Synthesis, characterization, and antitumor activity of 1,2-bis(diphenylphosphino) ethane platinum(II) and palladium(II) complexes

A number of 1,2-bis(diphenylphosphino)ethane monomeric platinum(II) and palladium(II) complexes have been synthesized in light of their potential antitumor activity. The metal center is coordinated with a number of carboxylate anions in the cis-configuration. These complexes have been characterized by elemental analysis, conductivity measurement, and various spectroscopic techniques [IR and 195Pt NMR]. In vivo screening tests for activity of these complexes were performed against the L1210/0 murine leukemia cancer model, but none displayed a significant level of antitumor activity.     

Novel platinum(II) and palladium(II) complexes with cyclin-dependent kinase inhibitors: synthesis, characterization and antitumour activity

The Pt(II) and Pd(II) complexes of the types cis-[Pt(L(1))(2)Cl(2)].H(2)O (1), cis-[Pt(L(2))(2)Cl(2)].3H(2)O (2), trans-[Pd(L(1))(2)Cl(2)].H(2)O (3), trans-[Pd(L(2))(2)Cl(2)].H(2)O (4), trans-[Pd(L(3))(2)Cl(2)].2DMF (5) and trans-[Pd(L(4))(2)Cl(2)].2DMF (6) (L(1)-L(4)=cyclin-dependent kinase inhibitors derived from 6-benzylamino-9-isopropylpurine) have been prepared and characterized. The complexes have been studied by elemental analyses, conductivity measurements, ES+ MS, FT-IR, (1)H, (13)C and (195)Pt NMR spectra, differential scanning calorimetry and thermogravimetric analysis. The molecular structures of L(1), trans-[Pd(L(3))(2)Cl(2)].2DMF (5) and trans-[Pd(L(4))(2)Cl(2)].2DMF (6) have been determined by single crystal X-ray analysis. The complexes have been tested in vitro due to their presumable anticancer activity against the following human cancer cell lines: K-562, MCF7, G-361 and HOS. Satisfying results were obtained for the complex 1 with IC(50) values of 6 microM acquired against G-361 as well as against HOS cell lines. The lowest values of IC(50) were achieved for the complexes 3 and 4 against MCF 7 cell line with IC(50) 3 microM(for 3) and also 3 microM (for 4).     

Novel endothall-containing platinum(IV) complexes: synthesis, characterization, and cytotoxic activity

Two platinum(IV) complexes (OC-6-33)-dichlorido(ethane-1,2-diamine)dihydroxidoplatinum(IV) and (OC-6-33)-diammine(dichlorido)dihydroxidoplatinum(IV) were carboxylated using demethylcantharidin as carboxylation agent. The complexes were characterized by elemental analysis, mass spectrometry, multinuclear (1H, 13C, 15N, and 195Pt) NMR spectroscopy, and, in case of (OC-6-33)-diamminebis(3-carboxy-7exo-oxabicyclo[2.2.1]heptane-2-carboxylato)dichloridoplatinum(IV) via X-ray diffraction. Cytotoxicity of the complexes was studied in seven human cancer cell lines representing five tumor entities, i.e., ovarian carcinoma (CH1, SK-OV-3), cervical carcinoma (HeLa), colon carcinoma (SW480, HCT-116), osteosarcoma (U-2 OS), and hepatocellular carcinoma (Hep G2) by means of the MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium hydrobromide) assay.     

Preparation, characterization, and antitumor activity of water-soluble aminoalkanol platinum(II) complexes

A new series of highly water-soluble aminoalkanol platinum(II) complexes have been synthesized and characterized by elemental analysis, conductance, IR, and 195Pt NMR. Preliminary in vitro and in vivo screening tests for antitumor activities of these complexes against L1210 murine leukemia were performed. In general, these compounds were far less cytotoxic than cisplatin and possessed only a moderate degree of antitumor activity.     

Platinum(II) and palladium(II) complexes with dithiocarbamates and amines: synthesis, characterization and cell assay

The [M(ESDT)Cl]n (M = Pd or Pt; ESDT = EtO2CCH2(CH3)NCS2, methylamino-acetic acid ethyl ester-dithiocarboxylate) species have been reacted with various amines (py, pyridine; PrNH2, n-propylamine; c-BuNH2, cyclobutylamine; en, ethylenediamine) in dichloromethane or chloroform with the aim to obtain mixed ligand complexes. The neutral complexes [M(ESDT)(L)Cl] (L = py, PrNH2 or c-BuNH2) and the ionic species ([M(ESDT)(L)2]Cl and [M(ESDT)(En)]Cl) have been isolated, and characterized by IR and proton NMR spectroscopies. The crystal structure of [Pd(ESDT)(PrNH2)Cl] has been determined by X-ray crystallography. The behaviour of the complexes in various solvents was described on the basis of the proton NMR spectra. The complexes and the dithiocarbamato intermediates have been tested for in vitro cytostatic activity against human leukemic HL-60 and HeLa cells.     

