Cytosine Subject

The exocychc nitrogens on cytosine and the purine bases must be protected during the synthesis. The search is ongoing for protecting groups that are subject to fewer side reactions and that can be removed more easily in the final deprotection step (34). 

Thus, thymine-tyrosine, thymine-aliphatic amino acid and cytosine-tyrosine links have been identified in isolated calf thymus chromatin subjected to 7-irradiation, or treated with metal ions and H2O2 (Dizdaroglu, 1991 Nackerdien et al., 1991). 

The components of nucleic acids have been the subject of continuous DFT stud-ies61 S5,67 69. Jasien and Fitzgerald calculated dipole moments and polarizabilities for a series of molecules of biological interest including nucleic acid bases (adenine, thymine, cytosine, and guanine) and their pairs (adenine-thymine and cytosine-guanine)61. A good correlation between DFT(HL), experimental, and MP2 results was obtained for dipole moments and polarizabilities. More detailed analyses of DFT(SVWN) and DFT(B88/P86) results, which included vibrational frequencies, were reported for isolated bases and their... 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

As in the case of pyrimidine bases discussed previously, adenine and guanine are subject to nucleophilic displacement reactions at particular sites on their ring structures (Figure 1.50). Both compounds are reactive with nucleophiles at C-2, C-6, and C-8, with C-8 being the most common target for modification. However, the purines are much less reactive to nucleophiles than the pyrimidines. Hydrazine, hydroxylamine, and bisulfite—all important reactive species with cytosine, thymine, and uracil—are almost unreactive with guanine and adenine. 

David and Lubineau191 reported the synthesis of pseudocytidine [5-/3-D-ribofuranosylcytosine (270)] and its a anomer by a procedure analogous to that used in preparing pseudouridine.155-157 Thus, 2,4 3,5-di-O-benzylidene-a/de/iydo-D-ribose (223) was condensed with the dilithio derivative of 2-0,4-N-(trimethylsilyl)cytosine, and the resulting, epimeric, acyclic derivatives were subjected to acid-catalyzed cyclization. The anomeric configuration of the free C-nucleosides was ascertained by spectroscopic methods and by their transformation into a- and /3-pseudouridine in the presence of nitrous acid. The anomeric 5-(/3-D-ribofuranosyl)isocytosines have also been prepared by Fox and coworkers.1913... 

The dipole moment of cytosine has been calculated many times by different methods. Until very recently, no experimental data were available on this subject. A short time ago, an attempt was undertaken at the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, Warsaw, to measure the dipole moments of cytosine, of a number of its derivatives, and of some cytidines. Table X collects the preliminary results of these measurements. As we see, the value of the dipole moment of cytosine is relatively large (> 6.0 D), probably about... 

Barbituric acid reacted with bromine to give in turn the 5-bromo and 5,5-dibromo derivatives. Subjection of the latter to base-induced dehydro-bromination or reduction converted it back into the monobromo species. iV-Alkylbarbituric acids behaved similarly [62HC(16)172 74JCS(P1)2095]. Uracil was brominated in aqueous solution initially in much the same way. A 5-bromo derivative was formed at first, and then (38), apparently a consequence of addition of hypobromous acid. Although quite stable, (38) can be converted back into the monobromo derivative when boiled with mineral acid. 1,3-Dimethyluracil, substituted at C-6 by chlorine, bromine, or iodine, was both mono- and di-brominated at C-5 by bromine (81S701). Cytosine and related compounds behaved similarly [59JOC11 90AHC(47)325],... 

The CASPT2 vertical excitations (see Ref. [29] for details of the computations), displayed in Table 17-1, are approximately 4.5 eV (tt, tt state), 5.3 eV (nN,ir state), and 5.6 eV (nQ, tt state). For comparison, the experimental absorption maximum of the tt, tt state in the gas phase is 4.65 eV, and it is reproduced reasonably well by the calculations. In consequence, the study of the photophysics of gas-phase cytosine centers on the three low-lying states of tt, tt, nN, tt and nQ, tt character. In the past years, we have published several studies on this subject, where the level of theory has been improved gradually, and here we will refer mainly to the results obtained with the highest level of theory [29],... 

