The influence of methionine-containing peptides on the reaction of carboplatin with 5'-guanosine monophosphate: a comparison with cisplatin

The pH- and time-dependent reaction of the anticancer drug carboplatin, [Pt(cbdca-kappa(2)O,O')(NH(3))(2)] (cbdca=cyclobutane-1,1-dicarboxylate), with the tripeptides H-glyglymet-OH (glycylglycyl-L-methionine) and Ac-glyglymet-OH at 313 K was investigated by high-performance liquid chromatography, NMR and mass spectrometry. The relative stability of the initial ring-opened kappaS complex [Pt(cbdca-kappaO)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] leads to increased formation of the kinetically favoured kappaS:kappaS' bis-adduct [Pt(Ac-glyglymet-OH-kappaS)(2)(NH(3))(2)](2+) in comparison with cisplatin. As a result a second 1:2 reaction pathway kappaS-->kappaS:kappaS'-->kappa(2)N(M), S:kappaS'-->kappa(3)N(G2),N(M), S:kappaS', where N(M) and N(G2) represent, respectively, metallated methionine and glycine nitrogen atoms, competes with the 1:1 route kappaS-->kappa(2)N(M), S-->kappa(3)N(G2),N(M), S also observed for cisplatin. Cleavage of N-acetylglycine at the backbone C(O)-N bond to the second gly residue (G2) is observed after 100 h for the respective tridentate complexes [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S) (Ac-glyglymet-OH-kappaS)] and [Pt(Ac-glyglyH(-1)metH(-1)-OH-kappa(3)N(G2),N(M), S)(NH(3))] at pH <5.2. The longevity of the initial kappaS complex leads to about an eight-fold increase in the rate of formation of the kappaN7:kappaN7' bis-adduct [Pt(5'-GMP-kappaN7)(2)(NH(3))(2)](2-) for the reaction of carboplatin with 5'-GMP(2-) at pH 7 in the presence of Ac-glyglymet-OH. A mixed-ligand kappaS:kappaN7 species [Pt(5'-GMP-kappaN7)(Ac-glyglymet-OH-kappaS)(NH(3))(2)] provides the major precursor for this 1:2 nucleotide complex and kappaN7 coordination of 5'-GMP(2-) is also observed in the kappa(2)N(M),S:kappaN7 complex [Pt(5'-GMP-kappaN7)(Ac-glyglymetH(-1)-OH-kappa(2)N(M),S)(NH(3))(2)](-) formed by substitution of the ammine ligand trans to the methionine sulphur. As the intermediate kappaS:kappaN7 species is formed rapidly within the first 10 h of reaction, these results suggest that the transfer reaction pathway kappaS-->kappaS:kappaN7-->kappaN7:kappaN7' involving kappaS platinated peptides could play an important role in accelerating the rate of DNA binding for carboplatin.     

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.     

Interaction of liposome-encapsulated cisplatin with biomolecules

We prepared liposomes by hydrating 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid with aqueous solutions of three "probe" molecules-cis-diamminedichloroplatinum(II) (cis-[Pt(II)(NH(3))(2)Cl(2)], cisplatin), guanosine 5'-monophosphate (5'-GMP), and 9-ethylguanine (9-EtG)-in phosphate-buffered saline as well as N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid buffer. The positively charged hydrolysis product of cisplatin, [Pt(II)(NH(3))(2)Cl(H(2)O)](+), is in the inner core of the liposomes and negatively charged 5'-GMP embeds in the lipid bilayer of liposomes. In the presence of cisplatin, the size of the liposomes remains unchanged, and for 5'-GMP-embedded liposomes the size increases significantly compared with that of empty or control liposomes. In contrast, the neutral biomolecule 9-EtG was found to be dispersed in the exterior bulk water and the size of the liposomes remained the same as that of empty or control liposomes. When cisplatin-containing liposomes mix with 5'-GMP-embedded liposomes or liposomes with 9-EtG, the N7 nitrogen atom of 5'-GMP or 9-EtG binds the cisplatin, thus replacing the "leaving groups" and forming a bisadduct. After 48?h of mixing, the size of the liposomes changes for the mixture of 5'-GMP-embedded liposomes and cisplatin-containing liposomes. We used (1)H and (31)P NMR spectroscopic techniques to monitor incorporation or association of cisplatin and biomolecules with liposomes and their subsequent reactions with each other. The dynamic light scattering technique provided the size distribution of the liposomes in the presence and absence of probe molecules.     

