Nucleobases, aromaticity

In the B conformation, the aromatic rings of the nucleobases are stacked at a distance of... 

The bases occurring in nucleic acids are derivatives of the aromatic heterocyclic compounds purine and pyrimidine (see p. 80). The biosynthesis of these molecules is complex, but is vital for almost all cells. The synthesis of the nucleobases is illustrated here schematically. Complete reaction schemes are given on pp. 417 and 418. 

Because the chemical shifts of the nonexchangeable nucleobase proton signals are sensitive to (de)protonations of the aromatic structure, the absence of certain protonation shifts, or alterations in the expected pKa values, can give valuable information about the sites where platinum is bound. So, in N7-platinated guanine, no N7 protonation shift around pH 2 is observed, whereas the pKa of the N1 protonation decreases from 9.5 to 8.5 (54). 

Substitution of the aromatic C(5)H in uracil by a methyl group (to give thymine) decreases the acidity of N(3)H by 0.5 log units (cf. Table I). Replacement of protons of endocyclic N atoms and of exocyclic amino groups by alkyl groups in general has a relatively minor effect on the pkl, values of nucleobases. For example, the pvalues of N1 protonated 9-methyladenine (9-MeA), 6,9-dimethyladenine (6,9-DiMeA), and 6,6,9-trimethyladenine (6,6,9-TriMeA) are... 

To evaluate the participation of hydrogen bonding in DNA replication selectivity mechanisms Kool described a seminal functional strategy based on chemically modified DNA polymerase substrates [3a,d,g], He developed nucleotide analogs in which the polar natural DNA nucleobases are replaced by non-polar aromatic molecules, which closely mimic the shape and size of the natural nucleobases but have at least significantly diminished ability to form stable hydrogen bonds (Figure 4.1.4). 

Very few reports of the excited-state structural dynamics of the purine nucleobases have appeared in the literature. This lack of research effort is probably due to a number of factors. The primary factor is the lack of photochemistry seen in the purines. Although adenine can form photoadducts with thymine, and this accounts for 0.2% of the photolesions found upon UVC irradiation of DNA [67], the purines appear to be relatively robust to UV irradiation. This lack of photoreactivity is probably due to the aromatic nature of the purine nucleobases. A practical issue with the purine nucleobases is their insolubility in water. While adenine enjoys reasonable solubility, it is almost an order of magnitude lower than that of thymine and uracil, the two most soluble nucleobases [143], Guanine is almost completely insoluble in water at room temperature [143],... 

The activated internal conversion, which is a hallmark of the photoexcited DNA bases, also occurs in a number of aromatic ethynes and nitriles, including dipheny-lacetylene (DPA) and 4-(dimethylamino)benzonitrile (DMABN). Thus, as in the case of the nucleobases, DPA exhibits an abrupt break-off (loss) of fluorescence in supersonic free jet [35], Figure 15-16, and the strong thermal quenching of... 

The electron affinities (EA) of the nucleobases have not been determined experimentally. Calculated values for the vertical and adiabatic EA obtained by scaling experimental and calculated values for other aromatic molecules are summarized in Table 1 [33a]. The vertical values follow the order U>T>C>A>G, with U having the largest (most positive) EA. The calculated adiabatic EA for C is less positive than the values for T or U. Chen and Chen [36] have asserted that the electron affinities of the purines are larger than those of the pyrimidines. However, this claim appears to be based upon questionable reduction potential measurements (see p. 114). The nucleobase anion radicals are estimated to be stabilized by c. 3 eV in aqueous solution. 

Unlike the cation radicals of aromatic molecules, the anion radicals do not form stable dimer anion radicals, presumably due to an increase in electron-electron repulsion [42]. To our knowledge, there is no experimental or computational evidence for stabilization of nucleobase anion radicals upon r-stacking in duplex DNA. 

Various fluorinated aromatic nucleobases have been synthesised for PNA. As is found with similar fluorinated aromatic bases in DNA (section 1.3.3), they behave as universal bases with complementary DNA. PNA with a terminal 9-aminoacridine has been prepared to examine binding of monovalent ions. A Tio PNA oligomer was found to be sensitive to increasing the concentration of K(f) ions, but the presence of the terminal acridine significantly reduced the sensitivity. The incorporation of naphthalene diimide at the N-terminus of PNA stabilises DNA-PNA duplexes, whilst the bis-functionalised PNA (31) not only stabilises the duplex with DNA but also can be used to photocrosslink to DNA. The presence of the phosphonium ion in (31) aids mitochondrial location of the PNA. 

Gangl et al. [74] reported a 100-fold improvement in the detection of in vivo formed DNA adducts derived from the food-derived 2-amino-3-methyhmidaz[4,5-/ quinohne (TQ, one of the heterocyclic aromatic amines, Ch. 14.5) by the apphcation of capillary LC in combination with micro-ESI-MS. As a result, the detection limit approaches 1 adduct in 10 nucleobases using 500 pg DNA. In a subsequent study [75], this technology was applied to the quantitative analysis of the IQ-dG adduct in rat liver samples in a dose-response study. The major adduct (C8-lQ-dG) could be detected at 17.5 fmol in 300 pg of liver DNA (corresponding to 2 adducts in 10 nucleobases). 

Aliphatic and aromatic amines, alkaloids, amino adds, amino sugars, carboxylic and sul-fanfiic adds, drugs, indole derivatives, nucleobases, nucleosides, nucleotides, peptides, dipeptides, polypeptides, phenols, phenothiazine bases, steroids, sulfonamides, water-soluble food dyes... 

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