The mechanism of action of platinum(IV) complexes in ovarian cancer cell lines

The reduction potentials, lipophilicities, cellular uptake and cytotoxicity have been examined for two series of platinum(IV) complexes that yield common platinum(II) complexes on reduction: cis-[PtCl(4)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OAc)(2)(NH(3))(2)], cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)], [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)] and cis,trans-[PtCl(2)(OH)(2)(en)] (en=ethane-1,2-diamine, OAc=acetate). As previously reported, the reduction occurs most readily when the axial ligand is chloride and least readily when it is hydroxide. The en series of complexes are marginally more lipophilic than their ammine analogues. The presence of axial chloride or acetate ligands results in a slighter higher lipophilicity compared with the platinum(II) analogue whereas hydroxide ligands lead to a substantially lower lipophilicity. The cellular uptake is similar for the platinum(II) species and their analogous tetrachloro complexes, but is substantially lower for the acetato and hydroxo complexes, resulting in a correlation with the reduction potential. The activities are also correlated with the reduction potentials with the tetrachloro complexes being the most active of the platinum(IV) series and the hydroxo being the least active. These results are interpreted in terms of reduction, followed by aquation reducing the amount of efflux from the cells resulting in an increase in net uptake.     

Studies of the binding of a series of platinum(IV) complexes to plasma proteins

The platinum(IV) complexes: [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)], cis,trans-[PtCl(2)(OH)(2)(en)] and trans-[Pt(OH)(2)(ethmal)(en)], encompassing a range of reduction potentials and their platinum(II) analogue [PtCl(2)(en)], have been assayed for their protein binding ability in the presence of albumin, albumin and L-cysteine and RPMI 1640 tissue culture medium supplemented with foetal calf serum (RPMI/FCS). cis,trans-[PtCl(4)(en)] exhibited significant protein binding in all three experiments, in a similar fashion to the platinum(II) complex, presumably as a consequence of its rapid reduction. The remaining three platinum(IV) complexes displayed little if any protein binding, with the greatest amount of binding observed in the RPMI/FCS experiment. The extent of binding in the RPMI/FCS correlated with the reduction potentials of the complexes, with the most readily reduced species binding to the greatest extent.     

DNA-protein cross-linking by trans-[PtCl(2)(E-iminoether)(2)]. A concept for activation of the trans geometry in platinum antitumor complexes

The structure-pharmacological activity relationships generally accepted for antitumor platinum compounds stressed the necessity for the cis-[PtX(2)(amine)(2)] structure while the trans-[PtX(2)(amine)(2)] structure was considered inactive. However, more recently, several trans-platinum complexes have been identified which are potently toxic, antitumor-active and demonstrate activity distinct from that of conventional cisplatin (cis-[PtCl(2)(NH(3))(2)]). We have shown in the previous report that the replacement of ammine ligands by iminoether in transplatin (trans-[PtCl(2)(NH(3))(2)]) results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant antitumor activity, including activity in cisplatin-resistant tumor cells. In addition, we have also shown previously that this new trans compound (trans-[PtCl(2)(E-iminoether)(2)]) forms mainly monofunctional adducts at guanine residues on DNA, which is generally accepted to be the cellular target of platinum drugs. In order to shed light on the mechanism underlying the antitumor activity of trans-[PtCl(2)(E-iminoether)(2)] we examined oligodeoxyribonucleotide duplexes containing a single, site-specific, monofunctional adduct of this transplatin analog by the methods of molecular biophysics. The results indicate that major monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] locally distort DNA, bend the DNA axis by 21 degrees toward the minor groove, are not recognized by HMGB1 proteins and are readily removed from DNA by nucleotide excision repair (NER). In addition, the monofunctional adducts of trans-[PtCl(2)(E-iminoether)(2)] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA polymerases in vitro and to inhibit removal of this adduct from DNA by NER. It is suggested that DNA-protein ternary cross-links produced by trans-[PtCl(2)(E-iminoether)(2)] could persist considerably longer than the non-cross-linked monofunctional adducts, which would potentiate toxicity of this antitumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl(2)(E-iminoether)(2)] represents a quite new class of platinum antitumor drugs in which activation of trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism from 'classical' cisplatin and its analogs.     

