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Pt IV prodrugs can overcome resistance and side effects of conventional Pt II anticancer therapies. By 19 F-labeling of a Pt IV prodrug (Pt-FBA, FBA=p-fluorobenzoate), the activation under physiological conditions could be investigated. Unlike single-electron reductants, multi-electron agents can efficiently promote the two electrons reduction of Pt IV to Pt II . The activation of Pt-FBA in cell lysate is highly dependent upon the type of cancer cells. When administered to E. coli, Pt-FBA is reduced intracellularly and free FBA can shuttle out of the cell. The reduction rate greatly increases by inducing metallothionein overexpression and is lowered by addition of Zn II ions. When injected into mice, Pt-FBA undergoes fast reduction in the bloodstream accompanied by metabolic degradation of FBA; nevertheless, unreduced Pt-FBA can accumulate to detectable levels in liver and kidneys. The 19 F NMR approach has the advantage of avoiding the interference of all background signals., (© 2021 Wiley-VCH GmbH.)

The Menkes (MNK) and Wilson (WLN) disease proteins are two P-type ATPases responsible for active Cu efflux. These ATPases are also associated with resistance to cisplatin. In this work, different metal-binding domains (MBDs) of ATPases (9 out of 12 domains) were compared based on their reactivity towards cisplatin. The reaction rates of the MBDs can be largely different; the reaction of MNK6 is about six times faster than that of WLN2. Copper coordination favors the platination of the MBDs to different extents. The rate of platination was generally greater for holo-MBDs than for apo-MBDS (particularly in the case of WLN4 and WLN2); however, it was negligibly affected in the case of MNK6. Interestingly, the platinum binding weakens the Cu I coordination, but does not expel the copper ion from MBDs. The latter results nicely explain the inhibitory effect of Cu upon the cisplatin translocation promoted by Cu-ATPases and can help in understanding how copper levels can modulate the sensitivity of cancer cells to platinum chemotherapy., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ubiquitin-positive protein aggregates are biomarkers of neurodegeneration, but the molecular mechanism responsible for their formation and accumulation is still unclear. Possible aggregation pathways of human ubiquitin (hUb) promoted by both intrinsic and extrinsic factors, are here investigated. By a computational analysis, two different hUb dimers are indicated as possible precursors of amyloid-like structures, but their formation is disfavored by an electrostatic repulsion involving Glu16 and other carboxylate residues present at the dimer interface. Experimental data on the E16V mutant of hUb shows that this single-point mutation, although not affecting the overall protein conformation, promotes protein aggregation. It is sufficient to shift the same mutation by only two residues (E18V) to regain the behavior of wild-type hUb. The neutralization of Glu16 negative charge by a metal ion and a decrease of the dielectric constant of the medium by addition of trifluoroethanol (TFE), also promote hUb aggregation. The outcomes of this research have important implications for the prediction of physiological parameters that favor aggregate formation., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Folic acid has emerged as an interesting cell-targeting moiety and a number of drugs have been conjugated to folate. In this context, new conjugates of β-cyclodextrins with folate have been synthesised as drug carriers to improve their selectivity for cells overexpressing the folic acid receptor. In particular, both 3- and 6-functionalised β-cyclodextrins, linked to the α- or γ-carboxylic group of folic acid, have been synthesised and fully characterised. As a proof of concept, the antitumour platinum(IV) complex cis-trans-cis-[PtCl 2 (CH 3 CO 2 ) 2 (adamantylamine)(NH 3 )] (LA-12) has been used as a guest drug. The LA-12-cyclodextrin inclusion complexes have been tested on tumour cells. In the presence of cyclodextrin-folate conjugates, LA-12 exhibited IC 50 values four times smaller than those of LA-12 alone in MDA-MB-231 cells, which overexpress folic acid receptors on their membrane. No improvement of LA-12 cytotoxicity was found in control tumour cells that do not overexpress the folate receptor. Thus, the non-covalent