H exhibits comparable binding affinity for T and 5hmU, but 3-fold lower affinity for 5fU. Residues Phe292, Tyr217 and Arg190 play critical roles in substrate binding and catalysis, and the interactions of the C5 modification group of substrates with the cosubstrate and enzyme contribute to the slightly varied binding affinity and activity towards different substrates. After the catalysis, the products are released and new cosubstrate and substrate are reloaded to conduct the next oxidation reaction. Our data reveal the molecular basis for substrate specificity and catalytic mechanism of T7H and provide new insights into the molecular mechanism of substrate recognition and catalysis of TET proteins.
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
, (2020)
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.
Steric fixation of bromovinyluracil: Synthesis of furo[2,3-d]pyrimidine nucleosides
Eger,Jalalian,Schmidt
, p. 211 - 218 (1995)
A new synthetic proccdure for the preparation of 5,6-dihydrofuro[2,3-d]pyrimidin-2(3H)-one (3) and its deoxyriboside 8 is reported. Compound 3 undergoes nucleophilic reactions with various agents to yield 5-substituted uracil derivatives. The dehydro derivative of 3, furo[2,3-d]pyrimidin-2(3H)-one (18) was synthesized by cyclization of BVU 15, which made us develop a reproducible and high yield method for the synthesis of BV(D)U. Starting from 18, the α-deoxyriboside 20 and the β-riboside 22 were prepared.
Fluorescent biaryl uracils with C5-dihydro- And quinazolinone heterocyclic appendages in PNA
Heidari, Ali,Ghorbani-Choghamarani, Arash,Hajjami, Maryam,Hudson, Robert H.E.
, (2020)
There has been much effort to exploit fluorescence techniques in the detection of nucleic acids. Canonical nucleic acids are essentially nonfluorescent; however, the modification of the nucleobase has proved to be a fruitful way to engender fluorescence. Much of the chemistry used to prepare modified nucleobases relies on expensive transition metal catalysts. In this work, we describe the synthesis of biaryl quinazolinone-uracil nucleobase analogs prepared by the condensation of anthranilamide derivatives and 5-formyluracil using inexpensive copper salts. A selection of modified nucleobases were prepared, and the effect of methoxy- or nitro- group substitution on the photophysical properties was examined. Both the dihydroquinazolinone and quinazolinone modified uracils have much larger molar absorptivity (~4-8×) than natural uracil and produce modest blue fluorescence. The quinazolinone-modified uracils display higher quantum yields than the corresponding dihydroquinazolinones and also show temperature and viscosity dependent emission consistent with molecular rotor behavior. Peptide nucleic acid (PNA) monomers possessing quinazolinone modified uracils were prepared and incorporated into oligomers. In the sequence context examined, the nitro-substituted, methoxy-substituted and unmodified quinazolinone inserts resulted in a stabilization (?Tm = +4.0/insert; +2.0/insert; +1.0/insert, respectively) relative to control PNA sequence upon hybridization to complementary DNA. All three derivatives responded to hybridization by the “turn-on” of fluorescence intensity by ca. 3-to-4 fold and may find use as probes for complementary DNA sequences.
The detrimental effect of orotic acid substitution in the peptide nucleic acid strand on the stability of PNA2:NA triple helices
Hudson, Robert H. E.,Wojciechowski, Filip
, p. 1731 - 1740 (2005)
We have investigated the incorporation of C6 derivatives of uracil into polypyrimidine peptide nucleic acid oligomers. Starting with uracil-6-carboxylic acid (orotic acid), a peptide nucleic acid monomer compatible with Fmoc-based synthesis was prepared. This monomer then served as a convertible nucleobase whereupon treatment of the resin-bound methyl orotate containing hexamers with hydroxide or amines cleanly converted the ester to an orotic acid or orotamide-containing peptide nucleic acid. Peptide nucleic acid hexamers containing the C6-modified nucleobase hybridized to both poly(riboadenylic acid) and poly(deoxyriboadenylic acid) via triplex formation. Complexes formed with poly(riboadenylic acid) were more stable than those formed with poly(dexoyriboadenylic acid), as measured by temperature-dependent UV spectroscopy. However, both of these complexes were destabilized relative to the complexes formed by an unmodified peptide nucleic acid oligomers. Internal or doubly substituted hexamers are destabilized more strongly than a terminally substituted one, and the type of substitution (carboxamide, ester, carboxylic acid) affects the overall triplex stability. These results clearly show that incorporation of a C6-substituted uracil into polypyrimidine PNA is detrimental to triplex formation. We have also extended this chemistry to incorporate uracil-5-methylcarboxylate into a peptide nucleic acid hexamer. After on-resin conversion of the C5 ester to the 3-(N,N-dimethylamino)propylamide, significant stabilization of the triplex formed with poly(riboadenylic acid) was observed, which illustrates the compatibility of C5 substitution with peptide nucleic acid directed triple helix formation.
