Trans-platinum Complexes Research Articles

Methionine Can Favor DNA Platination by trans‐Coordinated Platinum Antitumor Drugs

Cisplatin (cis-DDP) and its cis-coordinated analogues, carboplatin and oxaliplatin, have been successfully used in the treatment of testicular and other solid tumors, but applications are restricted by side effects and intrinsic and acquired resistances. The discovery of trans-coordinated platinum complexes with antitumor activity provides a novel approach for cancer chemotherapy. Among several types of transplatinum complexes, trans-[PtCl2{E-HN=C(OCH3)CH3}2] (trans-EE) raised particular interest because of its higher cytotoxicity than the cis isomer and its activity towards several cis-DDP-resistant tumor cells. Mechanistic studies indicated that trans-EE has different DNA binding modes relative to cis-DDP, although their reaction rates were similar. DNAmodified by trans-EE could not be recognized by high-mobility group (HMG), the protein that interferes with DNA repair of cis-DDP adducts, whereas histone H1 could bind to trans-EE-modified DNA and prevent DNA polymerization and repair. A recent study also indicated that methionine was the preferable binding site of trans-EE in the reaction with cytochrome c, and different binding modes were observed between cisand trans-platinum complexes. Many cellular molecules, including proteins, peptides, and also some small molecules, can play significant roles in the functioning of and resistance to drugs, such as DNA platination, drug transport, and efflux. Sulfur-containing proteins are of special interest because of their high affinity for platinum, their abundance (e.g. albumin), and their involvement in metal-ion transport (e.g. the copper transporter protein CTR1, which contains methionine-rich extracellular motifs and appears to be involved in platinum-drug transport through the cell membrane). Kinetic studies indicated that the S platination of l-methionine (Met) or Nacetyl-l-methionine (AcMet) was kinetically preferred, whereas N7 coordination of guanine was thermodynamically favored. Studies using the model compound [PtCl(dien)] showed that the migration of platinum from S-Met to N7guanine (G–N7) was fairly slow (t1/2= 21–147 h at 310 K depending on DNA sequence), which was obviously slower than the direct DNA platination by [PtCl(dien)]. Although Met could slightly increase the rate of platination of cis-DDP to guanosine monophosphate (GMP), the reaction with synthetic DNA showed that the presence of Met actually inhibited platination on both single strand (ss) and double strand (ds) DNA. Herein we show that the platination rates of both GMP and DNA are substantially enhanced by a Met ligand bound to trans-EE. Moreover the reaction is highly pH-dependent. This enhancement has been observed for all nucleotides used in this work, including monomeric GMP, synthetic ssand dsDNA, and natural DNA. It has been observed that the formation of a Met intermediate is about seven times faster than G–N7 platination (Figure S1 in the Supporting Information). Accordingly, DNA platination is significantly faster via a Met intermediate (Scheme 1). On the basis of activity studies and the formation of this type of adducts also in the cellular system, it is suggested that the mechanism of trans-EE could differ substantially from that of conventional cisplatinum compounds.

The role of p53 in the cellular toxicity by active trans-platinum complexes containing isopropylamine and hydroxymethylpyridine

Despite some initial research that reported a lack of activity of trans geometry, complexes with general formula trans-[PtCl 2(L)(L′)] exhibit an important cytotoxic activity in cisplatin-sensitive and resistant cell lines. Based on the proposed mechanism of action for the trans-platinum compounds, they might form DNA adducts initiating a DNA-damage response and ultimately ending in the activation of the p53 protein. In the present work, we have studied the biochemical properties of the trans-[PtCl 2(isopropylamine)(L)] complexes (where L is 3- or 4-(hydroxymethyl)-pyridine) against several cell lines and the relationship between cytotoxicity and the protein p53. Both complexes showed different antitumoral properties depending on the presence or absence of protein p53 in isogenic colon carcinoma HCT116 cell lines. Cell cycle studies with the complexes in these cell lines were performed to investigate their antitumoral activity. Apoptosis was observed to be launched from G1 or G2/M accumulations. Confocal microscopy showed the different behaviour of isogenic tumoral cell lines treated with the trans-platinum complexes. Our data suggest that small differences in the carrier ligands could play an important role in the overall biological effects. The body of the research regarding structure–activity relationships such as the different position of groups in the carrier ligands will provide new rational basis for the design of new platinum antitumor drugs.

