Synthesis and antitumor activity of N-substituted iminodiacetato(1,1-bis[aminomethyl]cyclohexane)platinum(II) complexes

A number of water-soluble N-substituted iminodiacetato(1,1-bis[aminomethyl]cyclohexane)platinum(II) complexes have been synthesized, and their mode of coordination characterized by elemental analysis and infrared data. Preliminary in vitro screening test for antitumor activity of these complexes against L1210 murine leukemia cells were performed. The results indicate that these complexes have an acceptable in vitro cytotoxicity against L1210 leukemia.     

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.     

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.     

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, antitumor activity and structure-activity relationships of a series of Ru(II) complexes

A series of octahedral Ru(II) polypyridyl complexes, [Ru(phen)(2)L](2+) (L=R-PIP and PIP=2-phenylimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elementary analysis, (1)H NMR and ES-MS, as well as UV-visible spectra and emission spectra. The antitumor activities of these complexes and their corresponding ligands were investigated against mouse leukemia L1210 cells, human oral epidermoid carcinoma KB cells, human promyelocytic leukemia cells (HL-60) and Bel-7402 liver cancer cells by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. It was found that the complexes [Ru(phen)(2)L](2+) (L=R-PIP) exert rather potent activities against all of these cell lines, especially for the KB cells (IC(50)=4.7+/-1.3 microM). The binding affinities of these Ru(II) complexes to CT-DNA (calf thymus DNA), as well as the DNA-unwinding properties on supercoiled pBR322 DNA were also investigated. The results showed that these Ru(II) polypyridyl complexes not only had an excellent DNA-binding property but also possessed a highly effective DNA-photocleavage ability. The structure-activity relationships and antitumor mechanism were also carefully discussed.     

Synthesis, cytotoxicity and antitumor activity of platinum(II) complexes of cyclopentanecarboxylic acid hydrazide

New platinum(II) complexes of cyclopentanecarboxylic acid hydrazide (cpcah) were prepared, characterized by elemental analysis, IR and 1H NMR spectra, and evaluated for in vitro cytotoxicity in Friend leukemia (FL) and A2780 ovarian tumor cells, induction of apoptosis in FL cells, as well as for in vivo antitumor activity toward murine L1210 leukemia and Lewis lung carcinoma. The spectral analyses indicated a cis-square planar structure of the complexes with hydrazide ligand coordinated via the NH2 group. The compounds exerted significantly lower in vitro and in vivo toxicities as compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). On the other hand, the complex [Pt(NH3)(cpcah)Cl2] exhibited antitumor activity against L1210 leukemia in mice comparable to that of cisplatin, resulting at a dose of 42 mg/kg (administered 3 times) in a T/C (mean survival time) of 280%. This compound displayed an in vitro macromolecular synthesis inhibition pattern similar to that of DDP. At concentrations close to the cytostatic ones (10-20 microM) this complex, as well as DDP, was able to induce apoptosis in FL cells as shown by neutral comet assay and morphological analysis. We concluded that there is a correlation between the ability of platinum complexes to induce apoptosis and their antitumor activity.     

Synthesis and antitumor activity of a series of 1,2-diaminocyclohexanepalladium(II) dicarboxylate complexes

A series of complexes of the type [Pd(O O(DACH)] (O O = dicarboxylate ligand, DACH = 1,2-diaminocyclohexane) has been prepared. These complexes have been characterized by elemental analysis and infrared spectroscopy. The complexes have been screened in vivo for antitumor activity against the L1210 leukemia cell line. These palladium complexes lack antitumor activity, which may be due to (1) lack of solubility and/or (2) lack of stability of the complexes in solution.     

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, characterization, and antitumor activity of new chloroethylamine platinum complexes.

A series of cis-bis-(2-chloroethylamine)platinum(II) and platinum(IV) complexes were synthesized and characterized by elemental analysis, IR, and 1H and 195Pt NMR spectroscopic techniques. Complexes were tested in vitro against murine L1210 leukemia and human ovarian A2780 cell lines and in vivo against the L1210 leukemia model. Some of these complexes showed excellent antitumor activity in both systems. However, all were inactive against cisplatin-resistant A2780/CP cells.     

Synthesis, antimicrobial, and antitumor activity of a series of palladium(II) mixed ligand complexes.

