The Platinum-Pyrimidine Blues

The platinum—pyrimidine blues, derived from cisplatin, are an interesting class of complexes with antitumour activity. They were first discovered as a result of studies on the interaction of c/ [PtCl2(NH3)2] and its aquated products with pyrimidines. The identification of DNA as the target for platinum attack naturally led to a systematic study of the reactions of the complex with nucleic acid constituents. The observation that with polyuridine no immediate reaction took place but that a blue color slowly developed in solution, from which a blue solid could be isolated, led to the preparation of a series of complexes containing substituted uracils and thymines. 

---

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. 

Despite some indisputable progress in the understanding of the nature and composition of platinum blues derived from m-(NH3)2P(" which has been achieved within the last twenty years, in particular thanks to X-ray crystallography, there is still no comprehensive picture available on the -blues . This is true in particular for the platinum pyrimidine blues , on which this review had focused. The amorphous nature of these materials has restricted the methods of investigation to questions such as metal-metal separations [97] or delocalization of spins due to the presence of Ptm centers in a Pt chain [29] [51]. These methods have, however, not provided insight... 

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... 

The results cited above indicated the platinum—pyrimidine blues to be oligomeric, mixed-valent cations with metal—metal bonding, in line with opinions on the original platinblau , first described in 1908 from the reaction of platinum salts in the presence of amides [10]. The bridging, and thus chain extension, occurs through the pyrimidines and the remarkable propensity of platinum—ammine complexes to stack in species such as [Pt(NH3)2Br2Pt(NH3)2Br4] [11] undoubtedly contributes to the chain extension and indeed, the platinum—pyrimidine blues are another example of this tendency. 

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]. 

In the process of identifying the reaction products of the anticancer drug cis-DDP with DNA bases, unusually dark blue compounds were found, which were called platinum-pyrimidine-blues. Interestingly,... 

Much of the Pt2n chemistry came about as a result of the serendipitous discovery of the first platinum pyrimidine blue , formed from cis-[Pt(NH3)2(H20)2]2+ and polyuracil left incubating for several days at pH 7 and 37 °C. This material proved to have high antitumor activity as well as low renal toxicity [1-4], However, interest in Ptin chemistry [5-10] also arises from its possible occurrence in mixed-valence one-dimensional materials [11] [12] and from the participation of Ptm in Ptn/PtIV redox processes [13], as well as in the photocatalytic activation of C-M and C-X bonds [14],... 

Fig. 5.4. Representation of the structure of a mixed metal Pt, Ag complex which is a platinum—pyrimidine blue precursor, [Pt4(NH3)8(l-MeU)4Ag] . From Reference 31.

The first direct evidence for the structure of platinum-blues was provided by the single-crystal X-ray studies of cis-diammineplatinum a-pyridonate-blue, [Pt(2.25+)4(NH3)8(/x-a-pyridonato-N,0)4] (N03)5 H20 (48, 49). In the study, Barton and Lippard selected a-pyridone as a simplified model of pyrimidine bases (see Fig. 3), which must be the primary reason of their success in obtaining the first crystalline-blue material. 

The optical spectrum of platinum—a-pyridone blue, as with the pyrimidine analogues, varies with pH, counteranions, temperature and time. Polarized single-crystal spectra in conjunction with a SCF-X Sw calculation have elucidated the major features of the electronic structure [67]. The blue color has been attributed to transitions from the inner Pt—Pt bonding o orbital to an antibonding one (a ) and from the outer Pt—Pt 7t bonding orbital to outer Pt—Pt a. The effect of alteration of the Pt—Pt distances in the platinum—ethylenediamine—pyridone blue was correlated with the optical spectrum. The delocalization of the unpaired spin density classes the pyridone blue as a Robin—Day Class III-A compound [68]. 

---