Synthesis, characterization, DNA interaction studies and anticancer activity of platinum–clotrimazole complexes

New trans-platinum complexes of clotrimazole (CTZ) have been prepared and characterized. Their interaction with DNA and activity against tumour cell lines were evaluated. [Pt (CTZ)2I2] (1) was synthesized by the reaction of K2PtCl4, KI and CTZ, and [Pt(CTZ)2Cl2] (2) by direct reaction of K2PtCl4 with CTZ. These complexes were characterized by a combination of elemental analysis, molar conductivity, UV–Vis, IR, and NMR spectroscopy in one and two dimensions. DNA–platinum complex interactions were studied by spectroscopic, thermal denaturation and viscosity titration measurements. Covalent interaction studies were also performed. From these results we suggest that complexes 1 and 2 interact with the minor groove of DNA. Both complexes showed growth inhibitory effects on four out of the six tumour cells lines with GI50 (50% growth inhibition) values in the 5–25 μM range, but there was no indication of cytotoxicity over the range of concentrations tested.

Solution Behaviour and Biomolecular Interactions of Two Cytotoxic trans‐Platinum(II) Complexes Bearing Aliphatic Amine Ligands

A novel trans-platinum(II) complex bearing one dimethylamine (dma) and one methylamine (ma) ligand, namely trans-[PtCl(2)(dma)(ma)], recently synthesised and characterised in our laboratory, displayed relevant antiproliferative properties in vitro, being more active than the parent complex, trans-[PtCl(2)(dma)(ipa)], which has isopropylamine (ipa) in place of methylamine. We have analysed comparatively the solution behaviour of these two complexes under various experimental conditions, and investigated their reactivity with horse heart cytochrome c by mass spectrometry, inductively coupled plasma-optical emission spectroscopy (ICP-OES), 2D [(1)H,(15)N],[(1)H,(13)C] HSQC and [(1)H,(1)H] NOESY NMR. Some important changes that occurred in the [(1)H,(13)C] HSQC NMR spectrum of cytochrome c treated with trans-[PtCl(2)(dma)(ma)] in water, after two days' incubation, most probably arose from direct platinum coordination to the protein side chain; this was proved conclusively by [(1)H,(1)H] NOESY NMR and [(1)H,(15)N] HSQC NMR measurements. Met65 was identified as the primary Pt binding site on cytochrome c. Electrospray mass spectrometry (ESIMS) results provided evidence for extensive platinum-protein adduct formation. A fragment of the [Pt(amine)(amine')] type was established to be primarily responsible for protein metalation. ICP-OES analysis revealed that these trans-platinum(II) complexes bind preferentially to the serum proteins albumin and transferrin rather than to calf thymus DNA. Pt binding to DNA was found to be far lower than in the case of cisplatin. The implications of the results for the mechanism of action of novel cytotoxic trans-platinum complexes are discussed.

Strategies to Improve the Efficacy of Platinum Compounds

Platinum drugs are widely used in antitumour therapy and are a cornerstone of the treatment of different solid tumours. The pharmacological interest of cisplatin has led to the design of many analogues to broaden the spectrum of activity, reduce side effects, and overcome resistance. Although the cis configuration was initially identified as the only active one, trans-platinum complexes have shown significant antitumour activity in preclinical models. In addition to mononuclear platinum compounds, multinuclear platinum complexes have been generated that are characterised by a different mode of interaction with DNA. Since a major limitation to the clinical efficacy of platinum compounds is drug resistance, the most important feature of nonconventional platinum drugs should be the capability of overcoming cellular resistance. However, due to the multifactorial nature of clinical resistance, which also involves pharmacological factors, the optimisation of current platinum-based therapy also includes the development of drug delivery approaches. The present review focuses on recent studies on the molecular alterations of tumour cells that are associated with resistance to platinum drugs, the development of novel platinum drugs, and approaches that may contribute to improve the efficacy of platinum-based therapy.

