Cyclobutane cytosine

Figure 16-14. Computed energy levels for the ground state (S0) and the lowest triplet excited state (T) of the cytosine dimer in its triplet locally excited state 3(LE), step-wise intermediate 3(SWI), and ground-state cyclobutane cytosine (CBC) dimer. The main intermolecular geometric parameters (in A) for 3(SWI) are included. At the 3(SWI) optimized structure a singlet-triplet crossing, (T1/S0)x, takes place...

Roca-Sanjuan, D., Olaso-Gonzeiez, G.> Gonzalez-Ramirez, L, Serrano-Andres, L.> 8c Merchan, M. (2008b). Molecular basis of DNA photodimerization Intrinsic production of cyclobutane cytosine dimers. Journal of the American Chemical Society, 130,10768-10779. 

The Mutagenic Potential of the Cyclobutane Cytosine Dimer Lesions... 

The intramolecular photodimerization and [2 + 2]-photocycloaddition in DNA involves thymine or cytosine as the chromophore. This chemistry has been intensively investigated with regards to DNA damage and repair [131]. Despite the fact that the area is of continuous interest [132], the synthetic applications are limited and are not covered here in detail. However, some preparative aspects of 4-pyrimidinone photocycloaddition chemistry will be addressed. Aitken et al. have prepared a plethora of constrained cyclobutane P-amino acids by intra- or intermolecular [2 + 2]-photocycloaddition to uracil and its derivatives [133, 134]. In a chiral adaptation of this method, the uracil-derived enone 140 was employed to prepare the diastereomeric cyclobutanes 141 in very good yield (Scheme 6.49). The compounds are easily separated and were - despite the relatively low auxiliary-induced diastereoselectivity - well suited to prepare the as-2-aminocyclobutanecarboxylic acids 142 in enantiomerically pure form. Enantioselective access to the corresponding trans-products was feasible by epimerization in a-position to the carboxyl group [135],... 

The similarly linked dimer (155 R = Me, R = H) has been isolated213 after irradiation of DNA in vitro and in vivo possibly by combination of cytosine and thymine (accompanied by deamination). The macrocyclic tetramer (157) has also been isolated on irradiation of DNA 214 it is thought to be the dimer of the above product (155 R = Me, R = H). The trans-syn structure of 157 has been confirmed by X-ray diffraction analysis of the hexa-A -methyl derivative.215 These are all biologically significant photoreactions as described in Section III, B, 2. Further irradiation of the trans-syn and cis-syn cyclobutane-type dimers (see Section III,E, 2) of 1,3-dimethyluracil with a sensitizer has been found to produce the 5,5 -linked dimer (158).216... 

The foregoing is of obvious significance in relation to the photochemical behaviour of cyclobutane photodimers of natural pyrimidines such as uracil (III, Scheme 1), thymine, cytosine Photodissociation of such photodimers to the parent monomers, which proceed with quantum yields ranging from 0.5 to nearly unity, has, indeed, been employed as one of the criteria for identification of such dimers. The validity of this criterion is now, in the light of the behaviour of the dimer electroreduction product of pyrimidone-2, at best somewhat restricted, notwithstanding that the quantum yields for photodissociation of the latter are lower. 

The literature documents various situations in which C deamination is enhanced. These situations include the presence of C in cyclobutane pyrimidine dimers (a form of DNA damage caused by exposure to UV radiation see later discussion) or in mis-pairings with other bases or with alkylated bases (1). Cytosine deamination is also promoted in the presence of nitrons acid, a reaction that although not considered in this review, has lent much to our understanding of possible chemical mechanisms of spontaneous deamination (1). 

As a consequence of photodamage to DNA there is still considerable interest in the photochemical dimerization of pyrimidine derivatives. Thus, the synthesis of the pyrimidine dimers (157), (158) and (159) has been carried out by irradiation of the pyrimidine derivative (160). Sugiki et al. have studied the photochemical dimerization of the long-chain substituted thymine derivatives (161). The results of the measurement of the reduction potentials of thymine and cytosine cyclobutane dimers have been reported. In addition the electron-transfer-induced ring cleavage by electron donation from suitable sensitizers of the adducts (162) and (163) has also been examined. Calculations have been carried out on the photo-induced repair mechanism in DNA both by direct irradiation and by the use of SET induced photocleavage. ... 