DNA binding by antitumor trans-[PtCl2(NH3)(thiazole)]. Protein recognition and nucleotide excision repair of monofunctional adducts

Antitumor effects of cis-diamminedichloroplatinum(II) (cisplatin) and the clinical inactivity of its trans isomer (transplatin) have been considered a paradigm for the classical structure-activity relationships of platinum drugs. However, several new analogues of transplatin which exhibit a different spectrum of cytostatic activity including activity in tumor cells resistant to cisplatin have been recently identified. Analogues containing the planar amine ligand of the general structure trans-[PtCl(2)(NH(3))(L)], where L = planar amine, represent an example of such compounds. DNA is believed to be the major pharmacological target of platinum compounds. To contribute to the understanding of mechanisms underlying the activation of trans geometry in transplatin analogues containing planar amine ligands, various biochemical and biophysical methods were employed in previous studies to analyze the global modifications of natural DNA by trans-[PtCl(2)(NH(3))(L)]. These initial studies have revealed some unique features of the DNA binding mode of this class of platinum drugs. As the monofunctional lesions represent a significant fraction of stable adducts formed in DNA by bifunctional antitumor trans-platinum compounds with planar ligands, we analyzed in the present work short DNA duplexes containing the single, site-specific monofunctional adduct of a representative of this class of platinum drugs, antitumor trans-[PtCl(2)(NH(3))(thiazole)]. It has been shown that, in contrast to the adducts of monodentate chlorodiethylenetriamineplatinum(II) chloride or [PtCl(NH(3))(3)]Cl, the monofunctional adduct of trans-[PtCl(2)(NH(3))(thiazole)] inhibits DNA synthesis and creates a local conformational distortion similar to that produced in DNA by the major 1,2-GG intrastrand CL of cisplatin, which is considered the lesion most responsible for its anticancer activity. In addition, the monofunctional adducts of trans-[PtCl(2)(NH(3))(thiazole)] are recognized by HMGB1 domain proteins and removed by the nucleotide excision repair system similarly as the 1,2-GG intrastrand CL of cisplatin. The results of the present work further support the view that the simple chemical modification of the structure of an inactive platinum compound alters its DNA binding mode into that of an active drug and that processing of the monofunctional DNA adducts of the trans-platinum analogues in tumor cells may be similar to that of the major bifunctional adducts of "classical" cisplatin.     

The fate of platinum(II) and platinum(IV) anti-cancer agents in cancer cells and tumours

SRIXE mapping has been used to gain insight into the fate of platinum(II) and platinum(IV) complexes in cells and tumours treated with anticancer active complexes to facilitate the development of improved drugs. SRIXE maps were collected of thin sections of human ovarian (A2780) cancer cells treated with bromine containing platinum complexes, cis-[PtCl(2)(3-Brpyr)(NH(3))] (3-Brpyr=3-bromopyridine) and cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] (OAcBr=bromoacetate), or a platinum complex with an intercalator attached cis-[PtCl(2)(2-[(3-aminopropyl)amino]-9,10-anthracenedione)(NH(3))]. After 24h the complexes appear to be localised in the cell nucleus with a lower concentration in the surrounding cytoplasm. In cells treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] the concentration of bromine was substantially higher than in control cells and the bromine was co-localised with the platinum consistent with the 3-bromopyridine ligand remaining bound to the platinum. The cells treated with cis,trans,cis-[PtCl(2)(OAcBr)(2)(NH(3))(2)] also showed an increased level of bromine, but to a much lesser extent than for those treated with cis-[PtCl(2)(3-Brpyr)(NH(3))] suggestive of substantial reduction of the platinum(IV) complex. Maps were also collected from thin sections of a 4T1.2 neo 1 mammary tumour xenograft removed from a mouse 3h after treatment with cis,trans,cis-[PtCl(2)(OH)(2)(NH(3))(2)] and revealed selective uptake of platinum by one cell.     

Protein phosphatase 2A inhibition and circumvention of cisplatin cross-resistance by novel TCM-platinum anticancer agents containing demethylcantharidin

Novel TCM-platinum compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)] 1-5, derived from integrating demethylcantharidin, a modified component from a traditional Chinese medicine (TCM) with a platinum moiety, possess anticancer and protein phosphatase 2A inhibition properties. The compounds are able to circumvent cisplatin resistance by apparently targeting the DNA repair mechanism. Novel isosteric analogues [Pt(C(9)H(10)O(4))(NH(2)R)(2)] A and B, devoid of PP2A-inhibitory activity, were found to suffer from an enhanced DNA repair and were cross-resistant to cisplatin. The results advocate a well-defined structure-activity requirement associating the PP2A-inhibiting demethylcantharidin with the circumvention of cisplatin cross-resistance demonstrated by TCM-Pt compounds 1-5.     