Fluorescent analogues of quinoline reveal amine ligand loss from cis and trans platinum(II) complexes in cancer cells

Analogues of cytotoxic cis and trans dichloridoplatinum(II) complexes with one ammonia and one aromatic amine (cis- and trans-[PtCl(2)(aromatic amine)(NH(3))]) were synthesised in which the aromatic group was replaced by the fluorescent ligand 7-azaindole (1). Coordination resulted in almost complete quenching of the fluorescence and the ligand had a effect on the biological activities of the cis and trans isomers similar to that previously reported for aromatic amines as is exemplified by them having similar cytotoxicities (IC(50) 3.6(5) and 6.0(19)microM, respectively). Observation of fluorescence following treatment of the cis complex with cysteine, glutathione, or methionine suggests labilisation and subsequent loss of the putative non-leaving group ligands. No such effect was observed for the trans complex which does not experience trans labilisation. Two-photon excitation of cells that had been treated with the complexes gave rise to observable fluorescence, suggesting ligand displacement for both complexes. The fluorescence appears to be localised in the lysosomes or late endosomes. These complexes are excellent models of analogues of cytotoxic cis and trans complexes with aromatic amine ligands and can be used to study the metabolism of the non-leaving group positions.

Theoretical study of ammonia nucleophilic addition to nitriles in platinum complexes

The mechanism of the reaction of the ammonia nucleophilic addition to nitriles RC≡N, both free and activated in the platinum complex trans-[PtCl2(N≡CCH3)2], was studied in detail by theoretical quantumchemical methods. The reaction resulting in the formation of free or coordinated amidines proceeds through consecutive formation of an orientation complex, a six-membered cyclic transition state, and a final reaction product, in which an amidine is in the E-configuration. Water containing in a solvent plays a role of a promoter of this process. The activation effect is interpreted from the viewpoint of both kinetic and thermodynamic factors. It was shown that the mechanism of the reaction product E-Z-isomerization includes the deprotonation of the amino-group nitrogen atom, the change of the coordinated ligand conformation, and the protonation of the nitrogen atom.

Synthesis, cytotoxicity and cucurbituril binding of triamine linked dinuclear platinum complexes

The platinum complexes trans-[{PtCl(NH3)2}2(micro-NH2(CH2)3NH2(CH2)3NH2)]3+ (CT033) and the corresponding N4-dimethyl linked analogue trans-[{PtCl(NH3)2}2(micro-NH2(CH2)3N(Me)2(CH2)3NH2)]3+ (CT233) have been synthesised, and their cytotoxicity, ability to bind cucurbit[7,8]uril (Q[7,8]) and reaction with cysteine studied. Both platinum complexes show good activity in the L1210 cell line and maintain their activity in the corresponding cisplatin L1210/DDP cell line. However, the N4-dimethyl analogue CT233 is approximately 50-times less active than the CT033 complex. This suggests that the insertion of a positive charge into the linking ligand may not, per se, be responsible for the higher cytotoxicity generally observed for dinuclear platinum complexes linked by polyamines. The upfield shifts of the resonances from the methylene protons in the linking triamine ligand observed in the 1H NMR spectra of either CT033 and CT233 upon addition of either Q[7] or Q[8] indicate that the cucurbituril is positioned over the linking ligand. However, the results show that the protonated secondary amine in CT033 acts as a barrier to encapsulation, with the Q[7,8] being positioned over only one propyl-arm at a time. Alternatively, the entire triamine linking ligand of CT233 is fully encapsulated within the Q[7,8] cavity. Encapsulation by Q[7,8] was found to reduce the rate of reaction of CT033 and CT233 with the thiol containing amino acid cysteine, with a greater rate reduction observed for CT233. These results are consistent with the NMR results of the Q[7,8] binding studies of the two platinum complexes. For CT033 encapsulated in Q[7,8], one of the two platinum centres is completely exposed to the solvent, whereas, for CT233 both platinum centres are simultaneously positioned within the portals of the cucurbit[n]uril, thereby, affording greater protection.

