Preparation, characterization, and antitumor activity of new cisplatin analogs with homopiperazines: crystal structure of [PtII(1-methylhomopiperazine)(methylmalonato)].2H2O

A series of new platinum(II) and (IV) complexes with homopiperazine have been synthesized and characterized by elemental analysis, infrared, and 195Pt nuclear magnetic resonance spectroscopic techniques. The complexes are of two types: [PtIILX] (where L = homopiperazine (hpip), 1-methylhomopiperazine (mhpip), or 1,4-dimethylhomopiperazine (dmhpip), and X = 1,1-cyclobutanedicarboxylato (CBDCA), or methylmalonato ligand) and [PtIV(L-)trans-(Y)2Cl2] (where Y = hydroxo, acetato, or chloro ligand). Among the complexes synthesized, the crystal structure of [PtII(mhpip)(methylmalonato)].2H2O was determined by the single crystal X-ray diffraction method. The crystallographic parameters were orthorhombic, P2(1)2(1)2(1) (no. 19), a = 7.2014(14), b = 7.3348(15), c = 26.971(5) A, and Z = 4. The structure refinements converged to R1 = 0.0641 and wR2 = 0.1847. In this complex, platinum has a slightly distorted square planar geometry with the two adjacent corners being occupied by two nitrogens of the mhpip ligand, whereas the remaining cis positions are coordinated with two oxygen atoms of the methylmalonato group. The mhpip ligand is in a boat conformation and forms five and six membered chelating rings with platinum. The intricate network of intermolecular hydrogen bonds holds the crystal lattice together. Some of these synthesized cisplatin analogs have good in vitro cytotoxic activity against the cisplatin-sensitive human ovarian A2780 (IC50 = 0.083-17.8 microM) and the isogenic cisplatin-resistant 2780CP (IC50 = 20.1-118.1 microM) cell lines.     

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.     

Structure-antitumor activity relationship for new analogs of thecis-dichloro(l,2-diamino cyclohexane) platinum(II) complex

In 1977, Gale and associates reported the synthesis and antitumor activity of a series of Pt(II) complexes containing 1,2-diaminocyclohexane as the ligand. Certain of these complexes showed superior activity and greater water solubility compared to cis-Pt(NH₃)₂Cl₂ complexes (“Neoplatin”). In this paper we report the synthesis and antitumor activity of some 40 new water soluble platinum(II) and platinum(IV) complexes. The following classes of the cis-Pt(L)Cl₂ complexes were obtained, where L = 1,2-diaminocyclohexane: (a) cis-Pt(L)(X), where X is a derivative of homophthalic acid or a derivative of 1,3-benzendicarboxylic acid, (b) cis-Pt(L)(X)(OH)₂ and cis-Pt(L)(X)(Cl)₂ complexes, where L and X are the above-mentioned ligands, (c) cis-Pt(L)(X)₂ complexes where X is the monoanion of an organic xanthate or dithiocarbamate and L = 1,2-diaminocyclohexane, (d) their corresponding Pt(IV) analogues, Pt(L)(X)₂(OH)₂ and Pt(L)(X)₂(Cl)₂. All complexes were assayed against P388 tumors and/or KB cell-bearing mice. The observed antitumor activities were correlated with the structures and spectra of the complexes as well as with the results of EHMO calculations performed on the leaving ligand molecules. A number of the most active complexes were also tested for activity against ADJ/PC6 Yoshida and S-180 tumors in vivo.     

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.     

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.     