Cooperative effects in long-range 1,4 DNA-DNA interstrand cross-links formed by polynuclear platinum complexes: an unexpected syn orientation of adenine bases outside the binding sites

The novel phase II anticancer drug BBR3464 ([[ trans-PtCl(NH(3))(2)](2)- micro -[ trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2)]](NO(3))(4)) forms a 1,4-interstrand cross-link adduct with the self-complementary DNA octamer 5'-d(ATG*TACAT)(2)-3', with the two platinum atoms coordinated in the major groove at the N7 positions of guanines that are four base pairs apart on opposite DNA strands. The "central" tetraamine linker [ trans-H(2)N(CH(2))(6)NH(2)Pt(NH(3))(2)NH(2)(CH(2))(6)NH(2)] was located in or close to the minor groove. The adduct was characterized and analyzed by MS, UV and NMR spectroscopy. NMR analysis of the adduct shows strong H8/H1' intraresidue crosspeaks observed for the A1 and A7 resonances, consistent with a syn conformation for these bases which is usually not observed for adenine residues and bases not directly involved in the cross-link in oligonucleotides. The strong intraresidue H8/H1' crosspeak is also observed for G3. Examination of the structure thus reveals unusual cooperative effects unique to this class of anticancer drugs and is the first demonstration of cooperative effects in solution for an anticancer drug. The significant characteristic of the structure is the lack of severe DNA distortion such as a kink, directed bend or significant unwinding of the helices which are characteristic for DNA adducts of mononuclear complexes. This may contribute to the lack of protein recognition of the cross-link by HMG-domain proteins, a biological consequence significantly different from that of mononuclear complexes such as cisplatin. Since DNA is the principal target in vivo for these Pt cross-linking agents, the unique structural perturbations induced by BBR3464 cross-links are likely related to its increased cytotoxicity and antitumor activity as compared to cisplatin ( cis-DDP).     

Synthesis, characterization, and cytotoxic studies of alpha-diimine/1,2-diamine platinum(II) and palladium(II) complexes of selenite and tellurite and binding of some of these complexes to DNA.

Eleven new complexes of formula [M(NN)(XO3)] (where M is Pd(II) or Pt(II); NN is 2,2'-bipyridine, 1,10-phenanthroline, 2,2'-dipyridylamine, ethylenediamine or (+-)trans-1,2-diaminocyclohexane, and XO3(2-) is SeO3(2-) or TeO3(2-)) have been synthesized. These water soluble complexes have been characterized by chemical analysis and conductivity measurements as well as ultraviolet-visible and infrared spectroscopy. In these complexes the selenite or tellurite ligand coordinates to platinum(II) or palladium(II) as bidentate with two oxygen atoms. These complexes inhibit the growth of P 388 lymphocytic leukemia cells, their targets are DNA. The selenite complexes invariably show I.D.50 values less than cisplatin. However, the I.D.50 values of the tellurite complexes are usually higher than cisplatin, except that of [Pd(dach)(TeO3)] which has comparable I.D.50 values, as compared to cisplatin. [Pt(bipy)(SeO3)] and [Pd(bipy)(SeO3)] have been interacted with calf thymus DNA and bind to DNA through a coordinate covalent bond.     

Chiral differentiation of DNA adducts formed by enantiomeric analogues of antitumor cisplatin is sequence-dependent

1,2-GG intrastrand cross-links formed in DNA by the enantiomeric complexes [PtCl(2)(R,R-2,3-diaminobutane (DAB))] and [PtCl(2)(S,S-DAB)] were studied by biophysical methods. Molecular modeling revealed that structure of the cross-links formed at the TGGT sequence was affected by repulsion between the 5'-directed methyl group of the DAB ligand and the methyl group of the 5'-thymine of the TGGT fragment. Molecular dynamics simulations of the solvated platinated duplexes and our recent structural data indicated that the adduct of [PtCl(2)(R,R-DAB)] alleviated this repulsion by unwinding the TpG step, whereas the adduct of [PtCl(2)(S,S-DAB)] avoided the unfavorable methyl-methyl interaction by decreasing the kink angle. Electrophoretic retardation measurements on DNA duplexes containing 1,2-GG intrastrand cross-links of Pt(R,R-DAB)(2+) or Pt(S,S-DAB)(2+) at a CGGA site showed that in this sequence both enantiomers distorted the double helix to the identical extent similar to that found previously for the same sequence containing the cross-links of the parent antitumor cis-Pt(NH(3))(2)(2+) (cisplatin). In addition, the adducts showed similar affinities toward the high-mobility-group box 1 proteins. Hence, whereas the structural perturbation induced in DNA by 1,2-GG intrastrand cross-links of cisplatin does not depend largely on the bases flanking the cross-links, the perturbation related to GG cross-linking by bulkier platinum diamine derivatives does.     