Mixed ligand complexes of cisdichloromethioninepalladium(II) with 2-mercaptopyrimidine and 2-aminopyrimidine were synthesized and characterized by elemental analysis, conductivity data, infrared, and 1H NMR and 13C NMR spectra. In these mixed ligand complexes methionine coordinates to palladium through amino nitrogen and sulphur, thus leaving a free carboxylic acid group. The pyrimidine ligand coordinates to metal ion through N3. Mixed ligand complexes of cisdichloroethioninepalladium(II) with cytosine and guanosine were synthesized and characterized earlier. All the above mixed ligand complexes were screened for antimicrobial activity against Vibrio parahaemolyticus, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli, Shigella flexnerri, Salmonella typhii, Klebsella pneumoniae, and Vibrio cholerae. It was found that complexes [Pd(meth)Cl2]: [Pd(meth)(2merpy)Cl]Cl; [Pd(meth)(2ampy)Cl]Cl; [Pd(ethio)Cl2]; [Pd(ethio)(cyt)Cl]Cl; and [Pd(ethio)(guo)Cl]Cl showed broad spectrum antimicrobial activity against all the human pathogens tested, however [Pd(meth)(2merpy)Cl]Cl eliminated plasmid with 100% frequency. These complexes have also been screened in vitro for antitumor activity against Hela (Epidermoid Carcinoma Cervix) and CHO cell lines. An excellent correlation between the antitumor activity of Pd(II) complexes and their ability to cure plasmids exists.     

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.     

Synthesis,cytotoxicity, antibacterial and antitumor activity of platinum(II) complexes of 3-aminocyclohexanespiro-5-hydantoin

New platinum(II) complexes of 3-aminocyclohexanespiro-5-hydantoin (achsh) were prepared and characterized. Ab initio calculation of the structure and the measurements of IR and NMR spectra of [Pt(NH(3))(achsh)Cl(2)] were also performed. Quantum-chemical and spectroscopic studies indicated a cis-square planar structure with a hydantoin ligand coordinated via the NH(2) group. The complexes were evaluated for in vitro cytotoxicity in murine erythroleukemia (MEL) cells, clone F4N, as well as for in vivo antitumor activity toward murine L1210 leukemia. The complexes exerted significantly lower in vitro and in vivo toxicities compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). The complex [Pt(NH(3))(achsh)Cl(2)] exhibited antitumor activity against L1210 leukemia, comparable to that of cisplatin, resulting at a dose of 72 mg/kg in a %T/C (increased survival time) of 191%. This complex, as well as cisplatin, induced apoptosis in F4N cells, and exerted antibacterial activity as assessed in 10 bacterial strains.     

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.     

The synthesis and characterization of N-substituted iminodiacetato cis-, trans-R, R- and trans-S, S-1, 2-diaminocyclohexane platinum(II) complexes: steric effects on the diastereomeric ratios

A series of platinum(II) complexes of the type [Pt(N-R-IDA)(DACH)], where DACH was either cis-1,2-diaminocyclohexane, trans-R, R-1, 2-diaminocyclohexane, or trans-S, S-1, 2-diaminocyclohexane, and N-R-IDA was either the iminodiacetate, N-methyliminodiacetate, N-n-propyliminodiacetate, or N-t-butyliminodiacetate ion, has been prepared and characterized. A detailed NMR investigation shows that the N-R-IDA ions bind to the platinum (II) ion through one of the acetate oxygens and the imino nitrogen, forming a five-membered ring. The second acetate ion does not bind to the platinum. By virtue of the prochiral N-atom of N-R-IDA and the absence of a horizontal plane of symmetry of the Pt(DACH) moiety, two diastereomers are observed corresponding to the two different orientations of the unbound acetate and the R-group with respect to the platinum coordination plane. The ratio of the two geometric isomers is controlled by steric factors depending upon both the isomeric form of 1,2-diaminocyclohexane and the nature of the R group bound to the imino nitrogen of N-R-IDA.     