The microwave synthesis of platinum(II) phosphine complexes

The microwave synthesis of a series of platinum(II) phosphine complexes is reported. The complexes dppePtCl₂ (dppe = bis(diphenylphosphino)ethane), dpppPtCl₂ (dppp = bis(diphenylphosphino)propane), dppmPtCl₂ (dppm = bis(diphenylphosphino)methane) and cis-(Ph₃P)₂PtCl₂ are synthesized from the reaction of potassium tetrachloroplatinate(II) and the phosphine. The isolated yields are 65% or better.     

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, molecular structure determination, and antitumor activity of platinum(II) and palladium(II) complexes of 2-substituted benzimidazole

The complexes of 2-aminomethyl benzimidazole, 2-(beta-aminoethyl)benzimidazole, and 2-(alpha-aminoethy-l)benzimidazole with Pt(II) and Pd(II) have been prepared. The molecular structure of the free ligands and their complexes were studied by IR and 1H NMR. It was concluded that the substituted benzimidazole derivatives behave as bidentate ligands, being bound to the metal atoms via the nitrogen of the -N = group and the amino group of the side chain of the benzimidazole ring. The metal complexes were tested for antineoplastic activity both in cultures of neoplastic cells (MEL-745, K-562, Colon 205, IMP-32, SK-N-SH) and in vivo in rodents bearing L-1210 leukemia. The antiproliferative activity of these agents was compared to that of cis-platin.     

Palladium(II) complexes of quinolinylaminophosphonates: synthesis, structural characterization, antitumor and antimicrobial activity

Three types of palladium(II) halide complexes of quinolinylaminophosphonates have been synthesized and studied. Diethyl and dibutyl [α-anilino-(quinolin-2-ylmethyl)]phosphonates (L1, L2) act as N,N-chelate ligands through the quinoline and aniline nitrogens giving complexes cis-[Pd(L1/L2)X₂] (X═Cl, Br) (1-4). Their 3-substituted analogues [α-anilino-(quinolin-3-ylmethyl)]phosphonates (L3, L4) form dihalidopalladium complexes trans-[Pd(L3/L4)₂X₂] (5-8), with trans N-bonded ligand molecules only through the quinoline nitrogen. Dialkyl [α-(quinolin-3-ylamino)-N-benzyl]phosphonates (L5, L6) give tetrahalidodipalladium complexes [Pd₂(L5/L6)₃X₄] (9-12), containing one bridging and two terminal ligand molecules. The bridging molecule is bonded to the both palladium atoms, one through the quinoline and the other through the aminoquinoline nitrogen, whereas terminal ligand molecules are coordinated each only to one palladium via the quinoline nitrogen. Each palladium ion is also bonded to two halide ions in a trans square-planar fashion. The new complexes were identified and characterized by elemental analyses and by IR, UV-visible, ¹H, ¹³C and ³¹P nuclear magnetic resonance and ESI-mass spectroscopic studies. The crystal structures of complexes 1-4 and 6 were determined by X-ray structure analysis. The antitumor activity of complexes in vitro was investigated on several human tumor cell lines and the highest activity with cell growth inhibitory effects in the low micromolar range was observed for dipalladium complexes 11 and 12 derived from dibutyl ester L6. The antimicrobial properties in vitro of ligands and their complexes were studied using a wide spectrum of bacterial and fungal strains. No specific activity was noted. Only ligands L3 and L4 and tetrahalidodipalladium complexes 9 and 11 show poor activities against some Gram positive bacteria.     

Synthesis, structural characterization, and antitumor activity of palladium(II) complexes containing a sugar unit

Six palladium(II) complexes as cisplatin derivatives with a sugar unit (D-glucose, D-galactose, D-mannose, D-xylose, and maltose) have been prepared. The structural features of the complexes have been characterized by NMR spectroscopy, elemental analysis, mass spectroscopy, and X-ray crystallography. The complexes have been tested for in vivo cytotoxicity against P388 cells implanted in mice. All of Pd compounds are apparently nontoxic. A T/C value of 120% was obtained for maltose derivative at the dose of 400 mg/kg, which indicates that the compound may be endowed with antitumor activity.     

2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design,synthesis, and antitumor activity

Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1’s substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D.     

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.     

