Sleep-Promoting Substance (SPS) and Nucleosides
Shojiro Inoué in Biology of Sleep Substances, 2020
On the basis that natural pyrimidines and related compounds contain a heterocyclic, six-membered ring which forms part of the structure of many hypnotics (see Figure 12), and that some of these substances exert hypnotic activity,50 Krooth et al.14 postulated that uracil and other natural pyrimidines may depress the level of arousal. Indeed, they found that a certain dosage of uridine, 6-azauridine, cytidine, thymidine, thymine, uracil, 6-azauracil, barbital, and phenobarbital could depress the spontaneous activity of mice. However, the minimal dose required for reducing spontaneous activity to 50% of the level observed in animals who received an inactive control substance (D-ribose) was as large as 6.5 mmol/kg for uridine, 14.0 mmol/kg for uracil, 13.8 mmol/kg for cytidine, and so on. An earlier study of Wenzel and Keplinger51 also mentions that hexobarbital-induced narcosis was markedly potentiated by i.p. (1 mmol/kg) or oral (2 mmol/kg) administration of uracil in mice.
Mutagenic Consequences Of Chemical Reaction with DNA
Philip L. Grover in Chemical Carcinogens and DNA, 2019
It is not possible to consider chemical mutagenesis separately from DNA repair, because of the dual importance of repair in removing potentially mutagenic lesions from the DNA, and in converting such lesions into mutations. As a starting point, the author will try to describe our current knowledge of how DNA damage is accurately repaired by E. coli. Primarily, ultraviolet light (UV) induced damage will be discussed, and the responses of the bacterium to the whole spectrum of chemical carcinogens can then be considered as variations on a basic theme. UV is by far the most comprehensively investigated DNA damaging agent, and E. coli its most studied victim. As a reference agent, UV has several advantages, including easy administration, accurate dosimetry, and virtually instant treatment for kinetic studies. Moreover, the principal lesion is well characterized. Pyrimidine dimers are formed in which adjacent pyrimi-dines on the same DNA strand are joined by a cyclobutane type ring.38 Formation of the cyclobutane structure saturates the 5,6-double bond in the pyrimidine ring, causing it to become nonplanar.
Synergistic Combinations of Hyperthermia and Inhibitors of Nucleic Acids and Protein Synthesis
Leopold J. Anghileri, Jacques Robert in Hyperthermia In Cancer Treatment, 2019
The biosynthesis of pyrimidine involves the transfer of the methyl group of thymine onto 2′-deoxyuridine-5′-phosphate by the thymidylate synthetase system. Fluorouracil, like uracil, is converted enzymatically to the corresponding ribonucleoside and ribonucleotide, the latter of which may be responsible for some of the toxic effects of fluorouracil,57 can be reduced through a sequence of enzymatic steps to 5-fluoro-2-deoxyuridine-5-phosphate (F-dUMP). The fraudulent nucleotide F-dUMP acts as a competitive inhibitor with dUMP on the enzyme thymidylate synthetase, which catalyzes the transfer of a methyl group from N5,N10-methylene-tetrahydrofolic acid to deoxyuridylic acid (dUMP). The unusually powerful inhibition (F-dUMP binds from 250 to 4000 times more tightly to the enzyme than dUMP) of a key enzyme in the synthesis of thymidylate can readily explain most of the cytotoxic effects of fluorouracil and related derivatives (Figure 3).
Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Samar El-Kalyoubi, Mohamed M. Khalifa, Mahmoud T. Abo-Elfadl, Ahmed A. El-Sayed, Ahmed Elkamhawy, Kyeong Lee, Ahmed A. Al-Karmalawy
The spirooxindole-based structures are among the most vital nitrogen-containing compounds, particularly in the treatment of cancer due to the structural rigidity attributed to the spirocarbon present in these heterocycles27–29. However, spirooxindoles were reported to inhibit Topo I as well as Topo II enzymes30,31. In accordance with this, high interest was directed towards either discovering novel anticancer spirooxindole-based members or finding a simple and novel way to synthesise spirooxindoles. On the other hand, pyrimidine-based scaffolds also have a clear role in building several biologically active compounds, particularly in the field of cancer treatment32. The biological significance of pyrimidines may be ascribed to the ability of the nitrogen atom to bind with DNA by hydrogen bonding33. However, several pyrimidine-based structures were reported to inhibit topoisomerases including, benzo[4,5]thieno[2,3-d]pyrimidines34, thiazolo[3,2-a]pyrimidines35, triazolo[4,3-a]pyrimidines36, imine-pyrazolopyrimidinones37, pyrimido[5,4-b]indoles38, pyrazolo[3,4-d]pyrimidines38, thieno[2,3-d]pyrimidine34, and pyrido[2,3-d:6,5-d′]dipyrimidine39.
Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Nehad M. El-Dydamony, Rana M. Abdelnaby, Rasha Abdelhady, Omaima Ali, Mohamed I. Fahmy, Rasha R. Fakhr Eldeen, Amira A. Helwa
Through studying the binding pattern of the most active compound 7f within the AKT-1 allosteric site represented in Figure 10 and the scores in Table 8, it was found that it has a similar binding mode like the reference compound (OR4). The core pyrimidine is stacked hydrophobically between the key amino acids Val270, Leu264, and Trp80. Also, the hydrazono linker at C-6 helps orienting the terminal phenyl ring towards the hydrophobic lock containing ILe84 similar to the amide linker of the reference ligand, and the trimethoxy phenyl interacts with Arg273 similar to the m-fluorophenyl of the reference compound. This suggests that its mechanism of inhibiting AKT-1 isoform might be through non-competitive allosteric binding.
Dihydropyrimidine dehydrogenase (DPD) genotype and phenotype among Danish cancer patients: prevalence and correlation between DPYD-genotype variants and P-uracil concentrations
Published in Acta Oncologica, 2022
Niels Herluf Paulsen, Camilla Qvortrup, Fie Juhl Vojdeman, Peter Plomgaard, Stig Ejdrup Andersen, Anne Ramlov, Birgitte Bertelsen, Maria Rossing, Claus Gyrup Nielsen, Elke Hoffmann-Lücke, Eva Greibe, Hanne Spangsberg Holm, Heidi Hvid Nielsen, Ihab Bishara Yousef Lolas, Jonna Skov Madsen, Marianne Lerbaek Bergmann, Morten Mørk, Palle B. Nielsen Fruekilde, Pernille Bøttger, Peter Clausager Petersen, Peter Henrik Nissen, Søren Feddersen, Troels K. Bergmann, Per Pfeiffer, Per Damkier
The DPD-phenotype can be measured using different methods, including dihydrouracil/uracil ratio, uracil measurements in saliva, or uracil in plasma. The latter method was implemented into clinical practice in Denmark because it is commonly used in Europe and is recommended by the EMA [6,7,9,12]. The physiological role of the DPD-enzyme is to metabolize the two endogenous pyrimidines, thymine, and uracil, leading to an elevated plasma-uracil concentration ([U]) in patients with DPD-deficiency. [U] is affected by food intake and circadian rhythm [13,14] and is significantly increased in patients with end-stage renal disease [15]. The [U] concentration may also be affected in patients with tumor lysis syndrome, where a pronounced increase in [U] has been reported [16]. Furthermore, [U] is not stable in whole blood, so plasma must be isolated immediately after blood sampling and stored at −20 °C or analyzed. Incorrect or prolonged handling of samples could lead to falsely elevated [U] values [17]. Recently, De With et al. found significant between-center variance in pretreatment [U], underlining that measurement of [U] can be susceptible to preanalytical errors as well as the difference between unstandardized methods [18]. Patients with [U] ≥ 16 ng/mL and >150 ng/mL are categorized as having partial DPD deficiency and complete DPD deficiency, respectively [19].