Biological activity of palladium(II) and platinum(II) complexes of the acetone Schiff bases of S-methyl- and S-benzyldithiocarbazate and the X-ray crystal structure of the [Pd(asme)2] (asme=anionic form of the acetone Schiff base of S-methyldithiocarbazate) complex

Palladium(II) and platinum(II) complexes of general empirical formula, [M(NS)(2)] (NS=uninegatively charged acetone Schiff bases of S-methyl- and S-benzyldithiocarbazate; M=Pt(II) and Pd(II)) have been prepared and characterized by a variety of physicochemical techniques. Based on conductance, IR and electronic spectral evidence, a square-planar structure is assigned to these complexes. The crystal and molecular structure of the [Pd(asme)(2)] complex (asme=anionic form of the acetone Schiff base of S-methyldithiocarbazate) has been determined by X-ray diffraction. The complex has a distorted cis-square planar structure with the ligands coordinated to the palladium(II) ions as uninegatively charged bidentate NS chelating agents via the azomethine nitrogen and the mercaptide sulfur atoms. The distortion from a regular square-planar geometry is attributed to the restricted bite angles of the ligands. Antimicrobial tests indicate that the Schiff bases exhibit strong activities against the pathogenic bacteria, Bacillus subtilis (mutant defective DNA repair), methicillin-resistant Staphylococcus aureus, B. subtilis (wild type) and Pseudomonas aeruginosa and the fungi, Candida albicans (CA), Candida lypotica (2075), Saccharomyces cerevisiae (20341) and Aspergillus ochraceous (398)-the activities exhibited by these compounds being greater than that of the standard antibacterial and antifungal drugs, streptomycin and nystatin, respectively. The palladium(II) and platinum(II) complexes are inactive against most of these organisms but, the microbe, Pseudomonas aeruginosa shows strong sensitivity to the platinum(II) complexes. Screening of the compounds for their cytotoxicities against T-lymphoblastic leukemia cancer cells has shown that the acetone Schiff base of S-methyldithiocarbazate (Hasme) exhibits a very weak activity, whereas the S-benzyl derivative (Hasbz) is inactive. However, the palladium(II) complexes exhibit strong cytotoxicities against this cancer; their activities being more than that of the standard anticancer drug, tamoxifen. The [Pt(asme)(2)] complex exhibits a very weak cytotoxicity, whereas [Pt(asbz)(2)] is inactive against leukemic cells.     

Platinum(II) complexes with l-methionylglycine and l-methionyl-l-leucine ligands: synthesis, characterization and in vitro antitumoral activity

Four dipeptide complexes of the type [PtX(2)(dipeptide)] x H(2)O (X=Cl, I, dipeptide=l-methionylglycine, l-methionyl-l-leucine) were prepared. The complexes were characterized by (1)H, (13)C, (195)Pt NMR and infrared spectroscopy, DTG and elemental analysis. From the infrared, (1)H and (13)C NMR spectroscopy it was concluded that dipeptides coordinate bidentately via sulfur and amine nitrogen donor atoms. Confirmed with (13)C and (195)Pt NMR spectroscopy, each of the complexes exists in two diastereoisomeric forms, which are related by inversion of configuration at the sulfur atom. The (1)H NMR spectrum for the platinum(II) complex with l-methionylglycine and chloro ligands exhibited reversible, intramolecular inversion of configuration at the S atom; DeltaG( not equal)=72 kJ mol(-1) at coalescence temperature 349 K was calculated. In vitro cytotoxicity studies using the human tumor cell lines liposarcoma, lung carcinoma A549 and melanoma 518A2 revealed considerable activity of the platinum(II) complex with l-methionylglycine and chloro ligands. Further in vitro cytotoxic evaluation using human testicular germ cell tumor cell lines 1411HP and H12.1 and colon carcinoma cell line DLD-1 showed moderate cytotoxic activity for all platinum(II) complexes only in the cisplatin-sensitive cell line H12.1. Platinum uptake studies using atomic absorption spectroscopy indicated no relationship between uptake and activity. Potential antitumoral activity of this class of platinum(II) complexes is dependent on the kind of ligands as well as on tumor cell type.     

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)].     