Cytotoxic effect, differentiation, inhibition of growth and theoretical calculations of an N,N-donor ligands and its platinum(II), palladium(II) and copper(II) complexes

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-carboxylic acid methyl ester (2) and the corresponding Pt(II), Pd(II) and Cu(II) complexes 3-5 have been synthesized as potential anticancer compounds, and characterized using IR, and (1)H NMR as well as mass spectrometry. The 3-D structures of the Cu(II) complexes were determined by quantum mechanic calculation DFT methodology (density functional theory). The cytotoxicity assay of the ligand and complexes has been performed on leukemia cell lines. In general, the complexes showed lower cytotoxicity than cisplatin, and the Pt(II) and Cu(II) complexes were found to be more efficient in the induction of leukemia cell death than the Pd(II) complex. Our investigations indicate that the antiproliferating activity of the Pt(II) and Cu(II) complexes was partly due to the modulation of cellular differentiation.     

Characterization of a DNA damage-recognition protein from mammalian cells that binds specifically to intrastrand d(GpG) and d(ApG) DNA adducts of the anticancer drug cisplatin

A factor has been identified in extracts from human HeLa and hamster V79 cells that retards the electrophoretic mobility of several DNA restriction fragments modified with the antitumor drug cis-diamminedichloroplatinum(II) (cisplatin). Binding of the factor to cisplatin-modified DNA was sensitive to pretreatment with proteinase K, establishing that the factor is a protein. Gel mobility shifts were observed with probes containing as few as seven Pt atoms per kilobase of duplex DNA. By competition experiments the dissociation constant, Kd, of the protein from cisplatin-modified DNA was estimated to be (1-20) X 10(-10) M. Protein binding is selective for DNA modified with cisplatin, [Pt(en)Cl2] (en, ethylenediamine), and [Pt(dach)Cl2] (dach, 1,2-diaminocyclohexane) but not with chemotherapeutically inactive trans-diamminedichloroplatinum(II) or monofunctionally coordinating [Pt(dien)Cl]Cl (dien, diethylenetriamine) complexes. The protein also does not bind to DNA containing UV-induced photoproducts. The protein binds specifically to 1,2-intrastrand d(GpG) and d(ApG) cross-links formed by cisplatin, as determined by gel mobility shifts with synthetic 110-bp duplex oligonucleotides; these modified oligomers contained five equally spaced adducts of either cis-[Pt(NH3)2d(GpG) or cis-[Pt(NH3)2d(ApG)]. Oligonucleotides containing the specific adducts cis-[Pt(NH3)2d(GpTpG)], trans-[Pt(NH3)2d(GpTpG)], or cis-[Pt(NH3)2(N3-cytosine)d(G)] were not recognized by the protein. The apparent molecular weight of the protein is 91,000, as determined by sucrose gradient centrifugation of a preparation partially purified by ammonium sulfate fractionation. Binding of the protein to platinum-modified DNA does not require cofactors but is sensitive to treatment with 5 mM MnCl2, CdCl2, CoCl2, or ZnCl2 and with 1 mM HgCl2.(ABSTRACT TRUNCATED AT 250 WORDS)     

The interaction of DNA-targeted 9-aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells

As part of an ongoing drug development programme, this paper describes the sequence specificity and time course of DNA adduct formation for a series of novel DNA-targeted analogues of cis-diaminedichloroplatinum(II) (cisplatin) (9-aminoacridine-4-carboxamide Pt complexes) in intact HeLa cells. The sequence specificity of DNA damage caused by cisplatin and analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification/polymerase stop assay. Primer extension is inhibited by a Pt-DNA adduct, and hence the sites of these lesions can be analysed on DNA sequencing gels. The repetitive alphoid DNA sequence was used as the target DNA in human cells. The 9-aminoacridine-4-carboxamide Pt complexes exhibited a markedly different sequence specificity relative to cisplatin and other analogues. The sequence specificity of the 9-aminoacridine-4-carboxamide Pt complexes is shifted away from a preference for runs of guanines. The 9-aminoacridine-4-carboxamide Pt complexes have an enhanced preference for GA dinucleotides. This is the first occasion that an altered DNA sequence specificity has been demonstrated for a cisplatin analogue in human cells. A time course of DNA damage revealed that the DNA-targeted Pt complexes, consisting of four 9-aminoacridine-4-carboxamide Pt complexes and one acridine-4-carboxamide Pt complex, damaged DNA more rapidly compared to cisplatin and non-targeted analogues. A comparison of the time taken to reach half the maximum relative intensity indicated that the DNA-targeted Pt complexes reacted approximately 4-fold faster than cisplatin and the non-targeted analogues.     

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.     

Coordination modes vs. antitumor activity: synthesis and antitumor activity of novel platinum(II) complexes of N-substituted amino dicarboxylic acids

The trans-(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of multidentate L-glutamate (Glu) and L-aspartate (Asp) were prepared and their antitumor activity was examined in relation with their coordination modes. All these complexes were obtained as a mixture of (O,O')- and (O,N)-chelate isomers due to rapid isomerization of the initially formed (O,O')-isomer to the thermodynamically more stable (O,N)-isomer. The (O,O')/(O,N)-isomeric mixture with the mole ratio of 80/20 exhibited excellent antitumor activity while the pure (O,N)-isomer was only marginally active. Therefore, in order to prevent the linkage isomerization of the active (O,O')-isomer to the inactive (O,N)-isomer, we have designed N-substituted amino dicarboxylic acids as a leaving group and prepared a new series of complexes, [Pt(dach)(RGlu)] and [Pt(dach)(RAsp)] (dach=trans-(+/-)-1,2-diaminocyclohexane; R=acetyl (Ac), propionyl (Pro), pivaloyl (Piv), carbobenzyloxy (Cbz) or phthaloyl (Phth)) and characterized by means of elemental analyses, and 1H NMR, 195Pt NMR and IR spectroscopies. The N-substituted amino dicarboxylate ligands were found to coordinate to platinum(II) ion through only the (O,O')-chelation mode, and their Pt(II) complexes were chemically stable in aqueous solution. The present Pt(II) complexes of N-substituted amino dicarboxylic acids showed excellent antitumor activity against both murine leukemia L1210 and human tumor cells. Especially, the highly hydrophobic N-phthaloylglutamate complex, [Pt(dach)(PhthGlu)], exhibited an outstanding in vitro activity (IC50=2.22 microM) on the human stomach cancer cells which are not responsive to cisplatin and carboplatin.     

Synthesis and characterization of a novel Pd(II) complex with the condensation product of 2-(diphenylphosphino)benzaldehyde and ethyl hydrazinoacetate. Cytotoxic activity of the synthesized complex and related Pd(II) and Pt(II) complexes

A new palladium(II) complex 1 of the condensation product of 2-(diphenylphosphino)benzaldehyde (dpba) and ethyl hydrazinoacetate (etha) was synthesized and characterized by elemental analyses, IR, and (1)H NMR spectroscopy. The bound ligand is a bidentate (PN chromophore), the remaining two coordination places being occupied by chloride ions in overall square planar geometry. The cytotoxic activity of the complex 1 and two related Pd(II) and Pt(II) complexes 2 and 3 was tested against a panel of four tumor cell lines. The activity of the complexes was similar to that of cisplatin, the most widely used metal-based antitumor drug. It is important to notice that complexes 2 and 3 were active to cisplatin-resistant U2-OS/Pt cells. Cell cycle alteration investigation, apoptotic assay and gelatin zymography in relation to invasion and metastasis of tumor cells, were performed with all the investigated complexes on Human cervix carcinoma (HeLa) cells. The results suggest that 1 has a similar effect to cisplatin, inducing apoptosis followed by arrest of cells in S phase of cell cycle, while 2 and 3 induce apoptosis without significant perturbations of cell cycle distribution.     

