Blues uracil

Platination of the N3 position in 1-substituted uracil and thymine derivatives requires proton abstraction and usually occurs only at high pH, but the Pt-N3 bond, once formed, is thermodynamically stable (log K 9.6) [7]. Platinum binding to N3 increases the basicity of 04, which becomes an additional binding site leading to di- and trinuclear complexes. A list of X-ray structurally characterized species is given by Lippert [7]. Pt complexes of uracil and thymine can form intensely colored adducts (e.g. platinum pyrimidine blues), which show anticar-cinogenic activity analogously to the monomeric species [7]. 

It has recently been shown by Spikes150 that uracil and a number of substituted uracils are subject to dye-sensitized photooxidation under certain conditions. Methylene blue and Eosin Y were active photosensitizers in the pH range 8-11.5, but were inactive below pH 8. FMN was very active over the pH range of 2.4-11.5. Photooxidation was measured with a rotating platinum oxygen electrode. 

Several blue tetra- and octanuclear Pt complexes, prepared upon reaction of cis-[Pt(NH3)2(H20)2]2+ with open and cyclic amides, as well as cyclic imides and a uracil nu-cleobase, and comprised of binuclear building blocks interacting through Pt-Pt bond formation, have been isolated and structurally characterized in recent years. Without exception, the average Pt oxidation state in these compounds is 2.25. Nevertheless, the structure and mode of action as antitumor agents of the Platinum Pyrimidine Blues , as prepared by Rosenberg in the early 70 s, remain elusive. This account represents a summary of our present knowledge on cationic Platinum Blues , with a focus on those blues obtained from cis-[Pt(NH3)2(H20)2]2+ and pyrimidine nucleobases, and presents speculations on reasonable alternative structures. 

A detailed study on the binding of Pt uracil blue to closed and nicked circular DNA, reported in 1978 [38], confirmed some of the salient features of the earlier study. However, it was also shown that presumably low-mo-lecular-weight Pt entities not carrying a uracil nucleobase had formed covalent adducts with DNA. Whether or not these Pt species were solvolysis products of the blue used or simply part of the complex mixture, was not obvious. Hints for a hydrolytic decomposition of another blue obtained from 1-methyluracil rather than uracil during reaction with DNA were later found [39], but there appears to be no consensus about the nature of the DNA-binding Pt species. 

Blues Derived from 1-Substituted Uracils and Imides... 

A comparison of aliphatic amides, cyclic amides, cyclic imides and 2,4-dioxopyrimidines (uracils) in their deprotonated and diplatinated form (Scheme 4) reveals an increasing steric shielding of the V-bonded Pt ion (Ptx). With respect to formation of stacked and partially oxidized dinuclear species, it is evident that application of the binding principles seen in the blues of cyclic amides to the uracils and imides allows for tetranuclear species only. On the other hand, the presence of an additional O-donor in the imides and uracils (and likewise the cytosines, vide infra) provides an... 

Although blues prepared from unsubstituted uracil, thymine and related bases (e.g., 6-methyluracil, 5,6-dihydrouracil etc.) were the first to be prepared and tested, their composition is the least clear. The author suspects that there is still long way to go to fully understand the nature of these blues . It is possible that there are even blues built on different principles. A main obstacle to the elucidation of Pt blues derived from the unsubstituted pyrimidine nucleobases lies in their versatility as ligands. Not only is there the possibility that these ligands bind to metal ions, specifically Pt, via N(l) or N(3) or (only with uracil) C(5), but also many possible combinations of two or more binding sites, e.g., N(l),0(2) N(3),0(2) N(3),0(4) N(1),N(3) N(3),0(2),0(4) N(1),0(2),N(3),0(4) etc. (Scheme 6). A series of these binding patterns has been established by X-ray crystal-structure analyses [68-70], and others are likely on the basis of spectroscopic studies [71] [72] or from comparison with results obtained for N(l) substituted derivatives. The possibility of different tautomers of platinated forms being... 

