Platinum complexes pyrimidine

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]. 

Tamasi G, Botta F, Cini R (2006) DFT-molecular modeling analysis of C-H- -N and C-H- - -S hydrogen bond type interactions in selected platinum-purine/pyrimidine complexes. J Mol Struct... 

At the start of this work, x-ray diffraction studies had established that the only platinum coordination sites which existed in isolable compounds prepared by reaction of chloro-platinum complexes, including PtCt2(NH3)2 with purine and pyrimidine bases were N7 for guanosine (21), Nl and N7 for adenosine (22,23), N3 for cytidine (24) and no reaction with thymidine. 

In this context the use of DMSO as carrier has been claimed to be applicable [23]. The clinically used pyrimidine analogue, iodouridine, is only sparingly water-soluble and is used in a DMSO solution for topical application. The reactivity of platinum complexes in DMSO, however, could be a potential problem and the approaches outlined in Section 3.3 may well be applicable for a pharmaceutically suitable formulation of antiviral activity. The toxic side effects of the platinum complexes, if also manifested in a localized application, would be a serious drawback in this present context since the desired selectivity is not present. Again, it is probable that the antiviral effect is manifested by killing of the host cell. 

Lippert and co-workers have reported a similar series of A-,O-bridged platinum(III) dimers in which the bridging ligands are the pyrimidines, 1-methyluracil, 1-methylthymine, or 1-ethylthy-mine. Chemical oxidation of dimeric platinum(II) complexes gave [Pt2XY(L)2(NH3)4]2+, X,Y = N03", N02, H20, Cl", or Br", L=l-MeU, 1-MeT, 1-EtT. 27 t30 They too found that the HT dimers are more stable than the HH.430... 

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

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]. 

Pyrimidine (pm) complexes of platinum(II) can be isolated. The cis compound is obtained by treating K2PtCLt with pyrimidine in water, while fr /w-PtCl2(pm)2 can be formed by isomerization of the cis isomer in DMSO (equation 349).1087 The structures of tram-PtX2(pm)2... 

Overlap Geometry A schematic representation of the proposed overlap geometry for proflavine intercalated into a deoxy pyrimidine(3 -5 )purine site is presented below with the (o) symbols representing the location of the phenanthridine ring protons. The mutual overlap of the two base pairs at the intercalation site involves features observed in the crystal structures of a platinum metallointercalator miniature dC-dG duplex complex (55) and the more recent proflavine miniature dC-dG duplex complex (48), as well as features derived in a linked-atom conformational calculation of the intercalation site in the proflavine DNA complex (51). [4]... 

Ruiz J, Villa MD, Cutillas N, Lopez G, de Haro C, Bautista D, Moreno V, Valencia L (2008) Palladium(II) and Platinum(II) Organometallic Complexes with 4, 7-dihydro-5-methyl-7-oxo[l, 2, 4]triazolo[l, 5-a]pyrimidine. Antitumor activity of the platinum compounds. Inorg Chem 47 4490 1505... 

In 1-substituted pyrimidine complexes, migration of platinum from en-docyclic to exocyclic nitrogen has been observed, i.e., migration of PtIV from N(3) to the exocyclic C(4)-NH2 group in 1 -MeCyt (1 -MeCyt = 1 -meth-ylcytosine) [36]. In the initial complex trans, trans, trans-[Pt(OH)2(NH3)2(l-MeCyt-N(3))2]2+, the V(3),A(4 )-chelate is formed with the elimination of H20 from the complex (Scheme 7). Addition of H20 to the chelated com-... 

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 comparative study of the tetrammine complex [Pt(NH3)4]+ has shown that for platinum, adenine is a better cr donor than ammonia but it has weak n capacity <93JCC45>. Mixed-ligand complexes of m-dichloroethionine-Pd(II) with purines and purine nucleosides have also been prepared. In the complexes of purines and their corresponding nucleosides, the ligand binding site is N-7 whereas in the case of pyrimidines and their nucleosides it is N-3 <90ICA129>. 

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