Cytosine compounds

To demonstrate the difficulty of using IR evidence, Table 35 lists the CO stretching vibrations for cytosine (cy = (133) and some cytosine compounds.369 It is known that the structure of CuCl2(cy)2... 

It is the parent substance of a group of compounds which includes cytosine, thymine and uracil, which are constituents of nucleic acids and barbituric acid and its derivatives, which are important medicinally. 

Any one nucleotide, the basic building block of a nucleic acid, is derived from a molecule of phosphoric acid, a molecule of a sugar (either deoxyribose or ribose), and a molecule of one of five nitrogen compounds (bases) cytosine (C), thymine (T), adenine (A), guanine (G), uracil (U). 

Fosfadecin (186) and fosfocytocin (187) are adenine and cytosine nucleotide antibiotics isolated from the culture filtrates of Pseudomonas viridiflava PK-5 and P. fluorescens PK-52, respectively (283). Hydrolysis produces fosfoxacin which is also isolated from the culture filtrates. Compounds (186) and (187) inhibit gram-positive and gram-negative bacteria. 

Pyridones and other six-membered compounds (functional tautomerism). The pyridone /hydroxypyridine tautomerism (76AHCS1, p. 87), especially 2-pyridone (15a)/2-hydroxypyridine (15b), has received more attention from theoreticians than any other example of tautomerism, probably in part because it is a simple model for biologically important molecules such as thymine, cytosine, and uracil (Scheme 8). 

The authors claim that these associations, which are destroyed in fixed compounds, play an important role in the calculation of Ty.The cases of 1,2,4-triazole-5-thiones 74 [97SA(A)699] and of pyridone dimers 15a-15a and 15a-15b were also studied [96MI(13)65]. (3) The recording of IR spectra in solution at different temperatures to determine the effect of the temperature on Kj-, for instance, in pyrazolinones [83JPR(325)238] and in cytosine-guanine base pairs [92MI(9)881]. (4) The determination of the equilibrium 2-aminopyridine/acetic acid 2-aminopyridinium acetate (see Section III.E) in the acid-base complex was carried out by IR (97NKK100). 

Attached by a covalent bond to carbon atom 1 of the deoxyribose ring is an amine (and therefore a base), which may be adenine, A (22) guanine, G (23) cytosine, C (24) or thymine, T (25). In RNA, uracil, U (26), replaces thymine. The base bonds to carbon atom 1 of deoxyribose through the nitrogen of the —NH— group (printed in red) and the compound so formed is called a nucleoside. All nucleosides have a similar structure, which we can summarize as the shape shown in (27) the lens-shaped object represents the attached amine. 

Kre merov4 M, H0I5 A, Piskala A, Masojidkovd M, Andrei G, Naesens L, Neyts J, Balzarini J, De Clercq E, Snoeck R (2007a) Antiviral activity of tiiazine analogues of l-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (cidofovir) and related compounds. J Med Chem 50 1069-1077... 

Because synthesis of l-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)cytosine (744, FAC), an elementary arabino type of nucleoside having a growth-inhibitory effect against L 1210 leukemia in mice, through direct introduction of a fluorine atom in the 2 - up (arabino) position was difficult, compound 744 was prepared by condensation of trimethylsilylated A -acetylcytosine with 3-0-acetyl-5-(7-benzoyl-2-deoxy-2-fluoro-D-arabin-ofuranosyl bromide (742), which had been prepared by periodate oxidation of 6-0-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (741). Similar condensa-... 

C]-FlAC was synthesized from [2- C]cytosine in the general manner used for unlabeled 748 (FIAC), and its metabolic fate in mice was studied. The compound (after i.v. injection) was deaminated by cytosine nucleoside deaminase and appeared as [2- C]-FIAU in plasma, as confirmed by experiments on rats having a very low level of the deaminase, and by treatment with tetrahydrouridine, a nucleoside deaminase inhibitor. This was further confirmed by the use of purified human deoxycytidine deaminase. It was... 

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy-2 -deoxycytidine (5-OHdCyd) (22) and 5-hydroxy-2 -deoxyuridine (5-OHdUrd) (23) that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro-2 -deoxycytidine (20) and 5,6-dihydroxy-5,6-dihydro-2 -deoxyuridine (21), respectively. MQ-photosen-sitized oxidation of dCyd also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of AT-(2-de-oxy-/j-D-eryf/iro-pentofuranosyl)-l-carbamoyl-4 5-dihydroxy-imidazolidin-2-one, h/1-(2-deoxy-J8-D-crythro-pentofuranosyl)-N4-ureidocarboxylic acid and the a and [5 anomers of N-(2-deoxy-D-eryfhro-pentosyl)-biuret [32, 53]. In contrast, formation of the latter compounds predominates in OH radical-mediated oxidation of the pyrimidine ring of dCyd, which involves preferential addition of OH radicals at C-5 followed by intramolecular cyclization of 6-hydroperoxy-5-hydroxy-5,6-dihydro-2 -deoxycytidine and subsequent generation of the 4,6-endoperoxides [53]. 

The same problem, the stability of the nucleobases, was taken up by Levi and Miller (1998). They wanted to show that a synthesis of these compounds at high temperatures is unrealistic, and thus they took a critical look at the high temperature biogenesis theories, such as the formation of biomolecules at hydrothermal vents (see Sect. 7.2). The half-life of adenine and guanine at 373 K is about a year, that of uracil about 12 years and of the labile cytosine only 19 days. Such temperatures could have easily been reached when planetoids impacted the primeval ocean. 

Reports of the synthesis of cytosine from cyanoacetylene (or its hydrolysis product cyanoacetaldehyde) with cyanate, cyanogens or urea show that these substances react faster with nucleophilic compounds to give side products than to give the required main product. In addition, the formation of cytosine requires concentrations which are unrealistic in prebiotic environments. 

In 1 JMSO-z4, or DMF-(/, the 1 1 condensation products of cytosine or iV-methylcytosine with triformylmethane, compounds 39a and 39b, showed ring-chain tautomerism with the ring-closed products 40a and 40b (see Equation (2), Section 12.04.2.4) <1996ACS1137>. 

Figure 1.45 Reaction of bisulfite with cytosine bases is an important route of derivatization. It can lead to uracil formation or, in the presence of an amine (or hydrazide) containing compound, transamination can occur, resulting in covalent modification.

Halogenation of pyrimidine bases may be done with bromine or iodine. Bromination occurs at the C-5 of cytosine, yielding a reactive derivative, which can be used to couple diamine spacer molecules by nucleophilic substitution (Figure 1.48) (Traincard et al., 1983 Sakamoto et al., 1987 Keller et al., 1988). Other pyrimidine derivatives also are reactive to bromine compounds... 

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. 

Figure 27.3 The reaction of cytosine with bisulfite in the presence of an excess of an amine nucleophile (such as a diamine compound) leads to transamination at the N-4 position. This process is a route to adding an amine functional group to cytosine residues in oligonucleotides.

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