Preparation,characterization, and antitumor activity of new cisplatin analogues with 1-methyl-4-(methylamino)piperidine: crystal structure of [PtII(1-methyl-4-(methylamino) piperidine)(oxalate)

A series of new platinum(II) complexes of the type [Pt(II)(mmap)X] (where mmap, 1-methyl-4-(methylamino)piperidine and X, 1,1-cyclobutanedicarboxylato (CBDCA), oxalato, malonato, methylmalonato, dimethylmalonato, ethylmalonato, diethylmalonato or 2,3-naphthalene dicarboxylato (NDCA)) have been synthesized and characterized by elemental analysis, infrared (IR), and 13C and 195Pt nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the analogue [Pt(II)(mmap)(oxalate)] was determined using the single crystal X-ray diffraction method. Based upon a total of 4964 collected reflections, we determined that the compound crystallizes in the monoclinic space group P2(1)/c (with a=11.890(2) A, b=9.6695(19) A, c=9.875(2) A, beta=102.03(3) degrees, Z=4, and R=0.0428). In this complex, platinum has a slightly distorted square planar geometry with the two adjacent corners being occupied by two nitrogen atoms of the mmap ligand, whereas the remaining cis positions are occupied by two oxygen atoms of the oxalate molecule. The mmap ligand is in a boat conformation and forms six-membered chelating rings as well as the oxalate molecule forms five-membered chelating rings with platinum. The complexes were evaluated for their cytotoxic potential against the sensitive A2780 tumor model and cisplatin-resistant clone derived in vitro from potential cells.     

Model platinum nucleobase and nucleoside complexes and antitumor activity: X-ray crystal structure of [PtIV(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-ethylguanine)Cl]NO3.H2O

A series of platinum(II) and (IV) monoadducts of the type [Pt(II)(DACH)LCl]NO3 and [Pt(IV)(DACH)trans-(X)2LCl]NO3 (where DACH=trans-1R,2R-diaminocyclohexane, L=adenine, guanine, hypoxanthine, cytosine, adenosine, guanosine, inosine, cytidine, 9-ethylguanine (9-EtGua), or 1-methylcytosine and X=hydroxo or acetato ligand) have been synthesized and characterized by elemental analysis and by 1H and 195Pt nuclear magnetic resonance (NMR) spectroscopy. The crystal structure of the model nucleobase complex [Pt(IV)(trans-1R,2R-diaminocyclohexane)trans-(acetate)2(9-EtGua)Cl]NO3.H2O was determined using a single crystal X-ray diffraction method. The compound crystallized in the monoclinic space group P2(1), with a=10.446(2) A, b=22.906(5) A, c=10.978(2) A, Z=4, and R=0.0718, based upon the total of 11,724 collected reflections. In this complex, platinum had a slightly distorted octahedron geometry owing to the presence of a geometrically strained five-member ring. The two adjacent corners of the platinum plane were occupied by the two amino nitrogen of DACH, whereas, the other two equatorial positions occupied by chloride ion and 9-ethylguanine. The remaining two axial positions were occupied by the oxygen atoms of acetato ligands. The DACH ring was in a chair configuration. An intricate network of intermolecular hydrogen bonds held the crystal lattice together. Some of these synthesized models of DACH-Pt-DNA adducts have good in vitro cytotoxic activity against the cisplatin-sensitive human cancer ovarian A2780 cell line (IC50=1-8 microM). Interestingly, a substituted nucleobase (9-ethylguanine) adduct was over 6-fold more potent than regular adducts. The cross-resistance factor against the 44-fold cisplatin-resistant 2780CP/clone 16 cells was about 3-9; thus, the cytotoxicity of adducts was indicative of low potency, but the resistance factors were also substantially low. These results suggest that DNA adducts of DACH-Pt are cytotoxic with low cross-resistance.     