Mixed ligand complexes of platinum(II) and palladium(II) with cytokinin-derived compounds Bohemine and Olomoucine: X-ray structure of [Pt(BohH+-N7)Cl(3)].9/5H2O [Boh=6-(benzylamino)-2-[(3-(hydroxypropyl)-amino]-9-isopropylpurine,Bohemine

The new square-planar Pt(II) and Pd(II) complexes with cytokinin-derived compounds Bohemine and Olomoucine, having the formulae [Pt(BohH(+))Cl(3)].H(2)O (1), [Pt(Boh)(2)Cl(2)].3H(2)O (2), [Pt(Boh-H)Cl(H(2)O)(2)].H(2)O (3), [Pt(OloH(+))Cl(3)].H(2)O (4), [Pd(BohH(+))Cl(3)].H(2)O (5), [Pd(Boh)Cl(2)(H(2)O)] (6), [Pd(Boh-H)Cl(H(2)O)].EtOH (7) and [Pd(OloH(+))Cl(3)].H(2)O (8), where Boh=6-(benzylamino)-2-[(3-(hydroxypropyl)amino]-9-isopropylpurine and Olo=6-(benzylamino)-2-[(2-(hydroxyethyl)amino]-9-methylpurine, have been synthesized. The complexes have been characterized by elemental analyses, IR, FAB+ mass, 1H, 13C and 195Pt NMR spectra, and conductivity data. The molecular structure of the complex [Pt(BohH(+)-N7)Cl(3)].9/5H(2)O has been determined by an X-ray diffraction study. Results from physical studies show that both Bohemine and Olomoucine are coordinated to transition metals through the N(7) atom of purine ring in all the complexes. The prepared compounds have been tested in vitro for their possible cytotoxic activity against G-361 (human malignant melanoma), HOS (human osteogenic sarcoma), K-562 (human chronic myelogenous leukemia) and MCF-7 (human breast adenocarcinoma) cell lines and IC(50) values have been also determined for all the complexes. IC(50) values estimated for the Pt(II)-Bohemine complexes (2.1-16 microM) allow us to conclude that they could find utilization in antineoplastic therapy. Thus, from a pharmacological point of view, Pt(II) complexes of Bohemine may represent compounds for a new class of antitumor drugs.     

Antitumor activity of a new platinum(II) complex with low nephrotoxicity and genotoxicity

Cisplatin is an important antineoplastic agent, but dose-limiting nephrotoxicity and the occurrence of cellular resistance prevent its potential efficacy. Moreover, cisplatin is known to be carcinogenic and genotoxic in mammalian cells and this feature is of a special interest due to the risk of inducing secondary malignancies. There is a great interest in developing new platinum agents that have broad spectrum of antitumor activity and reduced toxicity. We have recently synthesized a novel platinum(II) coordination complex containing a pyridine nucleus and a dithiocarbamate moiety as ligands, [Pt(ESDT)(Py)Cl], in order to obtain an agent with more favorable therapeutic indices than cisplatin. In this study, the new platinum(II) complex was tested for its cytotoxicity, by MTT assay, on various human cancer cell lines also including different cisplatin-resistant cells endowed with different mechanisms of resistance. On human peripheral blood lymphocytes we evaluated the genotoxic potential of [Pt(ESDT)(Py)Cl] via micronuclei and SCE detection. We also performed in vivo experiments with the purpose of investigating the antitumor and nephrotoxic effects of the new platinum(II) complex. The antitumor activity was studied in ascitic or solid Ehrlich carcinoma bearing mice while nephrotoxicity was monitored in male Wistar rats by means of histopathological findings of renal specimens and of biochemical investigation on urinary parameters (GS and NAG activities and of TUP excretion) of urine samples. The results reported here indicate that [Pt(ESDT)(Py)Cl] showed a remarkable in vitro antitumor activity (with IC50 values about twofold as low as those of cisplatin), moreover, it markedly circumvented the acquired cisplatin resistance in selected human cancer cells. The analysis of the cytogenetic damage in normal cells clearly attested that the new dithiocarbamate complex, tested at equitoxic concentrations, is less genotoxic than cisplatin. Chemotherapy in Ehrlich carcinoma bearing mice with [Pt(ESDT)(Py)Cl] was significantly better tolerated than that with cisplatin. Against the ascitic tumor, [Pt(ESDT)(Py)Cl], showed an activity noticeably higher than that of cisplatin in increasing the life span of treated animals (% T/C = 190 and 129, respectively). In solid-tumor-bearing mice, [Pt(ESDT)(Py)Cl] induced a tumor size reduction very close to that observed with the reference compound. Finally, our findings obtained from the nephrotoxicity studies demonstrated [Pt(ESDT)(Py)Cl] was not nephrotoxic, contrary to cisplatin which caused a notorious acute proximal tubular damage. In summary, [Pt(ESDT)(Py)Cl] may be considered as a new platinum(II) complex with remarkable antitumor activity and low nephrotoxicity and genotoxicity compared with cisplatin.     