approach, based on inclusion complexes with functionalised cyclodextrins, looks very promising for drug targeting., (Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are not known. Here a structural model by hybrid Car-Parrinello density functional theory-based QM/MM simulations is provided. The platinated site minimally modifies the fold of the protein. The calculated NMR and CD spectral properties are fully consistent with the experimental data. Our in silico/in vitro approach provides, together with previous studies, an unprecedented view into the structural biology of cisplatin-protein adducts., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The interaction of nanoparticles with proteins has emerged as a key issue in addressing the problem of nanotoxicity. We investigated the interaction of silver nanoparticles (AgNPs), produced by laser ablation with human ubiquitin (Ub), a protein essential for degradative processes in cells. The surface plasmon resonance peak of AgNPs indicates that Ub is rapidly adsorbed on the AgNP surface yielding a protein corona; the Ub-coated AgNPs then evolve into clusters held together by an amyloid form of the protein, as revealed by binding of thioflavin T fluorescent dye. Transthyretin, an inhibitor of amyloid-type aggregation, impedes aggregate formation and disrupts preformed AgNP clusters. In the presence of sodium citrate, a common stabilizer that confers an overall negative charge to the NPs, Ub is still adsorbed on the AgNP surface, but no clustering is observed. Ub mutants bearing a single mutation at one edge β strand (i.e. Glu16Val) or in loop (Glu18Val) behave in a radically different manner., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this paper we investigate the possibility of further increase the role of the N-donor aromatic base in antitumor Hollis-type compounds by conferring the possibility to act as a hydrogen-bond donor/acceptor. Therefore, we synthesized the Pt(II) complex cis-[PtCl(NH3 )2 (naph)]NO3 (1) containing the 1,8-naphthyridine (naph) ligand. The naphthyridine ligand is generally monodentate, and the second nitrogen atom can act as H-bond donor/acceptor depending upon its protonation state. The possibility of forming such an H-bond could be crucial in the interaction of the drug with DNA or proteins. Apart from the synthesis of the compound, in this study we evaluated its in vitro antitumor activity in a wide panel of tumor cell lines, also including cells selected for their sensitivity/resistance to oxaliplatin, which was compared with that of previously reported complex 2 ([PtI(2,9-dimethyl-1,10-phenanthroline)(1-methyl-cytosine)]I) and oxaliplatin and cisplatin as reference compounds. The cytotoxicity data were correlated with the cellular uptake and the DNA platination levels. Finally, the reactivity of 1 towards guanosine 5'-monophosphate (5'-GMP) and glutathione was investigated to provide insights into its mechanism of action., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance. Down-regulation of CTR1 and up-regulation of the Cu-ATPases, ATP7A and ATP7B, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on the COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, and adsorbed on a solid supported membrane. The experimental results indicate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation in a fashion similar to that of Cu. We then used NMR spectroscopy and ESI-MS to determine the binding mode of these drugs to the first N-terminal metal-binding domain of ATP7A (Mnk1)., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Zinc ions bridging two ubiquitin molecules (with His68 at the interface) contribute to select a subset of conformers from the noncovalent dimer ensemble, thus restricting quaternary structure dynamics, which hampers apo-protein crystallization. The type of selected conformer is shown to determine the crystal packing, which varies from orthorhombic to cubic symmetry., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Oxaliplatin and cisplatin belong to the class of platinum-based anticancer agents. Formation of DNA adducts by these complexes and the consequences for its structure and function, is the mechanistic paradigm by which these drugs exert their antitumor activity. We show that employing short oligonucleotide duplexes containing single, site-specific 1,3-intrastrand cross-links of oxaliplatin, its enantiomeric