Palladium and platinum 3,5-diacetyl-1,2,4-triazol bis(thiosemicarbazones): chemistry, cytotoxic activity and structure-activity relationships

The preparation of platinum(II) complexes derived from 3,5-diacetyl-1,2,4-triazol bis(4-phenylthiosemicarbazone) (H(5)L(1)), 3,5-diacetyl-1,2,4-triazol bis(thiosemicarbazone) (H(7)L(2)), 3,5-diacetyl-1,2,4-triazol bis(4-methylthiosemicarbazone) (H(5)L(3)) and 3,5-diacetyl-1,2,4-triazol bis(4-ethylthiosemicarbazone) (H(5)L(3)) is described. The new complexes [Pt(mu-H(3)L(1))](2), [Pt(mu-H(5)L(2))](2), [Pt(mu-H(3)L(3))](2) and [Pt(mu-H(3)L(4))](2) have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB(+)) and spectroscopic studies. The crystal and molecular structure of compounds [Pt(mu-H(3)L(1))](2), parent ligand H(5)L(1) and [Pt(mu-H(3)L(3))](2) have been determined by single crystal X-ray diffraction. The ligands coordinate, in a dideprotonate form to the platinum ions in a new tridentate fashion (NNS) and S-brigding bonding modes. Thus the molecular units of the platinum complexes are stacked as dimers. The testing of the cytotoxic activity of the synthesized compounds together with their palladium analogues against human A2780 and A2780cisR epithelial ovarian carcinoma cells lines suggests that the compounds may be endowed with important antitumor properties since they show IC(50) values in a micromolar range similar to those of cisplatin. The structure and antitumor activity relationships of platinum and palladium complexes are also discussed.     

Synthesis, characterization and cytotoxicity of new platinum(IV) axial carboxylate complexes: crystal structure of potential antitumor agent [PtIV(trans-1R,2R-diaminocyclohexane)trans(acetate)2Cl2

A series of new platinum(IV) complexes of the type [PtIV(DACH)trans(L)2Cl2] (where DACH = trans-1R,2R-diaminocyclohexane, and L = acetate, propionate, butyrate, valerate, hexanoate, or heptanoate) bearing the carboxylate groups in the axial positions have been synthesized and characterized by elemental analysis, IR, and 195Pt NMR spectroscopy. The crystal structure of the analogue [PtIV(DACH)trans(acetate)2Cl2] was determined by single crystal X-ray diffraction method. There were two crystallographically independent molecules, both of which lie on crystallographic two-fold axes. The bond lengths and bond angles of both the molecules were the same within the experimental error. The compound crystallizes in the monoclinic space group C2, with a = 11.180(2) A, b = 14.736(3) A, c = 10.644(2) A, beta = 112.38(3) degrees, Z = 4 and R = 0.0336, based upon a total of 1648 collected reflections. In this complex, the platinum had a slightly distorted octahedron geometry owing to the presence of a geometrically strained five-member ring. The two adjacent corners of the platinum plane were occupied by the two amino nitrogens of DACH, whereas the other two equatorial positions were occupied by two chloride ions. The remaining two axial positions were occupied by the oxygens of acetate ligands. The DACH ring was in a chair configuration. An intricate network of intermolecular hydrogen bonds held the crystal lattice together. These analogues were evaluated in vitro and demonstrated cytotoxic activity against the human ovarian 2008 tumor cell line (IC50 = 0.001-0.06 microM). Structure-activity study revealed that activity was highest for the analogue where L = butyrate.     

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.     

In vitro and in vivo antitumour activity and cellular pharmacological properties of new platinum-iminoether complexes with different configuration at the iminoether ligands

In order to widen our knowledge on antitumour trans-[PtCl2(iminoether)2] complexes, we have synthesised two new derivatives, trans-[PtCl2?E-HN = C(OEt)Me?2] (1) and trans-[PtCl2?Z-HN = C(OEt)Me?2] (2), which differ in the configuration of the iminoether ligands. Isomer 1 showed an in vitro cytotoxicity similar to that of cisplatin in a panel of human tumour cell lines (mean IC50 = 8 and 7.7 microM, respectively), whereas isomer 2 showed a lower activity (IC50 = 14.3 microM). Both 1 and 2 isomers overcame cisplatin resistance of ovarian cancer cell line A2780/Cp8. In agreement with the n-octanol/saline partition ratios, intracellular platinum content (and DNA platination) after a 2-h exposure to equimolar drug concentrations was in the order 1 > 2 > cisplatin, thus indicating that substitution of imminoethers for ammines determines a major lipophilicity and cellular uptake of the platinum drug. Both 1 and 2 showed a major toxic effect towards an excision repair-defective Drosophila strain, thus indicating cellular DNA as cytotoxic target. Finally, both 1 and 2 were active in vivo against the murine P388 system, but, contrary to the in vitro activity, isomer 2 was slightly more active than 1. On the whole, the results confirm the antitumour activity of trans-[PtCl2(iminoether)2] complexes, and indicate that the configuration of the iminoether ligands may affect the pharmacological properties of this class of complexes.     