Synthesis,characterization and antitumor activity of a series of N-substituted iminodiacetato(diammine) platinum(II) complexes

A series of water-soluble N-substituted iminodiacetato (diammine)platinum(II) complexes [Pt(NRIDA)(NH₃)₂] have been synthesized and characterized by measurement of physical properties (conductivity and pH) and by various spectroscopic techniques (infrared, ¹H and ¹³C{¹H} nuclear magnetic resonance). The iminodiacetate ligand is coordinated to platinum through an O,N linkage. The results obtained suggest that these complexes are relatively stable for more than 24 h in aqueous solution. Preliminary in vitro and in vivo screening test for antitumor activity of these complexes against L1210 murine leukemia were performed. Many of complexes had acceptable in vitro cytotoxicity, but none displayed a significant level of in vivo antitumor efficacy.     

Platinum(II) complexes with steroidal esters of L-methionine and L-histidine: synthesis, characterization and cytotoxic activity

Twelve steroidal platinum(II) complexes were synthesized by reaction of potassium tetrachloroplatinate with steroidal esters of L-methionine and L-histidine. The steroidal esters coordinated as bidentate ligands via S and N donor atoms of L-methionine and via two N donor atoms of L-histidine. Cholesterol, cholestanol, diosgenine, pregnenolone, dehydroepiandrosterone, testosterone, estrone, and estradiol were used as the steroidal compounds. The esters and complexes prepared were characterized by infrared, mass, and (1)H NMR spectroscopy and elemental analysis. Platinum complexes were tested for in vitro cytotoxicity against several cancer cell lines: T-lymphoblastic leukemia CEM, breast carcinoma MCF-7, lung carcinoma A-549, multiple myeloma RPMI 8226, and one normal cell line human fibroblast BJ.     

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.     

Synthesis, characterization, DNA binding, and cytotoxic studies of some mixed-ligand palladium(II) and platinum(II) complexes of alpha-diimine and amino acids

The syntheses of nine palladium(II) complexes of type [Pd(phen)(AA)]+ (where AA is an anion of glycine, L-alanine, L-leucine, L-phenylalanine, L-tyrosine, L-tryptophan, L-valine, L-proline, or L-serine) have been achieved. These palladium(II) complexes have been characterized by ultraviolet-visible, infrared, and 1H NMR spectroscopy. The binding studies of several complexes [M(NN)(AA)]+ (where M is Pd(II) as Pt(II), NN is 2,2'-bipyridine or 1,10-phenanthrodine, and AA is an anion of amino acid) with calf thymus DNA have been carried out using UV difference absorption and fluorescence spectroscopy. The mode of binding of the above complexes to DNA suggests the involvement of the hydrogen bonding between them. Several complexes [M(phen)(AA)]+ (where M is Pd(II) or Pt(II) and AA is an anion of amino acid) have also been screened for cytotoxicity in P388 lymphocytic cells. Of them, only two complexes, [Pd(Phen)(Gly)]+ and [Pd(phen)(Val)]+, show comparable cytotoxicity, as cisplatin does.     

Squarate complexes of diamine palladium(II) and platinum(II)

Reactions of cis-diaminediaqua palladium and platinum dinitrates and of trans-diaminediaqua platinum dinitrate give complexes of the type Pd(tmeda)(OH)(C₄O₄)Pd(tmeda)(C₄O₄H) (tmeda = tetramethylethylenediamine) (1), (en)M(C₄O₄)₂M(en) (en = ethylenediamine (M = Pd, Pt) and trans-[Pt- (NH₃)₂C₄O₄]_n, respectively. The structures of these compounds are discussed on the basis of their spectroscopic data.     

Synthesis,characterization and antitumor activity of novel octahedral Pt(IV) complexes

Novel platinum(IV) complexes were synthesized having octahedral structure for new antitumor agents. The series of (1,4-butanediamine)Pt(IV) complexes of the type trans,cis-[PtA(2)Cl(2)(1,4-butanediamine)] (A=hydroxo 9, acetato 12, trifluoroacetato 13 as axial ligands) and trans-[PtA(2)(malonate)(1,4-butanediamine)] (A=hydroxo 16, acetato 17, trifluoroacetato 18) were synthesized and characterized by IR, NMR and elemental analysis. The molecular structures of 12, 13 and 18 have been determined by X-ray diffraction methods. The crystals are monoclinic, P2 1/c with a=21.165 (5), b=9.050 (3), c=15.293 (3) A, beta=103.89 (2) degrees and Z=8 for 12, a=10.178 (5), b=12.894 (9), c=12.182 (8) A, beta=91.01 (5) degrees and Z=4 for 13 and a=10.460 (5), b=11.199 (8), c=15.641 (7) A, beta=98.41 (5) degrees, Z=4 for 18. Three crystallographically independent molecules of 12, 13 and 18 have octahedral coordination around Pt(IV) cation. The trans,cis-[PtA(2)Cl(2)(1,4-butanediamine)] were prepared by acetylation or trifluoroacetylation of trans,cis-[Pt(OH)(2)Cl(2)(1,4-butanediamine)]. The trans-[PtA(2)malonate(1,4-butanediamine)] 17 and 18 was prepared by a similar method. The in vitro cytotoxicity of theses Pt(IV) complexes have been evaluated against 12 cancer cell lines assayed by MTS method. The IC(50) values of the compounds 12 and 13 were shown to be lower than those of cisplatin. The in vivo antitumor activity of the Pt(IV) complexes was evaluated using mice bearing L1210 leukemia, B16 melanoma and L1210/cis-DDP cancer animal models. The compound 18 was found to highest activity against cisplatin-resistant cancer cells, L1210/cis-DDP, in vivo.     

