Nucleic acid electrophilic reactions

The photolytic activation of 5m was also shown to lead to DNA cleavage [33,35-38]. This reaction appeared to be faster and more efficient than the Cu+-catalyzed cleavage conditions. The mechanism(s) of DNA cleavage should be different because aryl cations (not aryl radicals) are believed to be produced under photolytic conditions (Fig. 12) [7]. Such electrophiles should target the nucleic acid bases and/or the positively charged phosphodiester backbone, and both of these could lead to DNA cleavage. 

Equation 4.9 has been extensively applied to study the mechanisms of electrophilic (e.g., protonation) reactions, drug-nucleic acid interactions, receptor-site selectivities of pain blockers as well as various other kinds of biological activities of molecules in relation to their structure. Indeed, the ESP has been hailed as the most significant discovery in quantum biochemistry in the last three decades. The ESP also occurs in density-based theories of electronic structure and dynamics of atoms, molecules, and solids. Note, however, that Equation 4.9 appears to imply that p(r) of the system remains unchanged due to the approach of a unit positive charge in this sense, the interaction energy calculated from V(r) is correct only to first order in perturbation theory. However, this is not a serious limitation since using the correct p(r) in Equation 4.9 will improve the results. 

Addition of P F]F2 (or CH3C02f F]F) at the double bond of substituted 2,4-dioxypyrimidines (Scheme 16) allows the preparation of the fluorine-18-labelled nucleic acid base 5-[ F]fluorouracil [91-94] and the nucleoside 2 -deoxy-5-[ F]fluorouridine [95-97]. The reaction, usually carried out in acetic acid, demonstrates an excellent regioselectivity, with only the 5-[ F]fluoro derivatives obtained because the C-5 position is the unique activated position for reaction with an electrophile in these systems. The mechanism of this reaction has been studied and the intermediate 5,6-fluoro-acetoxy adduct (or the 5,6-fluoro-hydroxy adduct if the solvent is water) has been isolated and characterised [92]. 

The enzymatic metabolism of the pre-carcinogen, i.e., conversion to an electrophile and its reaction with nucleic acid. 

Reactions with electrophilic reagents. Reactions of nucleic acids with the simplest electrophile, the proton, have been considered in Section A2. Somewhat similar are the reactions by which metal ions bind at many sites on both the bases and the phosphate groups of the backbone.550... 

Reuther A, Iglev FI, Laenen R, Lauberau A (2000) Femtosecond photo-ionization of nucleic acid bases electronic lifetimes and electron yields. Chem Phys Lett 325 360-368 Reynisson J, Steenken S (2002) DFT calculations on the electrophilic reaction with water of the guanine and adenine radical cations. A model for the situation in DNA. Phys Chem Chem Phys... 

Five-Membered Unsaturated Heterocycles 1151 Structures of Pyrrole, Furan, and Thiophene 1152 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene 1153 Pyridine, a Six-Membered Heterocycle Electrophilic Substitution of Pyridine Nucleophilic Substitution of Pyridine Fused-Ring Heterocycles 1158 Nucleic Acids and Nucleotides 1160 Structure of Nucleic Acids 1163 Base Pairing in DNA The Watson-Crick Model Nucleic Acids and Heredity 1166 Replication of DNA 1167... 

The reaction of nitrite with secondary or tertiary amines, though unimportant in quantitative respect, leads to Ai-nitroso compounds, which, for a considerable part, are potent carcinogens. These compounds may rearrange to form highly electrophilic dia-zonium ions that react with cellular nucleophiles such as water, proteins, and nucleic acids. 

There is, for example, no end-of-text chapter entitled Heterocyclic Compounds. Rather, heteroatoms are defined in Chapter 1 and nonaromatic heterocyclic compounds introduced in Chapter 3 heterocyclic aromatic compounds are included in Chapter 11, and their electrophilic and nucleophilic aromatic substitution reactions described in Chapters 12 and 23, respectively. Heterocyclic compounds appear in numerous ways throughout the text and the biological role of two classes of them—the purines and pyrimidines—features prominently in the discussion of nucleic acids in Chapter 27. 

With two heteroatoms in the ring, it is again useful to look for a recognisable fragment containing both. Uracil (47), one of the bases in the nucleic acids, can be disconnected to urea and a suitable electrophilic fragment, Michael addition to an electrophilic acetylene is a suitable reaction. 

GSTs catalyze a wide variety of reactions. The groups attacked include epoxides, haloalkanes, nitroalkanes, alkenes, methyl sulfoxide derivatives, and aromatic halo-and nitro- compounds. Because many of these electrophiles are reactive and capable of binding to critical nucleophiles, including proteins and nucleic acids, conjugation represents an important detoxication reaction. 

Oxamniquine is activated via esterification to a biological ester that spontaneously dissociates to an electrophile, which alkylates the helminth DNA, leading to irreversible inhibition of nucleic acid metabolism (Fig. 39.20) (72). Resistant helminths do not esterify oxamniquine therefore, activation does not occur. Other metabolic reactions consist of oxidative reactions, leading to inactivation (Fig. 39.20). The metabolites are excreted primarily in the urine. 

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