The work by Lippard and coworkers [2][24][25][88][95][98-100] derives its chief motivation from the understanding of the interaction between the anticancer drug cA-[PtCl2(NH3)2] and pyrimidine nucleobases. Unfortunately, the reaction of c7v-[PtCl2(NH3)2] with molecules such as uracil or thymine leads to non-crystalline dark blue materials ( platinum blues ) which are difficult to characterize. The use of a ligand with similar but more restricted number of donor sites, such as a-pyridone (hp), allowed isolation and full characterization of relevant platinum complexes. Related work has used 1-methyluracil (1-Me-urac) and 1-methylthymine (1-Me-thym) in which one of the pyrimidine nitrogens has been blocked [101]. 

Blue compounds are formed generally when cw-Pt(NH3)2Cl2 is treated in aqueous solution with uracils and uridines, and with thymine and other related pyrimidines. The pyrimidine blues have anti-tumor activity [cf. ds-PtCl2(NH3)2]. 

Figure 5.26. Complementarity between mRNA and DNA. The base sequence of mRNA (red) is the complement of that of the DNA template strand (blue). The sequence shown here is from the tryptophan operon, a segment of DNA containing the genes for five enzymes that catalyze the synthesis of tryptophan. The other strand of DNA (black) is called the coding strand because it has the same sequence as the RNA transcript except for thymine (T) in place of uracil (U).

A wide assortment of different possible geometries for the uracil dimer were examined [127] in 1998. The most stable of all these contained a pair of NH- -O bonds, but another was identified, only slightly less stable than the others, in which one of these conventional H-bonds was replaced by CH- -O = C. There was no way of estimating the energetic contribution of this particular interaction, as it was secondary to the stronger NH- -O bond. A study of the adenine thymine pair [128] noted a blue shift of the C-H stretching frequency, an indication of a H-bond, but the authors did not attempt to extract an interaction energy. 

Theoretical calculations on the nature of solvent effects which affect the n-Jt blue shifts for pyrimidine, pyridazine, and pyrazine have been compared with the results of experimental observation . A theoretical study of electronic spectra and photophysics of uracil derivatives , the luminescence of 4-phenylpyridine and... 

MeT as one base, and neutral cytosine, guanine or adenine as second nucleobase proceeds without formation of undesired side products only if the anionic ligand is attached to Pt first. On the other hand, reaction of cis-Pt(II) with uracil or thymine in 1 1 ratio results in formation of the complicated platinum blues... 

Fig. 12.17. Comparison of the structures of uracil and thymine. They differ in structure only by a methyl group, outlined in blue.

Figure 1.82 Structure of G.U, non-Watson-Crick base pairing involving the guanine base of guanosine and uracil base of uridine. Original G.C RNA equivalent Watson-Crick base pairing is shown (blue, top) for comparison.

Thymine being 5-methyluracil, electronic spectra of uracil and thymine are similar. Thus, both uracil and thymine show three absorption bands near 260, 205 and 180 nm (4.77, 6.05 and 6.89 eV, respectively). The first and third bands in thymine are generally sli tly red- and blue-shifted, respectively, with respect to the corresponding bands in yjacii 23.213.214.217.220.224.262.263 spectra reveal a composite nature of the 205 nm band corresponding to peaks near 215 and 195 nm (5.77 and 6.36 eV, respectively). The CD spectra... 

Fig. 34.3. Common interaction pattern of potent Protox inhibitors from uracil- (left) and pyridine-type. Each molecule consists of two ring systems and electron-rich functions on both sides of the linked rings (blue and red).

Since "aquo-complexes" of platinum(ll), prepared by treating the chloro-complexes with aqueous silver nitrate solution, did interact with both thymine and uracil to give the platinum-pyrimidine blues (25), it was evident that the interaction of the chloro-complexes with DNA bases could be different from that... 

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