Pyrimidine bases of DNA

Hydroxyl radicals are the most reactive free-radical species known and have the ability to react with a wide number of cellular constituents including amino-acid residues, and purine and pyrimidine bases of DNA, as well as attacking membrane lipids to initiate a free-radical chain reaction known as lipid peroxidation. 

The answer is a. (Hardman, p 1302.) Cyclophosphamide, an alkylating agent, reacts with purine and pyrimidine bases of DNA to form bridges and dimers. These products interfere with DNA replication. 5-FU, methotrexate, and 6-thioguanine are anti metabolites, and the steroid prednisone has some tumor-suppressive effects. 

Two important reactions of arene oxides in animal tissue are (1) detoxification and (2) formation of conjugates of arene oxides with purine pyrimidine bases of DNA. For both of these reactions to take place, the arene oxide should have a certain intrinsic stability to survive an aromatization reaction. Reaction with the thiolate bond of glutathione is responsible for detoxification, whereas the extent of involvement of arene oxides in the nucleophilic reactions with nonpolarized nitrogen bases of DNA is directly related to their carcinogenic activity. 

The alkaloids are basic compounds in which an N atom is typically part of a heterocyclic ring but in some cases is merely a substituent of an alicyclic or aromatic ring system (as for example with colchicine, some peptide alkaloids and some Amaryllidaceae alkaloids). Various N-based heterocyclics such as the purine and pyrimidine bases of DNA and RNA (see Chapter 2) and the methylxanthine purine derivatives variously found in tea and coffee (caffeine, theobromine and theophylline) are sometimes referred to as pseudoalkaloids and for consistency will be included as alkaloids in this classification. Indeed all plant heterocyclics with a ring N will be conveniendy lumped in with the alkaloids in the tables for didactic simplicity and consistency. 

FIGURE 16-17 Purine and Pyrimidine Bases of DNA and RNA. Adenine and guanine are purines, and cytosine, thymine, and uracil are pyrimidines. The hydrogen-bonding combinations of complementary base pairs are shown. 

Photochemotherapy is an efficient way to treat hyperproliferative diseases. Especially the so-called PUVA therapy (psoralen + UVA light) is very common in which the psoralen is irradiated with UVA light to give rise to a covalent adduct with the pyrimidine bases of DNA by means of a photoaddition reaction. There are several undesired side effects for the patients as a result of this therapy, so the synthesis and photobiological evaluation of novel benzosporalen derivatives was undertaken by the research team of L.D. Via. The key step in their synthetic sequence was the von Pechman reaction of 2-methoxyresorcinol with ethyl 2-oxocyclohexanecarboxylate. 

Since the proposal of the double helical structure of DNA, it has been recognized that the fidelity of replication of genetic information depends on the hydrogen bonding interaction between the purine and pyrimidine bases of DNA, i.e., the cytosine-guanine and thymine-adenine complementarity. The importance of hydrogen bonds for fidelity depends on two... 

Figure 2.4 Comparison of PNA and DNA. PNA contains neither phosphodiester links nor the fi-D-2 -deoxyribofuranose rings. Instead the backbone consists of W-(2-aminoethyl)-glycine repeat units conjoined by peptide links. The main purine and pyrimidine bases of DNA are linked to the the PNA backbone by methylene carbonyl bridge linkages. Watson-Crick base-complementary PNA strands are capable of Watson-Crick base pairing and hence anti-parallel double helix formation.

However, for adenine, guanine, and uracil, the dominant route of anabolism is by way of their ribonucleotide derivatives and traffic along the deoxyribosidic route is not ordinarily significant. Because cytosine is not a substrate for nucleoside phosphorylases, incorporation by the phos-phorylase-kinase route is not possible for this base. The other pyrimidine base of DNA, thymine, is poorly anabolized by both animal and bacterial cells, in spite of the fact that most cells possess thymidine phosphorylase, the action of which is readily reversible. This suggests that ordinarily cellular supplies of deoxyribose 1-phosphate are not available for base anabolism. Experiments are cited below in which it was demonstrated that a significant contribution to the biogenesis of deoxyribose of DNA in E. colt cells did not occur by a route other than ribonucleotide reduction. 

Cis-diamminedichloride platinum, cisplatin, shows a square-planar configuration with a central Pt atom surrounded by Cl atoms and NH3 in the cis position in the horizontal plane. There is evidence that the complex becomes aquated intracellularly to form positively charged Pt species that are likely to interact with nucleophilic sites. The purine and pyrimidine bases of DNA possess such receptor sites and thus provide the locus for effective intracellular binding. The biologically important lesions are most likely to be interstrand and/or intrastrand cross-links (Zwelling and Kohn 1979). 

There has been much interest in the biosynthesis of coumarins bearing isoprenoid-related substituents these are now considered to be mevalonate derived 338, 340, 341). In part this has stemmed from the important skin-sensitizing activity of some furanocoumarins which has been correlated with their photoreactivity towards pyrimidine bases of DNA 409). The proposal by Birch (72) that the two extra carbon atoms of the furan ring are derived by loss of three carbon atoms from an intermediate hydroxyisopropyldihydrofuranocoumarin has received considerable experimental support in recent years 152, 198, 199). Indeed, it has now been established that ( + )-marmesin (103), formed from umbelliferone (2) via 7-demethylsuberosin (86) is a key intermediate in the biosynthesis of linear furanocoumarins 105, 107,... 

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