Platinum cytosine

The interstrand cross-link also induces DNA bending.72 X-ray and NMR studies on this adduct show that platinum is located in the minor groove and the cytosines of the d(GC) base pair involved in interstrand cross-link formation are flipped out of the helix stack and a localized Z-form DNA is observed.83-85 This is a highly unusual structure and very distorting—implications for differential repair of the two adducts have been addressed. Alternatively, the interstrand cross-link of the antitumor inactive trans-DDP is formed between a guanine (G) and its complementary cytosine (C) on the same base p a i r.86,87/ nms- D D P is sterically incapable of producing 1,2-intrastrand adducts and this feature has been cited as a dominant structural reason for its lack of antitumor efficacy. It is clear that the structural distortions induced on the DNA are very different and likely to induce distinctly different biological consequences. 

Fig. 1. Bridging ligands employed in the original platinblau compounds prepared from the reaction of c/s-PtCl2(RCN)2 or K2PtCl4 with these ligands. Arrows show the most likely coordination atoms bridging two platinum atoms. The bridging modes of both cytidine and adenosine are assumed to have the same bridging mode as cytosine in Fig. 3. Numbers in parentheses correspond to the references.

Additionally, nucleic acid bases have been used in the dynamic assembly of mixed-metal, mixed-pyrimidine metallacalix[n]arenes [47]. In this approach, Lippert and coworkers investigated the dynamic assembly of metallacalixarenes based on platinum (Pt ), palladium (Pd°), uracil, and cytosine assemblies with mixed amines. These combinations form cyclic metallacalix[n]arenes structures with n = A and = 8. Of the metallacalix[4]arenes, compounds were formed with five, six, and eight bonded metals, and a variety of nucleobase coimecfivities (UCUC and UCCU). The dynamic nature of this assembly allows access to novel and structurally diverse set of nucleobase metallacalixarenes. 

Bardaji, E. G. Freisinger, E. Costisella, B. SchaUey, C. A. Briining, W. Sabat, M. Lippert, B. Mixed-metal (platinum, palladium), mixed-pyrimidine (uracil, cytosine) self-assembling metaUacalix[n]arenes Dynamic combinatorial chemistry with nucleobases and metal species. Chem. Eur. J. 2007,13, 6019-6039. 

Ruiz J, Lorenzo J, Sanglas L, Cutillas N, Vicente C, Villa MD, Aviles FX, Lopez G, Moreno V, Perez J, Bautista D (2006) Palladium(II) and platinum(II) organometallic complexes with the model nucleobase anions of thymine, uracil, and cytosine antitumor activity and interactions with DNA of the platinum compounds. Inorg Chem 45 6347-6360... 

NMR solution structures of two cisplatin-DNA decamers containing interstrand cross-links demonstrated that this minor adduct also has characteristic structural features [13] [14]. In particular, the platinum atom lies in the minor groove, the complementary cytosines are extrahelical, and there is a switch in the double helix to a left-handed form localized at the site of the adduct. These distortions bend the helix axis towards the minor groove by approximately 20°-40° and unwind the duplex by 76°-80°. More detailed descriptions of Pt-DNA complexes may be found in other chapters in this volume. 

The nature of the phosphodiester backbone of the sequences flanking the 1,3-intrastrand cross-link plays a role probably by acting on the local conformation of the hybrids, and subsequently on the relative position of the platinum and the attacking cytosine residue. The replacement of the complementary deoxy-strand by a ribo-strand results in a twenty-fold decrease of the rate (tm > 24 h). 

It has been demonstrated that the tran5 -[(NH3)2PtCl] adduct of 1-methylcytosine, bound via N-3, can form crosslinks with either 9-ethylguanine or 9-methyladenine as a result of Cl substitution by purine N-7 atoms. Additional H-bonds between exocyclic groups of cross-linked nucleic acid bases provide additional stabihzation of the individual complexes (Figure 13d). Binding of the related complex [(NH3)2Pt(N-3-cytosine)Cl]+ with d(GG) leads to the formation of a major product in which the platinum is bound only to N-7 of the 5 -nucleotide. ... 

The trans isomer, on the other hand, interacts monofunctionally at the N-7 and N-1 of adenine and the N-3 of cytosine. Both isomers react monofunctionally with the N-7 of guanine and hypox-anthine. X-ray diffraction studies of the complexes formed between cis Pt(NH3)2X2 and various bases have confirmed some of the conclusions obtained from the early spectrophotometric studies. The product of the reaction between inosine and Pt(NH3)2l2 consist of two hypoxanthine rings bound to the platinum ion via the N-7 position (25). A similar structure results from the interaction of PtCl2 (en) with guanosine (26,27) again the N-7 position becomes occupied by the metal. 

Other atoms which have been shown to have an affinity for platinum include the deprotonated N(l) and N(3) positions of guanine and thymine respectively as well as the deprotonated NH2 group of cytosine (28). 

Strand crosslinking of DNAs rich in guanine and cytosine was noted from studies of the renaturability of crosslinked DNAs of different G-C content (32), and from a study of the inhibition of intercalation of 9-aminoacridine as a function of (G + C) content of platinum-treated DNA or copolymers (3 ) ... 

GC base pairs appear to be the preferred site of fixation of platinum(II) compounds on DNA. This conclusion is supported by three types of arguments. First, the rate of fixation of eis-DDP to DNA is correlated with its GC content (53). Hence, if ( is-DDP is mixed with two DNAs of different GC content, it will fix preferentially to the DNA with highest percentage of guanine (54, 55) Second, the quantity of purine bases which have not reacted with platinum can be determined by means of paper chromatography of the depurinated platinum-DNA complex. This experiment shows that d is-DDP reacts with guanine before it binds to adenine (56). Finally, raman spectroscopy of platinum-DNA complexes reveals that fresh aqueous solutions of c is-DDP react preferentially with guanine at r 0.2 and also with adenine at r = 0.4 whereas no reaction with cytosine or thymine was observed (37). 

The stoichiometric reactions of nine oxy and deoxy guanine and/or cytosine containing dinucleotides with cis - [Pt(NH3>2(H20)2] (N03>2 00-5 - 5 X lO- M) in water give monomeric platinum dinucleotide chelates in every case. The complexes have been isolated by HPLC and characterized by NMR and CD analyses. GpG, d - GpG and d - pGpG give a single N7 - N7 anti-anti complex. CpC and d-pCpC... 

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