Preparation and cell growth inhibitory activity of [PtR(2)L(2)] (R=polyfluorophenyl,L(2)=diene,cyclohexane-1,2-diamine (chxn) or cis-(dimethyl sulfoxide)(2)) and the X-ray crystal structure of [Pt(C(6)F(5))(2)(cis-chxn)

A range of [PtR(2)(chxn)] (R=C(6)F(5), o-HC(6)F(4), p-HC(6)F(4), p-MeOC(6)F(4) or 3,5-H(2)C(6)F(3); chxn=cyclohexane-1,2-diamine) and cis-[PtR(2)(dmso)(2)] (R=C(6)F(5), p-HC(6)F(4) or p-MeOC(6)F(4); dmso=dimethyl sulfoxide) complexes have been prepared from the corresponding [PtR(2)(diene)] (diene=cis,cis-cycloocta-1,5-diene (cod), hexa-1,5-diene (hex), norbornadiene (nbd) or dicyclopentadiene (dcy)) derivatives and have been spectroscopically characterized. A representative crystal structure of [Pt(C(6)F(5))(2)(cis-chxn)] was determined and shows a slightly distorted square planar geometry for platinum with chxn virtually perpendicular to the coordination plane. The biological activity against L1210 and L1210/DDP cell lines of these compounds together with the behaviour of other organoplatinum complexes, [PtR(2)L(2)] (L(2)=ethane-1,2-diamine (en) or cis-(NH(3))(2)) have been determined. Despite the use of relatively inert fluorocarbon anions as leaving groups, moderate-high cell growth inhibitory activity is observed. None of the fluorocarbon complexes displayed any cross resistance with cisplatin.     

Preparation of platinum(II) complexes with L-serine using KI. X-ray crystal structure, HPLC and 195Pt NMR spectra

The preparation of platinum(II) complexes containing L-serine using K(2)[PtCl(4)] and KI as raw materials was undertaken. The cis-trans isomer ratio of the complexes in the reaction mixture differed significantly depending on whether KI was present or absent in the reaction mixture. One of the two [Pt(L-ser-N,O)(2)] complexes (L-ser=L-serinate anion) prepared using KI crystallizes in the monoclinic space group P2(1)2(1)2(1) with unit cell dimensions a=8.710(2) A, b=9.773(3) A, c=11.355(3) A, Z=4. The crystal data revealed that this complex has a cis configuration. The other [Pt(L-ser-N,O)(2)] complex also crystallizes in the monoclinic space group P2(1)2(1)2(1) with unit cell dimensions a=7.0190(9) A, b=7.7445(6) A, c=20.946(2) A, Z=4. The crystal data revealed that this complex has a trans configuration. The 195Pt NMR chemical shifts of trans-[Pt(L-ser-N,O)(2)] and cis-[Pt(L-ser-N,O)(2)] complexes are -1632 and -1832 ppm, respectively. 195Pt NMR and HPLC measurements were conducted to monitor the reactions of the two [Pt(L-ser-N,O)(2)] complexes with HCl. Both 195Pt NMR and HPLC showed that the reactivities of cis- and trans-[Pt(L-ser-N,O)(2)] toward HCl are different: coordinated carboxyl oxygen atoms of trans-[Pt(L-ser-N,O)(2)] were detached faster than those for cis-[Pt(L-ser-N,O)(2)].     

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 2h 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.     

Apoptosis induction and inhibition of H-ras overexpression by novel trans-[PtCl2(isopropylamine)(amine')] complexes

Hitherto, it has been generally accepted as a paradigm of the biochemical pharmacology of platinum antitumor drugs that a cis configuration of the leaving groups is necessary for antitumor activity of platinum compounds. However, it has been recently observed that certain trans-platinum complexes have both in vitro and in vivo antitumor activity. We previously reported the synthesis, characterization and cytotoxic activity against ras-transformed cells of several trans-[PtCl2LL'] complexes where L and L' are asymmetric aliphatic amines (L = dimethylamine and butylamine, L' = isopropylamine). The results reported in this paper show that the compounds trans-[PtCl2(isopropylamine)(dimethylamine)] and trans-[PtCl2(isopropylamine)(butylamine)] kill Pam 212-ras cisplatin resistant cells through apoptosis induction. Moreover, Western blot data show that both compounds inhibit overexpression of H-ras oncogene in Pam 212-ras cells. Altogether, these data indicate that, in contrast with cis-DDP, the apoptotic activity of these novel trans-Pt(II) compounds in ras-transformed cells is associated with their ability to abolish ras-overexpression.     