Cytotoxicity of some platinum(IV) complexes with ethylenediamine-N,N'-di-3-propionato ligand

The cytotoxicities of two platinum(IV) complexes of formula [PtX2(eddp)].nH2O (eddp=ethylenediamine-N,N'-di-3-propionate, X=chloro [I] or bromo [II], n=1 or 1.24) are reported. The complexes have been obtained by direct reaction of potassium hexahaloplatinate(IV) with H2eddp.2HCl followed by addition of a base (LiOH). The crystal and molecular structure has confirmed that the complex with bromo ligands, similarly to the complex with chloro ligands previously reported, has trans configuration of the halogens. In both the chloro and bromo complexes there appear to be intramolecular N-H...X interactions which account for a narrowing of the corresponding X-Pt-N angles below 90degrees. The trans isomer (configuration index OC-6-13, two nitrogens and two oxygens of eddp bound in the equatorial plane) is the only one obtained in the reaction of hexahaloplatinate(IV) with the eddp ligand while a similar reaction performed with ethylenediamine-N,N'-diacetate (edda) affords exclusively the symmetrical cis-isomer (configuration index OC-6-33, equatorial nitrogen and axial oxygen atoms of edda). The longer chain of the propionato groups (as compared to the acetato ones) is responsible for such a change in preferred configuration. NMR data have revealed a very large diastereotopic splitting of the propionato methylene protons to the nitrogens (0.88 ppm). The trans disposition of the halogen ligands in the compounds with eddp leads to deactivation of platinum(IV) complexes in comparison to those with edda having cis disposition of the leaving chlorides (human ovarian cancer cell line A2780, IC50 [muM] of 92.6 +/- 12 and 30.3 +/- 7.5 for [I] and [II], respectively).     

Synthesis and antitumour activity of platinum(II) and platinum(IV) complexes containing ethylenediamine-derived ligands having alcohol, carboxylic acid and acetate substituents. Crystal and molecular structure of [PtL4CL2].H20 where L4 is ethylenediamine-N,N'-diacetate

Several cisplatin analogues of ethylenediamine-derived ligands containing alcohol, carboxylic acid and acetate substituents have been prepared and characterised. Oxidation of some of these square planar platinum(II) complexes using aqueous hydrogen peroxide gave octahedral platinum(IV) complexes, containing trans hydroxo ligands. Acetylation of the hydroxo ligands was achieved by reaction with acetic anhydride, giving complexes which are analogues of the antitumour drug, JM-216. Oxidation of the complex [Pt(H2L4)Cl2], where H2L4 is ethylenediamine-N,N'-diacetic acid, with H2O2 gave the platinum(IV) complex [PtL4Cl2].H2O in which L4 is tetradentate as shown by a crystal and molecular structure. This complex was previously reported to be [Pt(HL4)(OH)Cl2] in which HL4 is tridentate. Several of the complexes were tested for antitumour activity against five human ovarian carcinoma cell lines. IC50 values range from 4.0 microM for cis,trans-PtCl2(OH)2(NH2CH2CH2NHCH2CH2OH) against the CH1 cell line to >25 microM indicating moderate to low activity relative to other platinum complexes.     

Novel cyclopalladated and coordination palladium and platinum complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazones): structural studies and cytotoxic activity against human A2780 and A2780cisR carcinoma cell lines

The preparation of new palladium(II) and platinum(II) complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazone), 1, and alpha-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2, is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB(+)) and spectroscopic studies (IR, (1)HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum complexes against human A2780 and A2780cisR (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC(50) values for compounds 1, 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780cisR cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested.     