Synthesis,characterization and in vitro cytotoxic,mutagenic and antimicrobial activity of platinum(II) complexes with substituted benzimidazole ligands

In this study, six Pt(II) complexes bearing 5(6)-H or -CH(3)-2-phenyl or -(2'-pyridyl) or -mercaptomethylbenzimidazole ligands as 'carrier groups' were synthesized and characterized by elemental analysis, IR and (1)H-NMR spectra and evaluated for their preliminary in vitro cytotoxic activity to the human RD Rhabdomyosarcoma cell line and mutagenic properties in Salmonella typhimurium strains TA 98 and TA 100 in the absence of the S9 rat liver fraction. The preliminary test results showed that the complexes had slightly greater cytotoxic activity on the RD cell line at 1 microM concentration than cisplatin. Among the compounds tested for their mutagenicity, Pt(II) complexes of 2-(2'-pyridyl)- and 5(6)-methyl-2-(2'-pyridyl)benzimidazoles were found to be mutagenic. A comparative study of the MIC (minimum inhibitory concentration) values indicated that, in general, there were no differences between the poor antimicrobial activity values of the ligands and their Pt(II) complexes with respect to the tested microorganisms. These results suggest that the synthesized Pt(II) complexes should be considered for further antitumor activity studies.     

Cytotoxic efficacy of a novel dinuclear platinum(II) complex used with anti-MUC1 in human breast cancer cells

Mucin 1 (MUC1) is overexpressed in various cancer cells especially in breast cancer cells. There are known research works on the use of anti-MUC1 antibody with docetaxel in ovarian cancer, but there are no data about combined therapy platinum compounds with anti-MUC1 in breast cancer. The aim of the study was to evaluate the antiproliferative properties of a new dinuclear platinum(II) complex (Pt12) used with anti-MUC1 in human breast cancer cells. The dinuclear platinum(II) complex (Pt12) has been synthesized, and its cytotoxicity with anti-MUC1 has been tested in both MCF-7 and MDA-MB-231 breast cancer cells. In this study, the effects of Pt12 with anti-MUC1 on collagen and DNA biosynthesis in human breast cancer cells were compared to those evoked by cisplatin and cisplatin with anti-MUC1. The mechanism of action of Pt12 with anti-MUC1 was studied employing flow cytometry assessment of annexin V binding assay. It was found that Pt12 with anti-MUC1 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than Pt12 alone and cisplatin with anti-MUC1. Cytotoxicity of Pt12 with anti-MUC1 against breast cancer cells is due to apoptotic cell death as well as necrotic cell death. These results indicate that the use of Pt12 with anti-MUC1 may constitute a novel strategy in the chemotherapy of breast cancer tumors.     