The pH-Dependence of the Hydration of 5-Formylcytosine: an Experimental and Theoretical Study
Zott, Fabian L.,Korotenko, Vasily,Zipse, Hendrik
, (2022/02/17)
5-Formylcytosine is an important nucleobase in epigenetic regulation, whose hydrate form has been implicated in the formation of 5-carboxycytosine as well as oligonucleotide binding events. The hydrate content of 5-formylcytosine and its uracil derivative has now been quantified using a combination of NMR and mass spectroscopic measurements as well as theoretical studies. Small amounts of hydrate can be identified for the protonated form of 5-formylcytosine and for neutral 5-formyluracil. For neutral 5-formylcytosine, however, direct detection of the hydrate was not possible due to its very low abundance. This is in full agreement with theoretical estimates.
Preparation method of 2, 4-dichloro-5-pyrimidinecarboxaldehyde and derivative thereof
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Paragraph 0013-0021, (2020/04/02)
The invention discloses a preparation method of 2, 4-dichloro-5-pyrimidinecarboxaldehyde and derivatives thereof. The method comprises the following steps:(1)by taking uracil as a raw material, addingDMF, slowly dropwise adding thionyl chloride at the temperature of 40 DEG C or below, controlling the temperature to be 35-40 DEG C after dropwise adding is finished, tracking by HPLC(High Performance Liquid Chromatography)until the raw material is completely reacted, cooling the system to room temperature, pouring into water, and separating out to generate 2, 4-dyhydroxyl-5-pyrimidinecarboxaldehyde; and(2)reacting the 2, 4-dihydroxy-5-pyrimidinecarboxaldehyde with phosphorus oxychloride to obtain 2, 4-dichloro-5-pyrimidinecarboxaldehyde; the method is good in operability and high in yield, and industrial production can be achieved.
Novel 1H-pyrazolo[3,4-d]pyrimidin-6-amino derivatives as potent selective Janus kinase 3 (JAK3) inhibitors. Evaluation of their improved effect for the treatment of rheumatoid arthritis
Chen, Cheng-Juan,Shu, Lei,Wang, Zhi-Jian,Yin, Yuan,Yu, Ru-Nan,Zhang, Da-Yong,Zhang, Tian-Tai
, (2020/03/17)
Selective JAK3 inhibitors have been shown to have a potential benefit in the treatment of autoimmune disorders. Here we report the identification of a series of pyrazolopyrimidine derivatives as potent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Most of these compounds (13k, 13n and 13 t), displayed stronger anti-JAK3 kinase activity and selectivity than tofacitinib. Furthermore, the most active inhibitor 13t (IC50 = 0.1 nM), also exhibited favourable selectivity for JAK3 in a panel of 9 kinases which contain the same cysteine. In a series of cytokinestimulated cellular analysis, compound 13 t, could potently block the JAK3-STAT signaling pathway. Further biological studies, including cellular antiproliferative activity assays and a rat adjuvant-induced arthritis model for in vivo evaluation, also indicated its efficacy and low toxicity in the treatment of rheumatoid arthritis. The results of these experimental explorations suggested that 13t is a promising lead compound for the development of selective JAK3 inhibitor with therapeutic potential in rheumatoid arthritis.