analogue, or cisplatin and by using gel electrophoresis that under physiological conditions the coordination bonds between platinum and the N7 position of guanine residues involved in the cross-links of the Pt(II) complexes can be cleaved. This cleavage may lead to linkage isomerization reactions between these metallodrugs and double-helical DNA. For instance, approximately 25 % 1,3-intrastrand cross-links of the platinum complexes isomerized after 192 h (at 310 K in 200 mM NaClO4). Differential scanning calorimetry of duplexes containing single, site-specific cross-links of oxaliplatin, its enantiomeric analogue, and cisplatin reveals that one of the driving forces that leads to the lability of DNA cross-links of these metallodrugs is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of the DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule. In addition, the differences in the kinetics of the rearrangement reactions and the thermodynamic destabilization of DNA observed for adducts of oxaliplatin and its enantiomeric analogue confirm that the chirality at the carrier 1,2-diaminocyclohexane ligand can considerably affect structural and other physical properties of DNA adducts and consequently their biological effects. In aggregate, interesting generalization of the results described in this work might be that the migration of oxaliplatin, its enantiomeric analogue, or cisplatin from one strand to another in double-helical DNA controlled by energetic signatures of these agents might contribute to a better understanding of their cytotoxic and mutagenic potential., (Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

To determine how the Y-family translesion DNA polymerase η (Polη) processes lesions remains fundamental to understanding the molecular origins of the mutagenic translesion bypass. We utilized model systems employing a DNA double-base lesion derived from 1,2-GG intrastrand cross-links of a new antitumor Pt(II) complex containing a bulky carrier ligand, namely [PtCl(2)(cis-1,4-dach)] (DACH=diaminocyclohexane). The catalytic efficiency of Polη for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the 1,2-GG cross-link was markedly reduced by the DACH carrier ligand. This reduced efficiency of Polη to incorporate the correct dCTP could be due to a more extensive DNA unstacking and deformation of the minor groove induced in the DNA by the cross-link of bulky [PtCl(2)(cis-1,4-dach)]. The major products of the bypass of this double-base lesion produced by [PtCl(2)(cis-1,4-dach)] by Polη resulted from misincorporation of dATP opposite the platinated G residues. The results of the present work support the thesis that this misincorporation could be due to sterical effects of the bulkier 1,4-DACH ligand hindering the formation of the Polη-DNA-incoming nucleotide complex. Calorimetric analysis suggested that thermodynamic factors may contribute to the forces that governed enhanced incorporation of the incorrect dATP by Polη as well., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Pt(II)-coordination complex [PtCl(2)(DAB)] (DAB=2,3-diaminobutane) belongs to a class of cytotoxic cisplatin analogues that contain chiral diamine ligands. Enantiomeric pairs of these compounds have attracted particular interest because they have different effects on different DNA conformations, which, in turn, influences the binding of damaged-DNA-processing enzymes that control downstream effects of the adducts, and thus exhibit different biological activities of the enantiomers. Herein, we studied the translesion synthesis across the major 1,2-d(GG) intrastrand cross-link formed by the R,R and S,S enantiomers of [Pt(DAB)](2+) in the TGGT sequence by using the enzyme that catalyzes the polymerization of deoxyribonucleotides into a DNA strand. We also employed differential scanning calorimetry (DSC) to measure the thermodynamic changes associated with replication-bypass past 1,2-d(GG) adducts of the [Pt(DAB)](2+) enantiomers. In the sequence TGGT, the 1,2-d(GG) intrastrand cross-links that were formed by the enantiomeric pairs of [Pt(DAB)](2+) inhibited DNA polymerization in a chirality-dependent manner. The thermodynamic data helped to understand the effect of the alterations in thermodynamic stability of DNA caused by the Pt-d(GG) adducts upon DNA polymerization across these lesions. Moreover, these data can possibly explain the influence of these alterations