Synthesis, structures and in vitro cytotoxicity of some platinum(II) complexes containing thiocarbamate esters

The thiocarbamate esters 4-RC6H4NHC(S)OMe (R=H, Cl, OMe, NO2, Me) react with cis-[PtCl2(PTA)2] (PTA=1,3,5-triaza-7-phosphaadamantane) in the presence of base to afford the platinum(II) complexes trans-[Pt{SC(OMe)NC6H4R}2(PTA)2] (R=H, Cl, OMe, NO2, Me) in high yields. The complexes were fully characterised spectroscopically and, in case of the NO2 derivate, by X-ray crystallography. Cytotoxicity of these complexes was studied in vitro in four human cancer cell lines (CH1, HT29, A549, SK-OV-3) using the MTT assay. The results show that the Cl substituted derivate is the most potent of these compounds in vitro. Moreover, this derivative is capable of partially circumventing primary cisplatin resistance in ovarian and colon carcinoma cells.

Current Status and Future Perspectives of Platinum Antitumor Drugs

Cisplatin, a simple inorganic compound, has been one of the leading antitumor drugs for near 30 years. However, cisplatin has several drawbacks such as toxicity and drug resistance. Therefore, much attention has been focused on the development of new platinum complexes with improved pharmacological properties and a broader spectrum of activity to tumors. The recent advance of research on the molecular mechanisms of drug action and the cellular mechanisms of the emergence of resistance to cisplatin assists the rational design of new classes of platinum antitumor drugs, though details of both mechanisms still remain elusive. Information on DNA binding mode of platinum complexes, recognition and repair of DNA damage is instructive. Since several not cis isomers but trans isomers and not neutral complexes but cation complexes have been found active in vitro and in vivo, the early empirical structure-activity relationships of cisplatin analogues should be reevaluated. The hypothesis that platinum complexes which bind to DNA in a different manner will have different pharmacological properties has been tested, and now cationic multi-nuclear complexes and even trans-platinum complexes comprise unique classes of antitumor platinum-based agents with chemical and biological properties different from cisplatin. These new type platinum complexes are often effective to acquired cisplatin resistant tumor cells. In conclusion, the following complexes appear to offer great potential as new antitumor agents: (1) Complexes with distinctively different DNA interaction modes from cisplatin, which may circumvent intrinsic and acquired resistance to cisplatin through eluding the vigilance of DNA repair systems and (2) complexes with different tissue distribution or mechanisms of membrane transport which may exhibit a different spectrum of activity.

Supramolecular Nanoencapsulation as a Tool: Solubilization of the Anticancer Drugtrans-Dichloro(dipyridine)platinum(II) by Complexation with β-Cyclodextrin

A novel, water-soluble trans-platinum complex was synthesized by inclusion complexation with beta-cyclodextrin. The complexation was confirmed by (1)H NMR, FT-IR, TGA, and XRD as well as by SEM and EDX. As the precursor complex is not water-soluble, it is difficult to employ it for biological applications. Here, we report that the encapsulation with cyclodextrin allowed to solubilize the complex to a solubility value of 1.6 mg/mL. Moreover, the cytotoxicity in vitro of the novel inclusion complex indicated a much higher activity after encapsulation.

Examination of Cucurbit[7]uril and Its Host−Guest Complexes by Diffusion Nuclear Magnetic Resonance

The self-diffusion of cucurbit[7]uril (CB[7]) and its host-guest complexes in D2O has been examined using pulsed gradient spin-echo nuclear magnetic resonance spectroscopy. CB[7] diffuses freely at a concentration of 2 mM with a diffusion coefficient (D) of 3.07 x 10(-10) m(2) s(-1). At saturation (3.7 mM), CB[7] diffuses more slowly (D = 2.82 x 10(-10) m(2) s(-1)) indicating that it partially self-associates. At concentrations between 2 and 200 mM, CsCl has no effect on the diffusion coefficient of CB[7] (1 mM). Conversely, CB[7] (2 mM) significantly affects the diffusion of 133Cs+ (1 mM), decreasing its diffusion coefficient from 1.86 to 0.83 x 10(-9) m(2) s(-1). Similar changes in the rate of diffusion of other alkali earth metal cations are observed upon the addition of CB[7]. The diffusion coefficient of 23Na+ changes from 1.26 to 0.90 x 10(-9) m(2) s(-1) and 7Li+ changes from 3.40 to 3.07 x 10(-9) m(2) s(-1). In most cases, encapsulation of a variety of inorganic and organic guests within CB[7] decreases their rates of diffusion in D2O. For instance, the diffusion coefficient of the dinuclear platinum complex trans-[[PtCl(NH3)2}2mu-dpzm](2+) (where dpzm is 4,4'-dipyrazolylmethane) decreases from 4.88 to 2.95 x 10(-10) m(2) s(-1) upon encapsulation with an equimolar concentration of CB[7].

Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine

Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.

Competitive Aryl−Iodide vs Aryl−Aryl Reductive Elimination Reactions in Pt(IV) Complexes: Experimental and Theoretical Studies

The platinum(IV) complex trans-(dmpe)Pt(IV)(Ar)2I2 (2, dmpe = 1,2-dimethylphosphinoethane, Ar = 4-FC6H4) rapidly reacts, upon moderate heating in solution under ambient light, via two distinct pathways: isomerization to the corresponding cis-isomer (3) and Ar-I reductive elimination to give (dmpe)Pt(II)(Ar)I (4). Complex 3 undergoes, upon prolonged heating at high temperatures, an exclusive Ar-Ar reductive elimination reaction to give (dmpe)Pt(II)I2. Experimental and DFT studies showed that the 2-to-3 isomerization proceeds via three pathways: photochemical or thermal phosphine chelate opening and a mechanism involving cleavage of the Pt-I bond. The isomerization reaction is significantly slowed down but not stopped in the absence of light or in the presence of an excess of tetra-n-butylammonium iodide. On the other hand, the Ar-I reductive elimination from 2 proceeds via the Pt(delta+)-I(delta-) ion pairlike transition state. Use of the rigid dmpe analogue 1,2-dimethylphosphinobenzene (dmpbz) as the ligand shuts down the chelate ring-opening isomerization pathway and enables faster Ar-I reductive elimination thus making the latter reaction the major reaction route for the dmpbz supported trans-diiodo Pt(IV) complex 8.

Cisplatinum and Transplatinum Complexes with Benzyliminoether Ligands; Synthesis, Characterization, Structure−Activity Relationships, and In Vitro and In Vivo Antitumor Efficacy

New benzyliminoether derivatives [PtCl2{N(H)=C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques, and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor models, as measured by prolonged survival and reduced tumor mass compared to control groups.

Trans-platinum(II) complexes with cyclohexylamine as expectator ligand induce necrosis in tumour cells by inhibiting DNA synthesis and RNA transcription

Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts. We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin. In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation. In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism.

Genotoxicity of novel trans-platinum(II) complex with diethyl (pyridin-4-ylmethyl)phosphate in human non-small cell lung cancer cells A549

The dynamic development of metal-containing anticancer drugs has started since the discovery of cis-diamminedichloroplatinum(II). For many years it was believed that trans platinum(II) compounds were non-active as antitumour agents because trans-diamminedichloroplatinum is biologically inactive although it binds to DNA and also forms monoadducts and cross-links. In the present work the ability of a novel platinum(II) compound trans-[PtCl 2(4-pmOpe) 2] to induce DNA damage in human non-small cell lung cancer cells A549 was examined using the alkaline comet assay. The obtained results revealed that the novel trans platinum(II) complex induced DNA strand breaks, which were effectively repaired during 2 h of post-incubation, and cross-links which remained unrepaired under these test conditions. Apart from that, the modified comet assay with incubation with proteinase K was used to verify the ability of trans-[PtCl 2(4-pmOpe) 2] and cis-DDP to form DNA–protein cross-links. It has been proved that only trans-[PtCl 2(4-pmOpe) 2] complex exhibits the ability to induce DNA–protein cross-links. The results suggest a different mechanism of action of this compound in comparison to cis-DDP. It seems that trans geometry and the presence of two diethyl (pyridin-4-ylmethyl)phosphates as non-leaving ligands can determine dissimilar properties of the adducts formed on DNA and the different mechanism of action of trans-[PtCl 2(4-pmOpe) 2] and in consequence the efficacy in killing cancer cells.