Platinum(II) complexes with 2-acetyl pyridine thiosemicarbazone. Synthesis, crystal structure, spectral properties, antimicrobial and antitumour activity

An interesting series of new platinum complexes has been synthesized by the reaction of Na(2)PtCl(4) with 2-acetyl pyridine thiosemicarbazone, HAcTsc. The new complexes, [Pt(AcTsc)Cl], [Pt(HAcTsc)(2)]Cl(2) and [Pt(AcTsc)(2)], have been characterized by elemental analyses and spectroscopic studies. The crystal structure of the complex [Pt(AcTsc)Cl] has been solved by single-crystal X-ray diffraction. The anion of HAcTsc coordinates in a planar conformation to the central platinum(II) through the pyridyl N, azomethine N and thiolato S atoms. Double intermolecular hydrogen bonds (NH-Cl), pi-pi and weak Pt-Pt and Pt-pi contacts lead to aggregation and to a two-dimensional supramolecular assembly. The antibacterial and antifungal effect of the novel platinum(II) complexes and the related palladium(II) complexes, [Pd(AcTsc)Cl], [Pd(HAcTsc)(2)]Cl(2) and [Pd(AcTsc)(2)], were studied in vitro. The complexes were found to have a completely lethal effect on Gram+ bacteria, while the same complexes showed no bactericidal effect on Gram- bacteria. Additionally, the complexes [Pt(AcTsc)(2)] and [Pd(AcTsc)(2)] showed effective antifungal activity towards yeast. Among these compounds [33], the most effective in inducing antitumour and cytogenetic effects are the complexes [Pt(AcTsc)(2)] and [Pd(AcTsc)(2)] while the rest, display marginal cytogenetic and antitumour effects.     

Synthesis,characterization and antitumor activity of platinum(II) complexes with diethyl and monoethyl 2-quinolylmethylphosphonates

A series of new platinum(II) complexes with diethyl (2-dqmp) and monoethyl (2-Hmqmp) 2-quinolylmethylphosphonates have been prepared and studied. Both organophosphorus ligands by reaction with [PtX(4)](2-) (X=Cl, Br) form either the molecular or ionic complexes depending on the acidity of the reaction solution. Dihalide adducts, trans-[PtL(2)X(2)] (L=2-dqmp, 2-Hmqmp), with N-bonded ligand through the quinoline nitrogen were obtained in the neutral medium, while under acidic conditions at pH<3 were isolated the ion-pair salt complexes, [LH](2)[PtX(4)], containing the protonated quinoline ligand as cation and tetrahaloplatinate complex as anion. In addition, 2-Hmqmp at pH approximately 3.5 forms quinolinium hexahalodiplatinum salt complexes, [2-H(2)mqmp](2)[Pt(2)X(6)], while the chelate complex, [Pt(2-mqmp)(2)].2H(2)O, with N,O-bonded ligand through the quinoline nitrogen and the deprotonated phosphonic acid oxygen was obtained at pH>6. The new complexes were characterized on the basis of elemental and thermogravimetric analyses, conductometric measurements, and by infrared and (1)H NMR spectral studies. As a preliminary assessment of their biological activity, complexes were evaluated for their in vitro cytostatic activity in an epidermoid human carcinoma (KB) and murine leukemia (L1210) cell lines. The results obtained were compared with those obtained for the corresponding Pd(II) complexes.     

Mixed complexes of Pt(II) and Pd(II) with ethylsarcosinedithiocarbamate and 2-/3-picoline as antitumor agents

The [M(ESDT)Cl](n) (M=Pt(II), Pd(II); ESDT=EtO(O)CCH(2)N(CH(3))CS(2)(-), ethylsarcosinedithiocarbamate ion) species have been reacted with 2- or 3-picoline in dichloromethane in order to obtain mixed ligand complexes of the type [M(ESDT)(L)Cl] (L=2-picoline, 3-picoline). The synthesized compounds have been isolated, purified and characterized by means of elemental analyses, (1)H-/(13)C-/(1)H(13)C-HMBC (heteronuclear multiple bonding coherence) NMR and FT-IR spectroscopy. The biological activity of the compounds reported here has been then determined in terms of cell growth inhibition, DNA synthesis inhibition, detection of interstrand cross-links and DNA-protein cross-links, and micronuclei (MN) detection on a panel of tumor cell lines both sensitive and resistant to cisplatin. On the basis of the experimental results, coordination in the above mentioned complexes takes place in a near square-planar geometry, the dithiocarbamate moiety acting as a chelating agent, whereas the two remaining coordination sites are occupied by a chlorine atom and an amino ligand. Above all, [Pt(ESDT)(2-picoline)Cl] complex has shown very encouraging cytotoxicity levels higher or, at least, comparable to those exerted by cisplatin in the same experimental conditions.     