on the ability of many DNA polymerases to bypass adducts of antitumor platinum drugs. These results also highlighted the usefulness of DSC in evaluating the impact of DNA adducts of platinum-coordinated compounds on the processing of these lesions by damaged-DNA processing-enzymes., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The metal-binding ability of human ubiquitin (hUb) towards a selection of biologically relevant metal ions and complexes has been probed. Different techniques have been used to obtain crystals suitable for crystallographic analysis. In the first type of experiments, crystals of hUb have been soaked in solutions containing copper(II) acetate and two metallodrugs, Zeise salt (K[PtCl(3)(η(2)-C(2)H(4))]·H(2)O) and cisplatin (cis-[PtCl(2)(NH(3))(2)]). The Zeise salt is used in a test for hepatitis, whereas cisplatin is one of the most powerful anticancer drugs in clinical use. The Zeise salt readily reacts with hUb crystals to afford an adduct with three platinum residues per protein molecule, Pt(3)-hUb. In contrast, copper(II) acetate and cisplatin were found to be unreactive for contact times up to one hour and to cause degradation of the hUb crystals for longer times. In the second type of experiments, hUb was cocrystallized with a solution of copper(II) or zinc(II) acetate or cisplatin. Zinc(II) acetate gives, at low metal-to-protein molar ratios (8:1), crystals containing one metal ion per three molecules of protein, Zn-hUb(3) (already reported in previous work), whereas at high metal-to-protein ratios (70:1) gives crystals containing three Zn(II) ions per protein molecule, Zn(3)-hUb. In contrast, once again, copper(II) acetate and cisplatin, even at low metal-to-protein ratios, do not give crystalline material. In the soaking experiment, the Zeise anion leads to simultaneous platination of His68, Met1, and Lys6. Present and previous results of cocrystallization experiments performed with Zn(II) and other Group 12 metal ions allow a comprehensive understanding of the metal-ion binding properties of hUb with His68 as the main anchoring site, followed by Met1 and carboxylic groups of Glu16, Glu18, Glu64, Asp21, and Asp32, to be reached. In the case of platinum, Lys6 can also be a binding site. The amount of bound metal ion, with respect to that of the protein, appears to be a relevant parameter influencing crystal packing., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In early studies of empirical structure-activity relationships, monodentate Pt(II) complexes were considered to be biologically inactive. Examples of such inactive monodentate Pt(II) compounds are [PtCl(dien)]+ (dien=diethylenetriamine) and [PtCl(NH3)3]+. DNA is considered the major biological target of platinum compounds. Thus, monodentate DNA binding of Pt(II) compounds was previously expected to display insignificant biological effects because it was assumed to affect DNA conformation and downstream cellular processes markedly less than the cross-links of bifunctional Pt(II) complexes. More recently it was shown that some monodentate Pt(II) complexes do exhibit biological effects; the active monodentate Pt(II) complexes commonly feature bulkier amine ligands than the hitherto used dien or NH(3) groups. We were therefore interested in determining whether a simple but marked enhancement of the bulkiness of the dien ligand in monodentate [Pt(NO3)(dien)]+ by multiple methylation of this ligand affects the early phases in which platinum compounds exert their biological activity. More specifically, the goals of this study, performed in cell-free media, were to determine how the modification of DNA duplexes by methylated analogues of [Pt(NO3)(dien)]+ affects their energetics and how the alterations of this biophysical parameter are reflected by the recognition of these duplexes by DNA polymerases and the DNA repair system. We have found that the impact of the methylation of [Pt(NO3)(dien)]+ on the biophysical properties of DNA (thermodynamic, thermal, and conformational properties) and its biochemical processes (DNA polymerization and the repair of DNA adducts) is remarkable. Hence, we conclude that monodentate DNA binding of Pt(II) compounds may considerably affect the biophysical properties of DNA and consequently downstream cellular processes as a result of a large increase in the bulkiness of the nonleaving ligands in this class of metal complex.