Structure and characterization of platinum(II) and platinum(IV) complexes with protonated nucleobase ligands

The reaction of H₂[PtCl₆] · 6H₂O and (H₃O)[PtCl₅(H₂O)] · 2(18C6) · 6H₂O (18C6 = 18-crown-6) with 9-methylguanine (MeGua) proceeded with the protonation of MeGua forming 9-methylguaninium hexachloroplatinate(IV) dihydrate (MeGuaH)₂[PtCl₆] · 2H₂O (1).The same compound was obtained from the reaction of Na₂[PtCl₆] with (MeGuaH)Cl.On the other hand, the reaction of guanosine (Guo) with (H₃O)[PtCl₅(H₂O)] · 2(18C6) · 6H₂O in methanol at 60 °C proceeded with the cleavage of the glycosidic linkage and with ligand substitution to give a guaninium complex of platinum(IV), [PtCl₅(GuaH)] · 1.5(18C6) · H₂O (2).Within several weeks in aqueous solution a slow reduction took place yielding the analogous guaninium platinum(II) complex, [PtCl₃(GuaH)] · (18C6) · 2Me₂CO (3).H₂[PtCl₆] · 6H₂O and guanosine was found to react in water, yielding (GuoH)₂[PtCl₆] (4) and in ethanol at 50 °C, yielding [PtCl₅(GuoH)] · 3H₂O (5).Dissolution of complexes 2 and 5 in DMSO resulted in the substitution of the guaninium and guanosinium ligands, respectively, by DMSO forming [PtCl₅(DMSO)]⁻.Reactions of 1-methylcytosine (MeCyt) and cytidine (Cyd) with H₂[PtCl₆] · 6H₂O and(H₃O)[PtCl₅(H₂O)] · 2(18C6) · 6H₂O resulted in the formation of hexachloroplatinates with N3 protonated pyrimidine bases as cation (MeCytH)₂[PtCl₆] · 2H₂O (6) and (CydH)₂[PtCl₆] (7), respectively. Identities of all complexes were confirmed by ¹H, ¹³C and ¹⁹⁵Pt NMR spectroscopic investigations, revealing coordination of GuoH⁺ in complex 5 through N7 whereas GuaH⁺ in complex 3 may be coordinated through N7 or through N9. Solid state structure of hexachloroplatinate 1 exhibited base pairing of the cations yielding (MeGuaH⁺)₂, whereas in complex 6 non-base-paired MeCytH⁺ cations were found. In both complexes, a network of hydrogen bonds including the water molecules was found. X-ray diffraction analysis of complex 3 exhibited a guaninium ligand that is coordinated through N9 to platinum and protonated at N1, N3 and N7. In the crystal, these NH groups form hydrogen bonds N–HO to oxygen atoms of crown ether molecules.     

Inhibitory activity of palladium(II) and platinum(II) complexes with isoxazole and its derivatives

The investigation of the inhibitory activity on the membrane bonded ATP-ase of the M(L)₂X₂ complexes [where M = Pd(II), Pt(II); L = isoxazole(isox), 3,5-dimethylisoxazole(3,5-diMeisox), 3-methyl,5-phenylisoxazole(3-Me,5-Phisox), 3,5-diphenylisoxazole-(3,5-diPhisox), and 4-amino-3,5-dimethylisoxazole(4-ADI); X = Cl, Br] is reported. These results show that the complexes with isox and its methyl and phenyl derivatives have a much stronger inhibitory effect than the corresponding free ligands; in the 4-ADI compounds this activity drops. The Pd(II) complexes have a greater effect than the Pt(II) derivatives. The interaction occurs with SH groups and probably also with other active centers of the enzyme. These conclusions have been correlated with the E.S.C.A. spectra. These measurements show that the electron density of the complexes on the central metal ion and N_ring atom or N_ring and N-hexocyclic atoms on passing from chloride to bromide derivatives changes slightly.