Synthesis, characterization, and antitumor activity of 5-iodouracil complexes.

Complexes of 5-iodouracil (5IU) with Mn(II), Co(II), Cu(II), Zn(II), and Cd(II) ions have been prepared, characterized, and subjected to a screening system for evaluation of antitumor activity against Sarcoma-180 (S-180) and L 929 tumor cells. The complexes were characterized by their elemental analysis, infrared spectra, electronic spectra, magnetic measurements, and powder x-ray diffraction. The antitumor activity results indicate that some complexes have good antitumor activity both in vivo and in vitro against S-180 and L 929 tumor cells.     

Synthesis and antitumor activity of platinum complexes of protonated diamines

Complexes of the formula cis-[Pt(H$\text{N}\text{+}$^～N)(L)Cl₂], where (H$\text{N}\text{+}$^～N) are the protonated diamines including 3-aminoquinuclidine, N-aminopiperidine, piperazine, N-methylpiperazine, 1,1,4-trimethylpiperazine, and N-methyl-1,4-diazabicyclo [2,2,2] octane (N-methyl-dabco) and L = SCN^?, NO₂^?, Br^?, and F^?, were synthesized from the protonated diamine complexes, [Pt(H$\text{N}\text{+}$^～N)Cl₃]. The antitumor activities of the complexes were evaluated in vitro against L1210 murine leukemia cells, and ID₅₀ values for the L-substituted complexes were compared to values of the parent complexes. In each case it was found that replacement of a chloride ion by SCN^?, NO₂^?, Br^?, or F^?, either reduced or completely eliminated antitumor activity. This effect is explained in terms of the trans-directing ability of the ligand, L, compared to chloride. The NO₂-substituted complex of 3- aminoquinuclidine was tested in vivo and found to exhibit little or no antitumor activity.     

Synthesis, structures and antitumor activity of the first crown ester-linked bipyridyl platinum complexes.

Three new crown ester-linked bipyridine homologs with three, four or five ethylene glycol units, which are bulky and soluble in both hydrophilic and lipophilic media, were synthesized. The reaction of the appropriate macrocycles with K2PtCl4 in water gave yellow cisplatin analogs in good yield. These complexes were converted to carboplatin analogs by exchange of the leaving group. All the compounds were characterized by elemental analysis and various spectroscopic methods. Carboplatin analogs showed good solubility in both hydrophilic and lipophilic media. The crystal structure of 2c, the carboplatin analog with macrocycles containing five ethylene glycol units, was determined by X-ray diffraction: space group P1, a = 9.798(1), b = 12.580(3), c = 13.945(2) A, alpha = 108.61(2), beta = 94.59(1), gamma = 97.42(2) degrees, Z = 2, R = 0.0618. Some of platinum complexes showed a moderate cytotoxic effect on both murine leukemia L1210 and P388 even though they do not have any NH proton.     

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.     

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 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.     

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,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.     

Synthesis,characterization, and biological activity of platinum II,III, and IV pivaloamidine complexes

Imino ligands have proven to be able to activate the trans geometry of platinum(II) complexes towards antitumor activity. These ligands, like aromatic N-donor heterocycles, have a planar shape but, different from the latter, have still an H atom on the coordinating nitrogen which can be involved in H-bond formation. Three classes of imino ligands have been extensively investigated: iminoethers (HN=C(R)OR′), ketimines (HN=CRR′), and amidines (HN=C(R)NR′R″). The promising efficacy of the platinum compounds with amidines (activity comparable to that of cisplatin for cis complexes and much greater than that of transplatin for trans complexes) prompted us to extend the investigation to amidine complexes with a bulkier organic residue (R = t-Bu). The tert-butyl group can confer greater affinity for lipophilic environments, thus potentiating the cellular uptake of the compound. In the present study we describe the synthesis and characterization of pivaloamidine complexes of platinum(II), (cis and trans-[PtCl₂(NH₃){Z-HN=C(t-Bu)NH₂}] and cis and trans-[PtCl₂{Z-HN=C(t-Bu)NH₂}₂]), platinum(III) ([Pt₂Cl₄{HN=C(t-Bu)NH}₂(NH₃)₂]), and platinum(IV) (trans-[PtCl₄(NH₃){Z-HN=C(t-Bu)NH₂}] and trans-[PtCl₄{Z-HN=C(t-Bu)NH₂}₂]). The cytotoxicity of all new Pt complexes was tested toward a panel of cultured cancer cell lines, including cisplatin and multidrug resistant variants. In addition, cellular uptake and DNA binding, perturbations of cell cycle progression, induction of apoptosis, and p53 activation were investigated for the most promising compound trans-[PtCl₂(NH₃){Z-HN=C(t-Bu)NH₂}]. Remarkably, the latter complex was able to overcome both acquired and intrinsic cisplatin resistance.     

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,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, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes

Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η⁶-benzyldimethylamine)tricarbonylchromium 2, [η⁶-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η⁶-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC₅₀ values of 33.9 nM versus 63.1 nM).     

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, 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 and characterization of new platinum(II) complexes containing thiazole and imidazole donors

A number of new complexes of Pt(II) of the type cis-Pt(NH₃)(L)Cl₂, where L = thiazole (Tz), 2-bromothiazole (2-Brt), benzothiazole (Bt), 2,1,3- benzothiadiazole (213-Btd), 1,2,3-benzothiadiazole (123-Btd), imidazole (Iz) and 1-methylimidazole (N-Miz) have been prepared. The complexes were characterized by infrared and UV—Vis spectroscopy, proton NMR and elemental analyses. The thiazoles and benzothiazoles were coordinated through the nitrogen heteroatom. However, both the benzothiadiazoles were coordinated through the sulfur heteroatom. Several of the complexes showed significant cytotoxic activity.     