The different antitumor and other biological effects of the third-generation antitumor platinum drug oxaliplatin [(1R,2R-diamminocyclohexane)oxalatoplatinum(II)] in comparison with those of conventional cisplatin [cis-diamminedichloridoplatinum(II)] are often explained by the ability of oxaliplatin to form DNA adducts of different conformation and consequently to exhibit different cytotoxic effects. This work describes, for the first time, the structural and biochemical characteristics of the interstrand cross-links of oxaliplatin. We find that: 1) DNA bending, unwinding, thermal destabilization, and delocalization of the conformational alteration induced by the cross-link of oxaliplatin are greater than those observed with the cross-link of cisplatin; 2) the affinity of high-mobility-group proteins (which are known to mediate the antitumor activity of platinum complexes) for the interstrand cross-links of oxaliplatin is markedly lower than for those of cisplatin; and 3) the chirality at the carrier 1,2-diaminocyclohexane ligand can affect some important structural properties of the interstrand cross-links of cisplatin analogues. Thus, the information contained in the present work is also useful for a better understanding of how the stereochemistry of the carrier amine ligands of cisplatin analogues can modulate their anticancer and mutagenic properties. The significance of this study is also reinforced by the fact that, in general, interstrand cross-links formed by various compounds of biological significance result in greater cytotoxicity than is expected for monofunctional adducts or other intrastrand DNA lesions. Therefore, we suggest that the unique properties of the interstrand cross-links of oxaliplatin are at least partly responsible for this drug's unique antitumor effects.

cis-[PtA2(nucleotide)2] complexes (A2 stands for two amines or a diamine) have been extensively investigated as model compounds for key cisplatin-DNA adducts. All cis-[metal(nucleotide/nucleoside)2] complexes with guanine and related purines characterized in the solid state thus far have the DeltaHT conformation (head-to-tail orientation of the two bases and right-handed chirality). In sharp contrast, the LambdaHT conformation (left-handed chirality) dominates in acidic and neutral aqueous solutions of cis-[PtA2(5'-GMP)2] complexes. Molecular models and solution experiments indicate that the LambdaHT conformer is stabilized by 5'-phosphate/N1H hydrogen-bond interactions between cis nucleotides with the normal anti conformation. However, this evidence, while compelling, is indirect. At last, conditions have been defined to allow crystallization of this elusive conformer. The structure obtained reveals three unique features not present in all other cis-[PtA2(nucleotide)2] solid-state structures: a LambdaHT conformation, very strong hydrogen-bond interactions between the phosphate and N1H of cis nucleotides, and a very small dihedral angle between the planes of the two guanines lying nearly perpendicular to the coordination plane. These new results indicate that, because there are no local base-base repulsions precluding the LambdaHT conformer, global forces rather than local interactions account for the predominance of the DeltaHT conformer over the LambdaHT conformer in the solid state and in both inter- and intrastrand HT crosslinks of oligonucleotides and DNA.

Extensive investigations of cis-[Pt(diA)G2] complexes (in which G = a guanine ligand; diA = a single diamine ligand) revealed the types of interactions between the two G ligands and between the G and the cis-amine substituents when diA is a diamine ligand with substituents on each nitrogen atom being a small hydrogen atom and a bulky group able to slow the rotation about the Pt-G bond. All these interactions are shown to apply also when diA = dach (1,2-diaminocyclohexane), even though this chiral primary diamine has only small N-H atoms on each side of the coordination plane. However, a slight difference in the stereochemistry of the two protons (one N-H has "quasi axial" and the other "quasi equatorial" character) is sufficient to induce a significant change in the relative stabilities of the [Pt(dach)G2] deltaHT and lambdaHT rotamers (HT = head-to-tail). The new results show that at acidic and neutral pH the induction of asymmetry from the dach ligand to the HT rotamers is governed by the G-to-G dipole-dipole interaction, which is greater for the six-membered ring of each guanine leaning towards the cis-G. Such a "six-in" canting of the two guanine ligands can be hampered by the steric interaction between the H8 of each guanine and the substituent on the cis-amine that is on the same side of the coordination plane. Such a repulsion is greater for a "quasi equatorial" N-H than for a "quasi axial" N-H. Under basic pH conditions, deprotonation of the guanine N1-H renders the O6 atom a much better hydrogen-bond acceptor; therefore, the stability of the HT rotamers is governed by the hydrogen-bond interaction of guanine O6 and the cis-amine N-H group. Such a guanine O6/N-H cis-amine interaction is stronger for a "quasi axial" than for a "quasi equatorial" N-H group. In the head-to-head (HH) rotamer, in which the electrostatic repulsion between electron-rich O6 atoms, both on the same side of the platinum coordination plane, tends to place the six-membered rings of each guanine further from the cis-guanine and closer to the cis-amine, we can expect better N-H...O6 hydrogen bonding for the "quasi equatorial" N-H groups.

