Bases nucleobases

Pyridine-based nucleobases have been used for silver(I) mediated base pairs. In one report it was shown that the pyridine self-pair (156) was significantly destabilising in a duplex, but in the presence of Ag(I) only slightly destabilising compared to an AT pair. In a second report the same pyridine self-pair was destabilising in the presence or absence of Ag(I), but the self-pair (157) was more stable than the corresponding CG duplex in the presence of Ag(I). A... 

As well as ribose and deoxribose, DNA and RNA contain nitrogenons bases and phosphate groups. There are two general types of nitrogenous base (nucleobases) in both DNA and RNA, purines and pyrimidines. 

Y. Huang and H. Kenttamaa, Theoretical estimations of the 298 K Gas-phase acidities of the pyrimidine-based nucleobases uracil, thymine, and cytosine, J. Phys. Chem. A 107 (2003), pp. 4893-4897. 

The most fundamental roles of nucleic acid bases (nucleobases) in biology and chemistry is their involvement in two qualitatively different mutual interactions hydrogen bonding (base pairing) and aromatic base stacking. 

The fundamental a-hehcal peptide nucleic acid (aPNA) concept is illustrated in Fig. 5.2. Our prototype aPNA module incorporated five nucleobases for Watson-Crick base pairing with a single-stranded nucleic acid target. These nucleobases... 

The amino acid sequence of our first aPNA (which we termed backbone 1 or bl) was designed based on this amphipathic hehx sequence (Fig. 5.3 B). Specifically, this aPNA backbone included hydrophobic amino acids (Ala and Aib), internal salt bridges (Glu-(aa)3-Lys-(aa)3-Glu), a macrodipole (Asp-(aa)i5-Lys), and an N-ace-tyl cap to favor a-helix formation. The C-termini of these aPNA modules end in a carboxamide function to preclude any potential intramolecular end effects. Each aPNA module incorporates five nucleobases for Watson-Crick base pairing to a target nucleic acid sequence. 

Since our original aPNA publication, there have been other reports of the incorporation of nucleobases into a-helical peptides. Mihara and coworkers reported that a-hehcal coiled-coiled peptides could be stabilized by base pairs between complementary y-nucleobase-a-aminobutanoic acids [78] They have also reported that the incorporation of such nucleoamino acids into a-hehcal segments of HIV-1 Rev and HIV-1 nucleocapsid protein can result in increased binding affinity and specificity to HIV-1 RRE RNA and SL3 RNA respectively [79, 80]. 

Figure 35-1. A segment of one strand of a DNA molecule in which the purine and pyrimidine bases guanine (G), cytosine (C), thymine (T), and adenine (A) are held together by a phosphodiester backbone between 2 -de-oxyribosyl moieties attached to the nucleobases by an W-glycosidic bond. Note that the backbone has a polarity (ie,a direction). Convention dictates that a single-stranded DNA sequence is written in the 5 to 3 direction (ie, pGpCpTpA, where G, C,T, and A represent the four bases and p represents the interconnecting phosphates).

Schimanski, A., Ereisinger, E., Erxleben, A. and Lippert, B. (1998) Interactions between [AuX4] (X = Cl, CN) and cytosine and guanine model nucleobases salt formation with (hemi-) protonated bases, coordination, and oxidative degradation of guanine. Inorganica Chimica Acta, 283, 223. 

Radicals can react with bases via hydrogen atom abstraction or, more commonly, by addition to the pi bonds in the heterocyclic nucleobases (Scheme 8.1). These reactions have been extensively studied in the context of hydroxyl radical (HO ), which is generated by y-radiolysis of water. When DNA is exposed to the hydroxyl radical, approximately 80% of the reactions occur at the bases. Many base damage products arising from the reaction hydroxyl radical with DNA have been characterized (Fig. 8.2). ... 

Radical attack yields nucleobase radical adducts that must undergo either oxidation or rednction to yield a stable final prodnct. The cellular oxidant in these reactions may be molecnlar oxygen or high-valent transition metal ions (e.g., Fe ), while the reduc-tant may be either thiols, snperoxide radical, or low-valent transition metal ions (e.g., Fe ). In many cases, the base remains largely intact and the seqnence of chemical events can be readily inferred. In some other cases, more extensive base decomposition occurs. Here, we will consider a set of representative examples that provide a framework for understanding virtnally all radical-mediated base damage reactions. 

There are examples in which base radicals undergo reaction with adjacent base residues. The 5-(2 -deoxyuridinyl)methyl radical (63, Scheme 8.30) can forge an intrastrand cross-link with adjacent purine residues. Cross-link formation is favored with a guanine residue on the 5 -side of the pyrimidine radical and occurs under low-oxygen conditions. A mechanism was not proposed for this process, but presumably the reaction involves addition of the nucleobase alkyl radical to the C8-position of the adjacent purine residue. Molecular oxygen likely inhibits crosslink formation by trapping the radical 63, as shown in Scheme 8.24. The radical intermediate 89 must undergo oxidation to yield the final cross-linked product 90,... 

Under low oxygen conditions, C5 -sugar radicals can react with the base residue on the same nucleotide. In purine nucleotides, the carbon-centered radical 91 can add to the C8-position of the nucleobase (Scheme 8.31). Oxidation of the intermediate nucleobase radical 92 yields the 8,5 -cyclo-2 -deoxypurine lesion 93197,224,225,230-233 Similarly, in pyrimidine nucleotides, the C5 -radical can add to the C6-position of nucleobase. Reduction of the resulting radical intermediate yields the 5, 6-cyclo-5,6-dihydro-2 -deoxypyrimidine lesion 94,234-236... 

Instead, this review seeks to cover less well-known and newly emerging aspects of metal-nucleobase chemistry. In addition to biomedical relevancies, nucleic acid chemistry offers a paradigm for organizing molecules via base pairing. Combining the hydrogen bonding... 

One approach, pursued by two groups in particular, is to use model nucleobases that feature an additional metal-ion binding group. Gokel and co-workers have used this strategy with aza-crown derivatives (50,51). X-ray crystallography of 6is-(3-(l-thyminyl)propyl)-4,13-diaza-18-crown-6, 4, reveals the Na+ is coordinated by T-02 [Na-0 distances 2.488 and 2.468 Al (51). Aza-crown derivatives with multiple base substi-... 

A series of amine-tethered nucleobases such as 8 has also been developed. These ligand systems have allowed the interaction of d-block metal ions with the N3pUrine site to be probed and an indication of base-specific metal-ion binding has begun to emerge (55-58). 

Significantly, it has been shown that coordination of nucleobases can enhance base pairing interactions (115). These findings confirm previous theoretical calculations (116). The association constant for Watson-Crick interactions between 9-EtG and 1-MeC was 6.9 M 1, determined... 

Base-pairing interactions have been realized in metal complexes by extending ligand functionalization to include two complementary nucleobases (136). Sequential alkylation of 1,2-dithioethane using 2-chloroethyl-9-adenine and 3-chloropropyl-l-thymine yields the AT-... 

A series of ferrocenylmethyl nucleobases has been synthesized and the interactions with DNA in aqueous solution have been studied by electrochemistry (109,110). The neutral (rf— C5H5)Fe(r/5 — CgH4CH2-) derivatives were prepared by alkylation of the corresponding base with (rf — Cr>H5)Fe(rf— C5H4CH2N(CH3)J (110). For thymine and cyto-... 

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