cis-1,4-diaminocyclohexane-Pt(II) and -(IV) adducts with DNA bases and nucleosides

A series of new platinum(II) and platinum(IV) adducts of type [P(II)(cis-1,4-DACH)LCl]NO(3,) where cis-1,4-DACH=cis-1,4-diaminocyclohexane, and L=9-ethylguanine, 1-methylcytosine, adenine, adenosine, cytosine, cytidine, guanine, and [Pt(IV)(cis-1,4-DACH)Ltrans-(X)(2)Cl]NO(3), (where Y=hydroxo or acetato), were synthesized and characterized by elemental analysis, infrared spectroscopy, and 1H and 195Pt nuclear magnetic resonance spectroscopy.     

Synthesis and characterization of N-methyliminodiacetato trans-R,R-, trans-S,S-, and cis-1,2-diaminocyclohexane platinum (IV) complexes: crystal structure of chloro(trans-R,R-1,2-diaminocyclohexane) (N-methyliminodiacetato) platinum(IV) chloride.

The compounds, chloro(trans-R,R-1,2-diaminocyclohexane) (N-methyliminodiacetato)platinum(IV) chloride, chloro(trans-S,S-1,2-diaminocyclohexane)(N-methyliminodiacetato) platinum(IV) chloride, and chloro(cis-1,2-diaminocyclohexane)(N-methyliminodiacetato)platinum (IV) chloride, were prepared and characterized by elemental analysis, IR, and 195Pt NMR. The crystal structure of one of these three compounds, chloro(trans-R,R-1,2-diaminocyclohexane) (N-methyliminodiacetato) platinum(IV) chloride, was determined by x-ray single crystal diffraction. This compound is particularly interesting because the 1,2-diaminocyclohexane (DACH) ring is in a twist-boat configuration rather than the chair configuration previously reported for other DACH platinum compounds. The crystal structure consists of two independent cations and anions, with all atoms between these two independent molecules (except those in the chiral DACH) related by a pseudo-inversion center. Both platinum atoms have slightly distorted octahedral coordination, with angles ranging from 81.8 to 100.8 degrees. Crystallographic details: space group P2(1) (monoclinic); a = 19.864(5) A, b = 7.026(2) A, c = 12.446(3) A, beta = 106.64(2) degrees; Z = 4; R = 0.036 for 2333 reflections.     

Octahedral complexes of anti-cancer Pt(IV)(cyclohexyldiamine) agents with 9-methylguanine

The compounds [Pt(IV)(dach)(9-methylguanine)2X2]2+ (X = Cl, OH) have been prepared and structurally characterized. Their existence shows that it is possible to accommodate two purine bases (in a cis configuration) and four other ligands around a Pt(IV) atom. The geometries of these complexes have very different orientations of the guanine rings as compared to their corresponding Pt(II) counterparts.     

Interaction of phenylthiolato-(2,2'',2"-terpyridine)platinum(II) cation with DNA.