The reactions of the anticancer complex trans-[PtCl(2)[(E)-HN==C(OMe)Me](2)] (trans-EE) with both single-stranded and double-stranded deoxyribonucleotides have been studied by HPLC and 2D [(1)H,(15)N] HMQC NMR spectroscopy and compared with those of cis-[PtCl(2)(NH(3))(2)] (cis-DDP). Reactions of trans-EE with the single-stranded oligonucleotides d(CCTCGCTCTC) and d(CCTGGTCC) proceed rapidly through solvolysis of the starting substrate and subsequent formation of G-N7/monochloro trans-EE adducts. The rate of reaction is comparable to that of formation of an adduct from trans-EE and the dinuclotide d(ApG). Quite unexpectedly, the double-helical duplexes, d(TATGGTACCATA)(2) and d(TATGGCCATA)(2), with no terminal G residues, are practically inert towards trans-EE, and only minor species (< 5 % as estimated from HPLC traces) appear during 24 h reaction time. However, the duplexes d[(CCTCGCTCTC). (GAGAGCGAGG)] and d(GATAGGCCTATC)(2), which contain both terminal and central G residues, undergo platination only at the terminal, solvent-exposed, G residues, thereby confirming that the interior of the duplex is not accessible to trans-EE due to steric hindrance. In contrast, cis-DDP was found to bind exclusively to the central GG pair in d(GATAGGCCTATC)(2).

The use of a sterically hindered diamine ligand (Me(4)DACH) has allowed for the first time, the isolation and characterization, both in the solid state (X-ray crystallography) and in solution (circular dichroism), of pure DeltaHT rotamers of [Pt(Me(4)dach)(5'-GMP)(2)] (compounds 1 and 2 for R,R and S,S configurations of the Me(4)DACH ligand, respectively). Comparison of the CD spectra obtained for each rotamer, which differ only in the chirality of the Me(4)DACH ligand (R,R or S,S) or in the chirality of the HT conformation (Delta or Lambda), allowed us to conclude that, in the 200-350 nm range, the contributions to the overall CD spectrum that stem from diamine chirality and diamine-induced chirality of platinum d--d transitions or from sugar chirality are negligible relative to the exciton chiral coupling that occurs for pi-pi* transitions of the cis guanines. Accurate molecular structures of 1.10 D(2)O and 2.14 D(2)O (conventional crystallographic agreement indexes R(1) convergent to 2.07 % and 2.18 %, respectively) revealed that the crystallized rotamers have a DeltaHT conformation that is in agreement with all previously reported X-ray structures of [Pt(diamine)(nucleos(t)ide)(2)] complexes. This conformation allows the 5'-phosphate to be located in proximity to the Me(4)DACH ligand so that (P)O...HC(N) hydrogen-bond interactions exists in both complexes. For both structures, the canting of the guanine planes on the coordination plane is right-handed (R; canting angle (Phi) of 80.9 degrees and 73.2 degrees, respectively); this indicates that the canting direction is driven by the HT conformation chirality (Delta for both compounds) and not by the chirality of the carrier ligand (different for the two compounds). Density functional theory analysis of the conformational space as a function of Phi indicated a good agreement between the computed and experimental structures. The increase in energy for Phi values below 65 degrees and 55 degrees (for 1 and 2, respectively) is mainly due to the short intramolecular contacts between C(8)H and the cis N-Me groups on the same side of the platinum coordination plane.