Synthesis, crystal structure, spectral properties and cytotoxic activity of platinum(II) complexes of 2-acetyl pyridine and pyridine-2-carbaldehyde N(4)-ethyl-thiosemicarbazones

The reactions of Na2PtCl4 with pyridine-2-carbaldehyde and 2-acetyl pyridine N(4)-ethyl-thiosemicarbazones, HFo4Et and HAc4Et respectively, afforded the complexes [Pt(Fo4Et)Cl], [Pt(HFo4Et)2]Cl2, [Pt(Fo4Et)2] and [Pt(Ac4Et)Cl], [Pt(HAc4Et)2]Cl2 x 2H2O, [Pt(Ac4Et)2]. The new complexes have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(Ac4Et)Cl] has been solved. The anion of Ac4E coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Intermolecular hydrogen, non-hydrogen bonds, pi-pi and weak Pt-pi contacts lead to aggregation and a supramolecular assembly. The cytotoxic activity for the platinum(II) complexes in comparison to that of cisplatin and thiosemicarbazones was evaluated in a pair of cisplatin-sensitive and -resistant ovarian cancer cell lines A2780 and A2780/Cp8. The platinum(II) complexes showed a cytotoxic potency in a very low micromolar range and were found able to overcome the cisplatin resistance of A2780/Cp8 cells.     

Synthesis, X-ray structure, and anti-leukemic activity of oxovanadium(IV) complexes

In a systematic effort to identify and develop effective anticancer agents, four oxovanadium(IV) complexes with 1,10-phenanthroline (Phen) or 4,7-dimethyl-1,10-phenanthroline (Me2-Phen) as ligand(s) were synthesized and characterized. Among the four oxovanadium(IV) complexes synthesized, the crystal structure of the bis(phenanthroline)oxovanadium(IV) complex bis(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Phen)2], compound 1) has been determined. Compound 1 crystallized in the space group P2(1)/n with unit cell parameters a = 14.2125(17) A, b = 10.8628(13) A, c = 20.143(2) A, alpha = 90 degrees, beta = 102.569(2) degrees, gamma = 90 degrees, V = 3035.3(6) A3, and Z = 4. The refinement of compound 1 by full-matrix least-squares techniques gave an R factor of 0.0785 for 4356 independent reflections. The structure contains two enantiomorphous molecules, lambda and delta, which are related by an inversion center. Compound 1 exhibited 3.5-fold more potent cytotoxic activity against NALM-6 human leukemia cells than the mono(phenanthroline)oxovanadium(IV) complex (diaqua)(1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Phen)(H2O)2], compound 2) (IC50 values: 0.97+/-0.10 microM versus 3.40+/-0.20 microM: P=0.0004). Methyl substitution in the phenanthroline ligand enhanced the anti-leukemic activity of the mono(phenanthroline)oxovanadium(IV) complex 4.4-fold (IC50 values: 0.78+/-0.10 microM, compound 4, versus 3.40+/-0.20 microM, compound 2; P=0.0003) and the anti-leukemic activity of the bis(phenanthroline)oxovanadium(IV) complex 5.7-fold (IC50 values: 0.17+/-0.02 microM, compound 3, versus 0.97+/-0.10 microM, compound 1; P=0.001). The leading oxovanadium compound, bis(4,7-dimethyl-1,10-phenanthroline)sulfatooxovanadium(IV) ([VO(SO4)(Me2-Phen)2], compound 3) triggered the production of reactive oxygen species (ROS) in human leukemia cells, caused G1-arrest and inhibited clonogenic growth at nanomolar concentrations.     

Synthesis, characterization, and cytotoxic activity of copper(II) and platinum(II) complexes of 2-benzoylpyrrole and X-ray structure of bis[2-benzoylpyrrolato(N,O)]copper(II)

Copper(II) and platinum(II) complexes of 2-benzoylpyrrole (2-BZPH) were synthesized and characterized with IR, 1H and 13C NMR spectroscopies and coordination geometry with ligands arranged in transoid fashion. The crystal structure of [Cu(II)(2-BZP)2] was determined by X-ray diffraction. Death of complex treated Jurkat cells was measured by flow cytometry. The bis-chelate complexes [Cu(II)(2-BZP)2] and [Pt(II)(2-BZP)2] adopt square-planar coordination geometry with ligands, arranged in transoid fashion. Concentrations of 1-10 microM Platinum(II) complexes reduced cell survival from 100% to 20%, in contrast to the copper(II) complex which caused no cell death at a concentration of 10 microM. While the Pt(II) complexes may have damaged DNA to induce cell death, treatment with the Cu(II) complex did not induce Jurkat cell death.     

cis-Dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.