DNA damage induced by novel demethylcantharidin-integrated platinum anticancer complexes

Oxaliplatin is a third generation platinum (Pt) drug with a diaminocyclohexane (DACH) entity, which has recently obtained worldwide approval for the clinical treatment of colon cancer, and apparently operates by a different mechanism of action to the classical cisplatin or carboplatin. Introducing a novel dual mechanism of action is one approach in designing a new platinum-based anticancer agent, whereby an appropriate ligand, such as demethylcantharidin (DMC), is released from the parent compound to exert a cytotoxic effect, in addition to that of the DNA-alkylating function of the platinum moiety. To investigate the likelihood of a novel dual mechanism of anticancer action, demethylcantharidin-integrated Pt complexes: Pt(R,R-DACH)(DMC) with the same Pt-DACH moiety as oxaliplatin, and Pt(NH(3))(2)(DMC) akin to carboplatin; were studied for their ability to induce DNA damage in HCT116 colorectal cancer cells by an alkaline comet assay. The results showed that the DMC ligand released from the novel complexes caused additional DNA lesions when compared with oxaliplatin and carboplatin. The comet assay also revealed that the DNA-damaging behavior of cisplatin is characteristically different; and this study is the first to demonstrate the ability of DMC to induce DNA lesions, thus providing sufficient evidence to explain the superior antiproliferative effect of the novel DMC-integrated complexes.     

Sequence specificity, conformation, and recognition by HMG1 protein of major DNA interstrand cross-links of antitumor dinuclear platinum complexes

Interactions of high mobility group (HMG) domain proteins with DNA modified by cisplatin plays a role in mechanisms underlying its antitumor activity. A structural motif recognized by HMG domain proteins on cisplatin-modified DNA is a stable, directional bend of the helix axis. In the present work, bending induced in DNA by major adducts of a novel class of antitumor compounds, represented by the formula [?trans-PtCl(NH(3))(2)?H(2)N(CH(2))(2-6)NH(2)]Cl(2), was investigated. The oligodeoxyribonucleotide duplexes containing various site-specific interstrand cross-links of these bifunctional dinuclear platinum drugs were purified and characterized by Maxam-Gilbert footprinting, chemical probing, and phasing assay. It was demonstrated that the cross-links of the dinuclear compounds bent the helix much less than those of cisplatin. Gel retardation assay revealed very weak recognition of DNA adducts of dinuclear complexes by HMG1 protein. Hence, the mediation of antitumor properties of dinuclear platinum complexes by HMG domain proteins is unlikely so that polynuclear platinum compounds may represent a novel class of platinum anticancer drugs acting by a different mechanism than cisplatin and its analogues. A further understanding of how polynuclear platinum compounds modify DNA and how these modifications are processed in cells should provide a rational basis for the design of new platinum drugs rather than searching for cisplatin analogues.     

Study by HPLC-MS of the interaction of platinum antitumor complexes with potato carboxypeptidase inhibitor (PCI)

The interaction of the well-known antitumor drug cisplatin cis-[PtCl(2)(NH(3))(2)] and the compound trans-[PtCl(2)NH(3)(4-hydroxymethylpyridine)] with the small protein potato carboxypeptidase inhibitor (PCI) and a PCI mutant in which glycine-39 was substituted by methionine has been followed by HPLC/mass spectrometry. Our results showed that both Pt drugs were able to bind PCI through Met-39 and histidines in mutated PCI, whereas only the trans complex interacted significantly with wild PCI. In the cytotoxic studies, the monofunctional adduct PCI-Met-cisplatin was neither more active nor more selective than cisplatin itself when tested against three tumor cell lines with different number of EGF receptors. Those results suggested that the poor activity of the adduct could be just due to the small fraction of cisplatin which was decoordinated from the adduct and able to penetrate the tumor cells, as well as to the changes in the structure of the platinum drug after the loss of NH(3) groups upon binding PCI-Met.     