DNA interactions of new cytotoxic tetrafunctional dinuclear platinum complex trans, trans-[{PtCl 2(NH 3)} 2(piperazine)

A new tetrafunctional dinuclear platinum complex trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] with sterically rigid linking group was designed, synthesized and characterized. In this novel molecule, the DNA-binding features of two classes of the platinum compounds with proven antitumor activity are combined, namely trans oriented bifunctional mononuclear platinum complexes with a heterocyclic ligand and polynuclear platinum complexes. DNA-binding mode of this new complex was analyzed by various methods of molecular biology and biophysics. The complex coordinates DNA in a unique way and interstrand and intrastrand cross-links are the predominant lesions formed in DNA in cell-free media and in absence of proteins. An intriguing aspect of trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] is that, using a semi-rigid linker, interstrand cross-linking is diminished relative to other dinuclear platinum complexes with flexible linking groups and lesions that span several base pairs, such as tri- and tetrafunctional adducts, become unlikely. In addition, in contrast to the inability of trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] to cross-link two DNA duplexes, the results of the present work convincingly demonstrate that this dinuclear platinum complex forms specific DNA lesions which can efficiently cross-link proteins to DNA. The results substantiate the view that trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] or its analogues could be used as a tool for studies of DNA properties and their interactions or as a potential antitumor agent. The latter view is also corroborated by the observation that trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] is a more effective cytotoxic agent than cisplatin against human tumor ovarian cell lines.

Trans-Platinum Complexes in Cancer Therapy

The research of new platinum drugs active towards cisplatin refractory/resistant tumors has been mostly focussed on compounds with cis geometry because transplatin, the trans-isomer of cisplatin, is inactive. It is widely accepted that transplatin inactivity stems from two major factors: i) the kinetic instability promoting its deactivation and ii) the formation of DNA adducts characterized by a regioselectivity and a stereochemistry different from those of cisplatin. However, several exceptions to the general rule that the presence of two leaving groups in cis positions is necessary for antitumor activity of platinum complexes, have been reported. Substitution of transplatin ammine ligands by aromatic N-donor heterocycles, branched aliphatic amines, or imino ligands has lead to compounds with relevant in vitro tumor cell growth inhibitory potency, often active towards cisplatin refractory/resistant tumor cells, and in some cases endowed with significant activity also in vivo. From a mechanistic point of view, substitution of bulky ligands for ammines can retard substitution of the two chloride ligands, thus reducing the kinetic instability of the trans-platinum compounds. On the other hand, the formation of DNA adducts qualitatively and quantitatively different from those of cisplatin strongly supports the hypothesis that antitumor-active trans-platinum complexes can have a different spectrum of activity. It is hoped that the increasing knowledge of the biochemical and cellular processes underlying the antitumor-activity of trans-platinum complexes will foster their clinical development.

Regioselective addition of bifunctional oximehydroxamic acid by the hydroxamic group to Pt(IV)-coordinated nitriles

The metal-mediated coupling between the nitriles RCN in the platinum(IV) complexes trans-[PtCl4(RCN)2] (RMe, Et, CH2Ph, Ph), cis/trans-[PtCl4(MeCN)(Me2SO)] and the newly synthesized bifunctional oximehydroxamic acid, viz. N,2-dihydroxy-5-(1-hydroxyiminoethyl)benzamide, proceeds smoothly in CH2Cl2 at 40–45°C to accomplish the new metallaligands HNC(R)ONHC(O)C6H3(2-OH)(5-C(Me)NOH) with pendant oxime functionalities due to the regioselective addition of the reagent via its hydroxamic groups. The obtained iminoligands exist in hydroxamic/hydroximic tautomeric equilibrium in solution. The structures of the isolated compounds are based on elemental analyses (C, H, N), IR, 1D 1H, 13C{1H}, and 2D NMR correlation experiments, i.e. 1H,13C-COSY, 1H,13C long range COSY, 1H,15N-COSY, and 1H,15N long range COSY.