Kang and coworkers (1991) reported a variant of methylene-tetrahydrofolate reductase, in which cytosine is replaced by thymidine, resulting in a change of alanine to valine, in people who were hyperhomocysteinemic (Section 10.3.4.2). The variant enzyme is thermolabile (i.e., it is unstable to heating to about 40° to 45°C), and subjects who are homozygous for the thermolabile enzyme have about 50% of normal enzyme activity in tissues. Not only is the enzyme labile on moderate heating in vitro, but it is also unstable in... 

The ability of adenine and cytosine to undergo reduction in aqueous medium is at least partially retained at the level of oligo- and polynucleotides. In both acid and neutral media, such residues in single-stranded RNA, DNA and synthetic polynucleotides, when subjected to d.c. polarography, undergo irreversible reduction in a protonated, adsorbed, state with the transfer of four electrons to adenine... 

The introduction of an azido substituent on the C-2 position of cytosine arabinoside (ara-C) (149) or adenosine arabinoside (ara-A) (154) has been found to confer favourable properties to these antimetabolites. Ara-C, one of the most effective drugs for the treatment of human acute myeloblastic leukaemia [176], is subject to rapid metabolic deamination, by deoxycytid-ine deaminase, to the inactive uridine derivative ara-U (152) Scheme 3.5), and the drug has a half-life of approximately 12 minutes in man [177]. Efforts to circumvent this problem by modifying the 2 -arah/ o-position led... 

This result supports the view that diverse ways exist to obtain chiral biomolecules via CPL or chiral inorganic or organic crystals combined with asymmetric autoctalysis. Kenso Soai and his team studied the effect of the structure of the substituents at position 2 of the pyrimidyl alkanol (Shibata et al. 1996). They found that using 2-alkynyl-pyrimidyl alkanol after three rounds of asymmetric autocatalysis, an astonishing amplification factor of 630,0000 was reached. In the reaction, either (+) or (—) crystals of Cytosine serve as initiators that were formed spontaneously by stirring. In the Soai reaction of chiral amplification, it is crucial that dimers of the O-Zinc diisopropyl intermediate are the active catalysts Racemic pyrimidine alcohols subjected to photolysis with either right- or left-handed CPL produced an ee of one isomer as shown in Fig. 3.4. 

Damaged bases in DNA that arise from ROS or by the deamination of cytosine to uracil are usually removed by BER however, there is no evidence for the existence ofTC-BER that would be analogous to TC-NER [11, 32]. Some oxidized bases may be repaired by TC-NER when they interfere with transcription elongation. In any case, oxidized bases that alter base incorporation events in nascent RNA could contribute significantly to the pool of altered proteins in cells. In fact, 8-oxo-G has been shown to be subject to TC-NER in E. coli and to induce altered proteins via transcriptional mutagenesis [62]. Furthermore, in a recent publication, Saxowsky et al. report that 8-oxo-G induces a change in the activity of the Ras protein in mammalian cells via transcriptional mutagenesis and that downstream phosphorylation events are dependent on Ras [117]. 

The relative stability of the tautomers of purine and pyrimidine bases is of fundamental importance to the structure and functioning of nucleic acids. The occurrence of rare tautomers was considered a factor responsible for the formation of mismatches leading to spontaneous mutations in the genetic code fl,2]. Cytosine, in particular, has been the subject of several studies, both experimental [3-5] and theoretical [5-15] which have provided a reliable picture of the relative stability of its tautomers, both in the gas phase and in solution. Tautomerization is generally the result of proton transfer (PT) reactions whose activation barriers may exert a kinetic control over the formation of some tautomers. As far as cytosine is concerned, a large majority of the studies available in the literature focus on the thermodynamic aspects of tautomerization and quite a few [16-19] are devoted to the elucidation of the kinetic aspects. The tautomerization of cytosine in the gas phase, with a special attention to the activation energy of the proton transfer reactions, has been afforded by this group in a previous paper [19]. By comparison with experimental data [4,5] it was... 

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