A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.     

Palladium(II) complexes of 2-benzoylpyridine-derived thiosemicarbazones: spectral characterization, structural studies and cytotoxic activity

Palladium(II) complexes of 2-benzoylpyridine thiosemicarbazone (H2Bz4DH) and its N4-methyl (H2Bz4M) and N4-phenyl (H2Bz4Ph) derivatives were obtained and fully characterized. [Pd(2Bz4DH)Cl] (1) crystallizes in the monoclinic space group P21/c with a=11.671(1), b=10.405(1), c=13.124(1), beta=115.60(1) degrees and Z=4; [Pd(2Bz4M)Cl] (2) in the monoclinic space group P21/c with a=9.695(1), b=15.044(1), c=10.718(1) A, beta=105.38(1) degrees and Z=4 and [Pd(2Bz4Ph)Cl] (3) in the triclinic space group P1 with a=9.389(1), b=13.629(1), c=15.218(1) A, alpha=70.25(1), beta=73.46(1), gamma=83.57(1) degrees and two independent molecules per asymmetric unit (Z=4). All complexes show a quite similar planar fourfold environment around palladium(II). A negatively charged organic molecule acts as a tridentate ligand and binds to the metal through the pyridine nitrogen, the imine nitrogen and the sulfur atom. A chloride ion occupies the fourth coordination site. The planar complexes stack nearly parallel to one another in the lattice conforming a layered crystal structure. The cytotoxic activity of the thiosemicarbazones and their metal complexes was tested against the MCF-7, TK-10 and UACC-62 human tumor cell lines. The ligands exhibit lower values of GI50 and LC50 than the complexes, H2Bz4Ph being the most active with GI50<0.003 microM; LC50=13.4 microM; GI50=9.3 microM, LC50=12.9 microM; GI50<0.003, LC50=13.8 microM in the MCF-7, TK-10 and UACC-62 cell lines, respectively. Among the complexes, [Pd(2Bz4Ph)Cl] (3) exhibited the lowest values of GI50 in the three studied cell lines.     

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5'-GMP

Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by ¹H NMR, ¹⁹⁵Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5′-monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.     

Synthesis, crystal structure, cytotoxic activity and DNA-binding properties of the copper (II) and zinc (II) complexes with 1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene

A new ligand L, 1-[3-(2-pyridyl)pyrazol-1-ylmethyl]naphthalene, and its two metal complexes, [Cu(L)3](ClO4)2 (1) and [Zn(L)3](ClO4)2(H2O)2 (2), have been synthesized and characterized. The crystal structure of complex 1 was determined by single crystal X-ray diffraction, which crystallized in monoclinic, space group P2(1)/n with unit cell parameters, a = 12.710(4) angstroms, b = 12.135(3) angstroms, c = 33.450(9) angstroms, beta = 93.281(5) degrees and Z = 4. The Cu atom was six-coordinated to N(1), N(2), N(4), N(5), N(7) and N(8) from three L ligands and formed a slightly distorted octahedral geometry. Complexes 1 and 2, and ligand L were subjected to biological tests in vitro using three different cancer cell lines (HL-60, BGC-823 and MDA-MB-435). Complex 1 showed significant cytotoxic activity against three cancer cell lines. The interactions of complexes 1 and 2, and ligand L with calf thymus DNA were then investigated by thermal denaturation, viscosity measurements and spectrophotometric methods. The experimental results indicated that complexes 1 and 2 bound to DNA by intercalative mode via the ligand L. The intrinsic binding constants of complexes 1 and 2, and ligand L with DNA were 1.8 x 10(4), 5.4 x 10(3) and 2.76 x 10(3) M(-1), respectively.     

Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5′-GMP

Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by ¹H NMR, ¹⁹⁵Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5′-monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.     