Synthesis,characterization and antitumor studies of transition metal complexes of o-hydroxydithiobenzoate

o-Hydroxydithiobenzoate (o-HOdtb) forms complexes, [Ni(o-HOdtb)(o-HOdtbS)], [Cu(o-Odtb)], [Co(o-HOdtb)(3)], [Fe(2)(o-Odtb)(3)], [Bu(n)(4)N][V(o-Odtb)(3)] and [Bu(n)(4)N][Zn(o-HOdtb)(3)] which were characterized by analyses and physicochemical studies. The bonding sites of o-HOdtb and the geometry of the complexes were determined by magnetic susceptibility, IR, ESR, NMR, M?ssbauer and electronic spectral data. The structure of [Bu(n)(4)N][Zn(o-HOdtb)(3)] and H(2)C(o-HOdtb)(2) were assigned by single crystal X-ray diffraction studies. The monomeric complex [Bu(n)(4)N][Zn(o-HOdtb)(3)] crystallizes in Pna2(1) space group. The M?ssbauer spectra of [Fe(2)(o-Odtb)(3)] at 298 and 80K suggest the presence of high spin iron(III) with an S=5/2 state. All the metal complexes were observed to inhibit the growth of tumor in vitro, whereas, ligand did not. In vivo administration of these complexes resulted in prolongation of survival of tumor-bearing mice. Tumor bearing mice administered with metal complexes showed reversal of tumor growth associated induction of apoptosis in lymphocytes. The paper discusses the possible mechanisms and therapeutic implication of the ligand and its metal complexes in tumor regression and tumor growth associated immunosuppression.     

Structure-antitumour activity relationships for new platinum complexes

Fourteen platinum (Pt) coordination complexes with different ligands, which include both Pt(II) and Pt(IV) complexes, were prepared, characterized and tested for their in vitro cytotoxic effects on KB cells and for their antitumour activity against some tumour systems (L1210 and P388 leukaemia, ADJ/PC6A plasma cell tumour and Yoshida sarcoma).The majority of the ligands were derivatives of aniline or pyridine, but complexes with tranylcypromine, guanethidine and octodrine were also synthetized.Depending on cytotoxicity the Pt-compounds could be divided into 3 groups. The compounds with a high cytotoxicity (ED₅₀ = 0.1–1 μg/ml) were also active against L1210 and P-388 leukaemia; a correlation between cytotoxicity and antitumour activity was not always observed.In these complexes the oxidation state of the Pt appears to be critical for their activity.     

Synthesis,characterization and antitumor activity of some metal complexes of 3- and 5-substituted salicylaldehyde o-hydroxybenzoylhydrazones

Complexes of Mn(II), Fe(III), Fe(II), Co(II), Ni(II), Cu(II), Zn(II) and Pt(II) with 3- and 5-substituted salicylaldehyde o-hydroxybenzoylhydrazones (XSBH, X = H, 3-NO₂, 3-CH₃O, 5-Cl, 5-Br, 5-CH₃ or 5-NO₂) have been prepared and characterized by elemental analysis, conductance measurements, magnetic susceptibilities (from room temperature down to liquid nitrogen temperature) and spectral studies. These studies indicate the following structures: monomeric, high-spin, distorted octahedral for Mn(XSBH)₂; monomeric, high-spin, five-coordinate for Fe(XSBH)SO₄·H₂O; dimeric, high-spin phenoxide bridged, five-coordinate for Fe(XSBH)Cl; dimeric, high-spin five-coordinate for Co(XSBH)Cl·2H₂O; dimeric low-spin, five-coordinate for Ni(XSBH)Cl·2H₂O; dimeric, four-coordinate for Zn(XSBH); and a square-planar structure for M(XSBH)Cl·H₂O (M = Cu(II) or Pt(II).Intermolecular antiferromagnetic exchange interactions are present in Fe(III) complexes, where the exchange parameter (J) is ca. −8.0 cm⁻¹ for these complexes. The Fe(III) complexes exhibit asymmetric quadrupole split doublets in their ⁵⁷Fe Mössbauer spectra. The asymmetry is found to be temperature dependent with relatively symmetrical doublets seen at low temperature. The polycrystalline ESR spectra of Cu(II) complexes are isotropic and indicate a d_x²−y² ground state in square-planar stereo-chemistry. All these metal complexes have been screened for their antitumor activity against the P 388 lymphocytic leukaemia test system in mice and enhanced antitumor activity relative to the free ligand was found but no significant activity at the dosages used.     

Cisplatin stops tubulin assembly into microtubules. A new insight into the mechanism of antitumor activity of platinum complexes

Despite numerous studies considering DNA as a primary target of cisplatin attack, this work is the first to show the pure effect of cisplatin on the process of tubulin assembly/disassembly in vitro. When platinated, tubulin does not assemble into microtubules (direct electron microscopic studies). In place of them, highly stable and inert circled rings arise. Such tubulin aggregates are unable to participate in the process of chromosome separation during the mitosis, thus blocking cell division in living cells, which is a direct evidence of cisplatin antitumor activity. Cisplatin attack on tubulin causing blockage of tubulin assembly occurs via a two-step binding to GTP in the GTP center of tubulin ((195)Pt, (31)P NMR studies). The calculated binding rates are close to those reported in cisplatin-DNA interactions. The mechanism of cisplatin attack on tubulin is proposed.