Synthesis and cytotoxic activity of benzopyran-based platinum(II) complexes

A series of benzopyran-based platinum complexes of types 4 and 5 were synthesized as potential anticancer agents. The novel compounds were synthesized in several steps using simple and efficient chemistry. The newly synthesized compounds were evaluated for their biological efficacy and showed significant in vitro cytotoxic activity in different hormone-dependent and -independent breast cancer cell lines. Docking and other molecular modeling experiments were also performed for one of the potent compounds, 5f, which showed that both the possible enantiomeric forms (5f with 3R,4R and 5f with 3S,4S) of the molecule have comparable lowest energy (for 5f with 3R,4R, −31.953 kcal/mol and for 5f with 3S,4S, −31.944 kcal/mol). The 3D QSAR was examined for the derivatives of both enantiomeric forms and a novel relationship for the 3S,4S derivatives is discussed.     

Methimazole complexes of platinum(II): Synthesis, characterization and redox behavior

A variety of platinum(II) complexes of methimazole (2-mercapto-1-methylimidazole; HImS = neutral form and ImS = thiolate form), coordinated in both thione and thiolate forms, have been isolated by reacting methimazole with [PtCl(terpy)]Cl (terpy = 2,2′:6′,2″ terpyridine), [PtCl₂(bipy)] (bipy = bipyridine), [PtCl₂(o-phen)] (o-phen = o-phenanthroline), [PtCl₂(CH₃CN)₂] and [PtCl₂(COD)] (COD = 1,5-cyclooctadiene). These complexes were characterized by electronic absorption, IR and NMR (¹H, ¹³C, ¹⁹⁵Pt) spectroscopies. Molecular structure of [Pt(bipy)(HImS)₂]Cl₂·3H₂O (3a·3H₂O) has been established by single crystal X-ray crystallography. Platinum thiolate complex, [Pt(ImS)₂(HImS)₂] (5), could be obtained by treatment of [Pt(HImS)₄]Cl₂ with sodium methoxide in methanol. The solution of 5 in organic solvents yielded bi- and tri-nuclear platinum complexes. The effect of diimine ligands on oxidation of methimazole moiety in the complexes has been studied by electrochemical oxidation and pulse radiolytic oxidation employing specific one-electron oxidant, radical.     

Molecular structure and antitumor activity of platinum(II) complexes containing purine analogs

Platinum(II) compounds containing purine analogs as ligands have gained increasing attention in pharmaceutical applications as, for example, antitumor drugs. This article reviews the molecular and antitumor properties of this class of compounds. The large amount of available spectroscopic and crystollographic data allows possible elucidation of geometrical parameters, such as bond lengths and angles, which may have an impact on the behavior of platinum(II) complexes against tumor cells.     

Synthesis, characterization and antitumor activity of quinolone-platinum(II) conjugates.

A new series of quinolone-platinum(II) conjugates, [Pt(Q'-NH2)(dmso)X2] and cis-[Pt(Q"-en)X2], where Q' and Q" are quinolones (flumequine, nalidixic acid or oxolinic acid) linked to monodentate and bidentate amine ligands, respectively, and X2 is Cl2 or 1,1-cyclobutanedicarboxylate, have been synthesized with the aim of examining the synergetic antitumor activity of quinolone intercalation and platinum(II) chelation. The complexes were characterized by elemental analyses and IR and multinuclear (1H and 195Pt) NMR spectroscopies, and then subjected to in vitro and in vivo bioassays using the leukemia L1210 cell line.     

Synthesis, characterization, and antitumor activity of iron(II) and iron(III) complexes of alpha-N-heterocyclic carboxaldehyde thiosemicarbazones

Complexes of iron(II) and iron(III) with 1-formylisoquinoline thiosemicarbazone (1-iqtsc-H), 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (4-Me-5-NH2-1-iqtsc-H) and 4-(m-aminophenyl)-2-formylpyridine thiosemicarbazone (4-m-NH2ph-2-pytsc-H) were synthesized and characterized by elemental analysis, conductance measurements, magnetic susceptibilities (from room temperature down to liquid N2 temperature), and M?ssbauer, electronic, and infrared spectral studies. On the basis of these studies, a highly distorted, high-spin, five-coordinate structure for Fe(HL)SO4 (HL = 1-iqtsc-H, 4-Me-5-NH2-1-iqtsc-H or 4-m-NH2ph-2-pytsc-H) and a distorted, low-spin, octahedral structure for Fe(HL)Cl2 are suggested. The EPR spectra of iron(III) complexes show that all have dxy low-spin ground state. All these complexes have been screened for their antitumor activity against the P 388 lymphocytic leukemia test system in mice and have been found to possess significant activity at the dosages employed.