Crystal structures and cytotoxicity of isopropylamine Pt(II) complexes: a trinuclear squarato-bridged [Pt3(mu2-C4O4)3(H2NPri)6].3H2O and a mononuclear cis-[Pt(NO3)2(H2NPri)2

Crystals of a novel platinum(II) complex with squarato ligand, [Pt(3)(mu(2)-C(4)O(4))(3)(H(2)NPr(i))(6)].3H(2)O (1) (H(2)NPr(i)=ipa), have been isolated from the aqueous solution of cis-[Pt(H(2)O)(2)(H(2)NPr(i))(2)]SO(4) and barium squarate. Slow evaporation of methanol solution of cis-[Pt(NO(3))(2)(H(2)NPr(i))(2)] (2) resulted in crystallization of nitrato complex. The single crystal X-ray diffraction method was used to determine structures of 1 and 2. Complex 1 crystallizes in a triclinic space group P1 with a=11.17380(10)A, b=14.4535(2)A, c=14.8010(2)A, alpha=86.0901(10) degrees , beta=78.4343(11) degrees , gamma=69.1915(5) degrees , and complex 2 in a monoclinic space group P2(1)/n, with a=10.1161(2)A, b=9.9188(2)A, c=13.3766(2)A, beta=102.7360(7) degrees . The X-ray structure analysis revealed that three platinum atoms in 1 are connected with three squarates which adopt bis(unidentate) binding modes. The squarato ligands span relatively long intramolecular Ptcdots, three dots, centeredPt distances (4.8842(3)-5.2699(3)A). A pair of cis positioned isopropylamine ligands completes a square planar coordination sphere of each Pt(II) ion. The square-planar coordination of complex 2 consists of two cis positioned isopropylamine ligands and two nitrato ligands. The results of cytotoxicity assay of trimer 1, monomer 2 and cis-diamminedichloroplatinum(II) (cisplatin) performed on human bladder tumor cell line T24 provide evidence that complex 2 is less cytotoxic compared to cisplatin and that the survival of tumor cells after exposure to 1 was minimally reduced.     

Reactions of cisplatin hydrolytes with methionine, cysteine, and plasma ultrafiltrate studied by a combination of HPLC and NMR techniques

The reactions of cis-[PtCl(NH3)2(H2O)]+ with L-methionine have been studied by 1D 195Pt and 15N NMR, and by 2D[1H, 15N] NMR. When the platinum complex is in excess, the initial product, cis-[PtCl(NH3)2(Hmet-S)]+ undergoes slow ring closure to [Pt(NH3)2(Hmet-N,S)]2+. Slow ammine loss then occurs to give the isomer of [PtCl(NH3)(Hmet-N,S)]+ with chloride trans to sulfur. When methionine is in excess, a reaction sequence is proposed in which trans-[PtCl(NH3)(Hmet-S)2]+ isomerises to the cis-isomer, with subsequent ring closure reactions leading to cis-[Pt(Hmet-N,S)2]2+. Near pH 7, methionine is unreactive toward cis-[PtCl(OH)(NH3)2]. By contrast, L-cysteine reacts readily with cis-[PtCl(OH)(NH3)2] at pH 7, but there were many reaction products, including bridged species. Cis-[PtCl(OH)(NH3)2] reacts with reduced thiols in ultrafiltered plasma but these are oxidized if the plasma is not fresh or appropriately stored. With very low concentrations of the platinum complexes (35.5 microM), HPLC experiments (UV detection at 305 nm) indicate that the thiolate (probably cysteine) reactions become simpler as bridging becomes less important.     

Syntheses, crystal structure and cytotoxicity of diamine platinum(II) complexes containing maltol

The cationic complexes (1,2-diaminoethane)(maltolato)platinum(II) ([Pt(en)(ma)]+) and (1R,2R-1,2-diaminocyclohexane)(maltolato)platinum(II) ([Pt(R,R-DACH)(ma)]+) have been prepared and the structure of [Pt(R,R-DACH)(ma)]NO3 has been determined by single crystal X-ray diffraction. The geometry of the metal in [Pt(R,R-DACH)(ma)]NO3 is essentially square planar and the maltolate ligand has a geometry similar to other chelate complexes involving this ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and the IC50 values are approximately 32 microM in HeLa cells and 26 microM in K562 cells. In these cell lines the cytotoxicity of cisplatin is higher than the maltolate complexes by a factor of 2 to 3 whereas the cytotoxicity of carboplatin is lower than the maltolate complexes.