Intramolecular photocycloaddition occurs with thymine derivatives and related compounds. Thus, the bis thymine dimer (116) is formed on irradiation at 254 nm of (117). Zinc complexes of 1,4,7,10-tetraazacyclododecane inhibit the intramolecular photodimerisation of the thymidilyl thymidine (118) and the same complexes are active in cleaving cyclobutane systems (119). Conventional (2+2)-cycloaddition does not occur on irradiation of (120) but instead the main product is the cytosine hydrate accompanied by the (6-4)-photoproduct (121). Dimerisation is reported to occur on irradiation in an acidic medium. 

T Tltraviolet irradiation of aqueous solutions of uracil, cytosine, and thymine derivatives has been shown to lead to the formation of two kinds of photoproducts (4, 13). One type is a dimer of the pyrimidine several such products seem to be formed but the best known are those containing a cyclobutane ring system (shown in I for uracil). 

The pyrimidine bases thymine (T) and cytosine (C) form dimers at sites with adjacent pyrimidine moieties, so-called dipyrimidine sites, in the DNA chain, which have been well characterized with respect to chemical structure and mutagenic potential. The dimerization presented in Scheme 8.1 is a [In+ln] cycloaddition (see Section 7.3) involving the two C(5)=C(6) double bonds, leading to cyclobutane structures denoted by the symbol T< >T, or generally Pyr< >Pyr. 

One of the most prevalent examples of reaction involving DNA excited states is pyrimidine-pyrimidine dimer formation. Thymine and cytosine are the two pyrimidine bases present in DNA, and pyrimidine-pyrimidine dimers can form between any combination of these two bases. The most common of these is the thymine-thymine (TT) dimer [4-7]. Two types of TT dimers are known (shown in Fig. 13.1). The first, and sole focus of this chapter due to its prevalence, is called cyclobutane pyrimidine dimer (CPD) and is formed by the [2-1-2] addition of the C5-C6 double bonds. The second is called the 6 photoadduct and is formed by the addition of the C5-C6 double bond on one thymine to the C4-04 double bond on the other. This leads to an oxetane intermediate that subsequently rearranges to form the 6-4 product. Both of these photoproducts are thought to form starting with initial excitation to a state. There is some debate in the literature... 

The photoinduced formation of cyclobutane pyrimidine dimers in the triplet excited state of the DNA/RNA pyrimidine nucleobases pairs has been studied in a related work. A stepwise mechanism via biradicals for the pairs of nucleobases cytosine and thymine is favored, with an efiidency depending on the formation of the triplet by sensitization and on the competing intersystem crossing to the ground state. " ... 

The first is the formation of cyclobutane pyrimidine dimers (CPDs), accounting for 75 % of direct UV-induced damage to DNA. Absorption of UV-B by thymine or cytosine causes a [2 - - 2] cycloaddition between the carbon-carbon double bonds of neighbouring bases, resulting in a four-membered ring structure, 47 or 52. 

Serrano-P rez, J., Gonzalez-Ramirez, 1., Goto, P., Serrano-Andrds, L., Merchan, M. (2008d). Theoretical insight into the intrinsic ultrafast formation of cyclobutane pyrimidine dimers in UV-irradiated DNA Thymine versus cytosine. The Journal of Physical Chemistry B, 112,14096-14098. 

Ultraviolet light, which is necessary in small doses for the activation of vitamin D (Section 25.6), is devastating in high doses because it causes a [2 + 2] photocycloaddition reaction to occur in DNA between two stacked thymine bases, or between thymine and cytosine. The result is a cyclobutane ring between the two bases. If this dimer forms in a gene that controls cell growth such as Src protein kinase or the tumor suppressor p53, the mutation can result in cancer. This mutation occurs at a rate of 50—100 dimers per second, so it is by no means rare. And that is why people who are out in the sun should always use sunscreen. 

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