The interaction between a novel aromatic thiolato derivative from the family of DNA-intercalating platinum complexes, phenylthiolato-(2,2',2"-terpyridine)platinum(II)-[PhS(ter py)Pt+], and nucleic acids was studied by using viscosity, equilibrium-dialysis and kinetic measurements. Viscosity measurements with sonicated DNA provide direct evidence for intercalation, and show that at binding ratios below 0.2 molecules per base-pair PhS(terpy)Pt+ causes an increase in contour length of 0.2 nm per bound molecule. However, helix extension diminishes at greater extents of binding, indicating the existence of additional, non-intercalated, externally bound forms of the ligand. The ability of PhS(terpy)Pt+ to aggregate in neutral aqueous buffers at a range of ionic strengths and temperatures was assessed by using optical-absorption methods. Scatchard plots for binding to calf thymus DNA at ionic strength 0.01 (corrected for dimerization) are curvilinear, concave upward, providing further evidence for two modes of binding. The association constant decreases at higher ionic strengths, in accord with the expectations of polyelectrolyte theory, although the number of cations released per bound unipositive ligand molecule is substantially greater than 1. Stopped-flow kinetic measurements confirm the complexity of the binding reaction by revealing multiple bound forms of the ligand whose kinetic processes are both fast and closely coupled. Thermal denaturation of DNA radically alters the shapes of binding isotherms and either has little effect on, or enhances, the affinity of potential binding sites, depending on experimental conditions. Scatchard plots for binding to natural DNA species with differing nucleotide composition show that the ligand has a requirement for a single G X C base-pair at the highest-affinity intercalation sites.     

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.     

Syntheses and structural studies of platinum(II) complexes of O-methylselenomethionine and related ligands

The complexes dichloro[2-(phenylselanyl)ethanamine]platinum(II), dichloro[2-(benzylselanyl)ethanamine]platinum(II) and dichloro(O-methylselenomethionine)platinum(II) have been prepared and the structure of dichloro(O-methylselenomethionine)platinum(II) has been determined by single crystal X-ray diffraction. The Pt(II) is in a square planar environment and is coordinated by two cis chloride ligands and a chelating O-methylselenomethionine ligand. The cytotoxicities of the compounds have been assessed in the human cell lines HeLa and K562 and they are at least threefold less toxic than cisplatin in both cell lines.     

Characterization studies and cytotoxicity assays of Pt(II) and Pd(II) dithiocarbamate complexes by means of FT-IR, NMR spectroscopy and mass spectrometry

The precursors [M(ESDTM)Cl(2)] (M=Pt(II), Pd(II); ESDTM=EtO(2)CCH(2)(CH(3))NCS(2)Me, S-methyl(ethylsarcosinedithiocarbamate)) were synthesized as previously reported [J. Inorg. Biochem. 83 (2001) 31] and used to obtain [M(ESDT)Cl](n) (ESDT=ethylsarcosinedithiocarbamate anion) species. The complexes formed through reaction between [M(ESDT)Cl](n) and the two chiral amino-alcohols synephryne (Syn) and norphenylephrine (Nor) have been synthesized, with the ultimate goal of preparing mixed dithiocarbamate/amino metal complexes of the type [M(ESDT)(Am)Cl] (Am=Syn, Nor). These compounds have been isolated, purified and characterized by means of FT-IR, mono- and bidimensional NMR spectroscopy and mass spectrometry ESI/MS (electronspray mass spectra). The experimental data suggest that in all cases coordination of the dithiocarbamate ligand (ESDT) takes a place through the two sulfur atoms, the -NCSS moiety acting as a symmetrical bidentate chelating group, in a square-planar geometry around the M(II) ion, while the other two coordination positions are occupied by the chlorine atom and the amino-alcohol ligand, respectively. In particular, synephrine and norphenylephrine appear to be bound to the metal atom through the amino nitrogen atom by means of a dative bond. Finally, the biological activity of the new complexes has been studied by MTT (tetrazolio salt reduction) test and by detecting the inhibition of DNA synthesis and of clonal growth in various cancer cell lines. All Pd(II) derivatives showed a noticeable activity very close to that of cisplatin, used as reference drug. Moreover, they showed significantly reduced cross-resistance to cisplatin in a pair of cell lines (2008/C13*) with known acquired cisplatin resistance mechanisms.     

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, 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.