The interaction of cisplatin and analogues with DNA in reconstituted chromatin

The influence of chromatin structure on cis-diamminedichloroplatinum(II) (cisplatin) DNA damage was investigated in a reconstituted nucleosome system. Nucleosomes were reconstituted on the somatic 5S rRNA gene from Xenopus borealis using the octamer transfer method of reconstitution. Footprinting techniques, utilising bleomycin and DNase I as the damaging agents, were employed to establish the precise location of positioned nucleosomes with respect to the DNA sequence. Reconstituted nucleosomal DNA was treated with cisplatin and drug-induced DNA adduct formation was quantitatively analysed with a polymerase stop assay using Taq DNA polymerase. A densitometric comparison of the relative damage band intensities between purified and reconstituted DNA revealed regions of relative protection corresponding to the sites of the positioned nucleosome cores. This indicated that the preferred site of cisplatin DNA binding was in the linker region of the nucleosome. Statistical analysis showed significant protection from cisplatin DNA damage in the core region of the nucleosome. Three cisplatin analogues were also investigated in this reconstituted nucleosome system. These analogues, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin), cis-dichlorobis(cyclohexylamine)platinum(II) (cis-[PtCl(2)(C(6)H(11)NH(2))(2)]) and dichloro(N-[3-[(2-aminoethyl)-amino]propyl]acridine-4-carboxamide)platinum(II) (ac-PtenCl(2)(n3)), were also found to target the linker region of the nucleosome. The latter DNA-targeted acridine-platinum complex gave rise to the most predominant footprints of all the Pt compounds tested.     

Novel C,N-chelate platinum(II) antitumor complexes bearing a lipophilic ethisterone pendant

The novel steroidal carrier ligand 17-α-[4′-ethynyl-dimethylbenzylamine]-17-β-testosterone (ET-dmba 1) and the steroid — C,N-chelate platinum(II) derivatives [Pt(ET-dmba)Cl(L)] (L = DMSO (2) and PTA (3; PTA = 1,3,5-triaza-7-phosphaadamantane)) have been prepared. Values of IC₅₀ were calculated for the new platinum complexes 2 and 3 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). At 48 h incubation time complexes 2 and 3 show very low resistance factors (RF of < 2) against an A2780 cell line which has acquired resistant to cisplatin and were more active than cisplatin (about 4-fold for 3) in T47D (AR+, AR = androgen receptor). Compound 1 retains a moderate degree of relative binding affinity (RBA = 0.94%) for androgen receptors. The cytotoxicity of the non steroidal platinum analogues [Pt(dmba)Cl(L)] (dmba = dimethylbenzylamine; L = DMSO (4) and PTA (5)) has also been studied for comparison purposes. Theoretical calculations at the BP86/def2-TZVP level of theory on complex 3 have been undertaken.     

Syntheses, Characterization, and Antitumor Activities of Platinum(II) and Palladium(II) Complexes with Sugar-Conjugated Triazole Ligands

Four platinum(II) and palladium(II) complexes with sugar-conjugated bipyridine-type triazole ligands, [Pt(II) Cl(2) (AcGlc-pyta)] (3), [Pd(II) Cl(2) (AcGlc-pyta)] (4), [Pt(II) Cl(2) (Glc-pyta)] (5), and [Pd(II) Cl(2) (Glc-pyta)] (6), were prepared and characterized by mass spectrometry, elemental analysis, (1) H- and (13) C-NMR, IR as well as UV/VIS spectroscopy, where AcGlc-pyta and Glc-pyta denote 2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (1) and 2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl β-D-glucopyranoside (2), respectively. The solid-state structure of complex 6 was determined by single-crystal X-ray-diffraction analysis. These complexes exhibited in vitro cytotoxicity against human cervix tumor cells (HeLa) though weaker than that of cisplatin.     