Binuclear copper(II) complexes of tolfenamic: synthesis, crystal structure, spectroscopy and superoxide dismutase activity

The synthesis and characterization of copper(II) complexes with a potent non-steroidal anti-inflammatory drug, tolfenamic acid, Htolf, with formula [Cu(tolf)(2)L](2) (where L is H(2)O or DMF, N,N-dimethylformamide) were investigated. The crystal and molecular structure of [Cu(tolf)(2)(DMF)](2) was reported. Crystallographic data are as follows: monoclinic system, space group P2(1)/n with cell constants a=9.068(2) A, b=14.514(3) A, c=22.826(4) A, V=2948.9(10) A(3) and Z=2. The crystal structure consists of binuclear, quadruply bridged neutral molecule with a Cu-Cu bond length of 2.6075(19) A. The complex is self-assembled via C-H-pi intermolecular stacking interactions. Spectroscopic and electrochemical studies were reported. The superoxide dismutase activity is measured and compared with those of superoxide dismutase enzyme, SOD, the free ligand and related copper complexes with non-steroidal anti-inflammatory drugs, NSAIDs. IC(50) value was measured by the Fridovich test (1.97+/-0.17 microM), which showed that [Cu(tolf)(2)L](2) is a good superoxide scavenger.     

Cytotoxic activity of platinum (II) complexes with tri-n-butylphosphine. Crystal structure of the dinuclear hydrazine-bridged complex, cis,cis-[PtCl(PBu3n)2(mu-N2H4)PtCl(PBu3n) 2] (ClO4)2.2CHCl3.

A series of platinum(II) tri-n-butylphosphine complexes having the formulas cis-[PtCl2L2], NEt4[PtCl3L], [PtCl(en)L]Cl, [Pt(en)L2](ClO4)2, sym-trans-[Pt2Cl4L2], [Pt2Cl2L4](ClO4)2, trans,trans-[PtCl2L(mu-N2H4)PtCl2L] trans,trans-[PtCl2L(mu-en)PtCl2L], and cis,cis-[PtClL2(mu-N2H4)PtClL2](ClO4)2 (L = tri-n-butylphosphine; en = ethylenediamine) have been synthesized and their cytotoxic activity in vitro and in vivo has been studied. The solution behavior of the novel dinuclear diamine-bridged platinum(II) complexes has been investigated by means of UV and 31P NMR spectroscopy. For the ionic hydrazine compound cis,cis-[PtClL2(mu-N2H4)PtClL2](ClO4)2, an x-ray structure determination is reported. Crystal data: space group P2(1)/a, a = 17.803(1), b = 18.888(3), c = 12.506(3) A, beta = 107.97(2) degrees, Z = 2, R = 0.052, RW = 0.058. The platinum coordination is approximately square-planar, with the bond lengths Pt-Cl = 2.358(5), Pt-N = 2.15(1), Pt-P(trans to Cl) = 2.260(5), and Pt-P(trans to N) = 2.262(6) A. All investigated compounds were cytotoxic in vitro against L1210 cells and showed no cross-resistance to cisplatin. On the other hand, no antitumor activity was observed vs L1210 leucemia in DBA2 mice.     

Pd(II) and Pt(II) complexes with aromatic diamines: study of their interaction with DNA

Pd(II) and Pt(II) new complexes with simple aromatic diamines were synthesised and characterised with the aim of studying their possible antitumour activity. The aromatic diamines chosen were 2,3-diaminotoluene (2,3 dat), 3,4-diaminotoluene (3,4 dat), 4,5-diaminoxylene (4,5 dax) and 2,3-diaminophenol (2,3 dap). The complexes, of formulae cis-[MCl(2)(diamine)], were characterised by elemental analysis, conductivity measurements, 1H, 13C(1H) and 195Pt NMR spectroscopy. The X-ray crystal structure was also resolved for the palladium complexes with 2,3-diaminotoluene and 4,5-diaminoxylene. The DNA adduct formation of the eight new complexes synthesised was followed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the modifications caused by the complexes on plasmid DNA pBR322 were also obtained. Values of IC50 were also calculated for the four platinum complexes against the cisplatin resistant tumour cell line A2780cisR.