Shikimic acid complexes of platinum. Preparation, reactivity, and antitumor activity of (R,R-1,2-diaminocyclohexane) bis(shikimato) platinum(II). Evidence for a novel rearrangement involving platinum-carbon bond formation

The complex (R,R-1,2-diaminocyclohexane)bis(shikimato)platinum(II) (shikimato = the anion of 3R,4S,5R-trihydroxy-1-cyclohexene-1-carboxylic acid), I, has been synthesized and purified by high performance liquid chromatography (HPLC). The complex is only moderately stable in aqueous solution. Its major hydrolysis product, also purified by HPLC, is proposed to be a unique complex type in which a single shikimate group is coordinated through both the carboxylate oxygen and the C(2) vinylic carbon of the shikimate moiety [Pt(R,R-dach)(O,C-shikimato)], II. In vitro, complex I is active against L1210 leukemia and against an L1210 cell line with acquired resistance to cisplatin. In vivo, the complex is active against L1210, P388, and B16 melanoma; this activity is highly schedule-dependent. Complex II is also active against L1210 leukemia.     

Superhelical torsion controls DNA interstrand cross-linking by antitumor cis- diamminedichloroplatinum(II).

Negatively supercoiled, relaxed and linearized forms of pSP73 DNA were modified in cell-free medium by cis-diamminedichloroplatinum(II) (cisplatin). The frequency of interstrand cross-links (ICLs) formed in these DNAs has been determined by: (i) immunochemical analysis; (ii) an assay employing NaCN as a probe of DNA ICLs of cisplatin; (iii) gel electrophoresis under denaturing conditions. At low levels of the modification of DNA (<1 Pt atom fixed per 500 bp) the number of ICLs formed by cisplatin was radically enhanced in supercoiled in comparison with linearized or relaxed DNA. At these low levels of modification, the frequency of ICLs in supercoiled DNA was enhanced with increasing level of negative supercoiling or with decreasing level of modification. In addition, the replication mapping of DNA ICLs of cisplatin was consistent with these lesions being preferentially formed in negatively supercoiled DNA between guanine residues in both the 5'-d(GC)-3' and the 5'-d(CG)-3' sites. Among the DNA adducts of cisplatin the ICL has the markedly greatest capability to unwind the double helix. We suggest that the formation of ICLs of cisplatin is thermodynamically more favored in negatively supercoiled DNA owing mainly to the relaxation of supercoils.     

Structural characterization, kinetic studies, and in vitro biological activity of new cis-diamminebis-cholylglycinate(O,O') Pt(II) and cis-diamminebis-ursodeoxycholate(O,O') Pt(II) complexes

The complexes cis-diamminebis-cholylglycinate (O,O') [Pt(II) C(52)H(90)N(4)O(12)Pt, for convenience referred to as Bamet-R1] and cis-diamminebis-ursodeoxycholate (O,O') Pt(II) (C(48)H(84)N(2)O(8)Pt, Bamet-UD2) were prepared. The structural integrity of the compounds was confirmed by elemental analysis, FT-IR, NMR, FAB-MS, and UV spectroscopies. The kinetic study of both compounds was accomplished by combining the conductivity measurement and those of the analysis of the electronic spectra in aqueous solution for NaCl concentrations of 4 mM (similar to cytoplasmatic concentration), 150 mM (similar to plasmatic concentration), and 500 mM. In water, the compound Bamet-R1 showed a half-life, t(1/2), of 3.0 h. This compound forms the chelate species through loss of a ligand, and the other one acts as a bidentate ligand. Ring opening in the presence of chloride ion was produced with a k(Cl)()-of 0.25 M(-)(1) h(-)(1). The half-life of Bamet-UD2 in aqueous solution was 3.2 h. However, since this species is not able to chelate and has a lower degree of solubility in the presence of chloride ion, its kinetic behavior was very different from that of the other compound. We consider this to be of great interest with regards to its cytostatic activity. All kinetic measurements were performed under pseudo-first-order conditions, and a pseudo-first-order behavior was found. The antitumoral effect of Bamet-UD2 on several cell lines derived from rat hepatoma, human hepatoma, mouse leukemia, and human colon carcinoma was found to be, in general, similar to that of cisplatin, but higher than that observed for Bamet-R1.