Iron(III)-adriamycin and Iron(III)-daunorubicin complexes: physicochemical characteristics, interaction with DNA, and antitumor activity

Fe(III) complexes of two anthracyclines, adriamycin and daunorubicin, have been studied. Using potentiometric and spectroscopic measurements, we have shown that adriamycin and daunorubicin form two well-defined species with Fe(III), which can be formulated as respectively Fe(HAd)3 and Fe(HDr)3. In these formulas, HAd and HDr stand for adriamycin and daunorubicin in which the 1,4-dihydroxy-anthraquinone moiety is half-deprotonated. Both complexes are six-membered chelates. The stability constant is beta = (2.5 +/- 0.5) X 10(28) for both complexes. Interaction with DNA has been studied showing that, despite strong coordination to Fe(III), anthracyclines are able to intercalate between DNA bases pairs, releasing the metal. These complexes display antitumor activity against P 388 leukemia that compares with that of the free drug. Fe(HAd)3, unlike adriamycin, does not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. Moreover, it is shown that the triferric adriamycin compound so called "quelamycin" is in fact a mixture of Fe(HAd)3 and polymeric ferric hydroxide.     

Cis-platinum (II) complexes of carboxymethyl-dextran as potential antitumor agents. II. In vitro and in vivo activity

Cis-diamminedichloro platinum (II) (cis-DDP) and cis-diamminediaquo platinum (II) nitrate (cis-aq) were complexed to a macromolecular carrier carboxymethyl dextran (CM-dex). Two carriers were used in this study, one derived from dex-T-10 (Mr-10000) and the other from dex-T-40 (Mr-40000). The two platinum (II) drugs formed soluble complexes with both carriers. Uncomplexed and complexed drugs were tested and found to be cytotoxic in vitro against 5 murine and 2 human derived tumor cell lines. The two free platinum (II) drugs were cytotoxic against these cells to a similar extent. In comparison to the free drugs the complexes were somewhat less active, up to 3 fold, against murine 38C-13, L1210, EL-4 and RDM-4 leukemias, as well as against human HeLa and osteogenic sarcoma, and as active as the free drugs against murine F9 embryonal carcinoma. There were no major differences in the in vitro cytotoxic activity between CM-dex T-10 and CM-dex T-40 complexes. Differences due to the molecular size of the carrier were observed in vivo: The CM-dex T-10 complexes were significantly less toxic than the free drugs, whereas the reduction of toxicity by complexing to CM-dex T-40 was less profound. As for the efficacy, when tested in vivo against a cis-DDP sensitive tumor (F9) the T-40 complexes were equally or even more effective than the respective free drugs. The T-10 complexes were less effective than the free drugs at equal drug doses but their effectivity increased at increasing drug levels. These complexes were, however, very effective in inhibiting tumor growth upon repeated injections, leading to 100% survival.     

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.     

Resonance Raman spectroscopic studies of adriamycin and copper(II)-adriamycin and copper(II)-adriamycin-DNA complexes

Characteristic resonance Raman spectra are observed on ionization of the phenolic groups in adriamycin. On the basis of these results, vibrational assignments for the Raman bands of adriamycin are reported. Distinct Raman spectra are observed for Cu(II)-adriamycin complexes at pH approximately 5 and pH approximately 13. The data indicate that at lower pH a bis complex of Cu(II) is formed, which transforms to a polymeric Cu(II) chelate at higher pH. Upon interaction of the metal-drug complex with calf thymus DNA at pH approximately 5, a ternary complex is formed in which the Cu(II)-complexed adriamycin is intercalated into DNA.     

Thiourea derivatives and their nickel(II) and platinum(II) complexes: antifungal activity

We have synthesized two thiourea derivatives of methyl anthranilate (1, 2) and their complexes with nickel (3) and platinum(II) (4). We have also prepared the complexes of nickel(II) with two benzoylthiourea derivatives (5, 6). The obtained compounds were characterized by elemental analysis, spectroscopic methods (FT-IR, UV-vis, NMR), mass spectrometry and thermal analysis. Compound 1, C(20)H(23)N(3)O(2)S, crystallizes in monoclinic space group P21/n, with Z=4, and unit cell parameters, a=8.8042(4) A, b=7.6608(3) A, c=28.834(2) A, alpha=gamma=90 degrees, beta=90.94(1) degrees. Compound 2, C(20)H(21)N(3)O(3)S, crystallizes in monoclinic space group P21/c, with Z=4, and unit cell parameters, a=7.7345(4) A, b=8.6715(4) A, c=29.113(2) A, alpha=gamma=90 degrees, beta=90.67(1) degrees. Compound 5, C(24)H(30)N(4)NiO(2)S(2), crystallizes in monoclinic space group P21/n, with Z=4, and unit cell parameters, a=10.4317(8) A, b=18.517(2) A, c=13.299(1) A, alpha=gamma=90 degrees, beta=104.53(1) degrees. Compound 6, C(25)H(28)Cl(2)N(4)NiO(4)S(2), crystallizes with a molecule of CH(2)Cl(2) in triclinic space group P-1, with Z=2, and unit cell parameters, a=10.362(1) A, b=11.849(2) A, c=12.536(2) A, alpha=90.04(2) degrees, beta=84.73(1) degrees, gamma=113.43(2) degrees. Compounds 1 and 2 show antifungal activity against the major pathogens responsible for important plant diseases (Botrytis cinerea, Colletotrichum fragariae, Fusarium oxysporum and Phoma betae). The antifungal activity is practically the same for morpholine and ethyl derivatives.     

Relevance of the leaving group for antitumor activity of new platinum(II) compounds containing anthracene derivatives as a carrier ligand

A new anticancer-active platinum(II) compound [Pt(A9pyp)(dmso)(cbdca)], containing the E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone ligand (abbreviated as A9pyp) has been synthesized by the replacement of the anionic chloride ligands in cis-[Pt(A9pyp)(dmso)Cl₂] by the dianionic chelating cyclobutanedicarboxylate ligand (abbreviated as cbdca). The in vitro relevance of the leaving group of these new platinum(II) compounds has been investigated. Measurements of the time-dependent intracellular accumulation of both compounds in human ovarian carcinoma cell lines show that the leaving group affects their cellular uptake. In addition, the leaving group also influences DNA platination, and, therefore, has an effect on the biological activity against a pair of human ovarian carcinoma cell lines, i.e. sensitive and resistant to cisplatin.     

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.     

Unprecedented sugar-dependent in vivo antitumor activity of carbohydrate-pendant cis-diamminedichloroplatinum(II) complexes.

Eight carbohydrate-pendant platinum(II) complexes have been synthesized from carbohydrate-diamine conjugates. D-Glucose, D-mannose, D-galactose, D-xylose, and L-glucose are attached to the dichloroplatinum(II) moiety by 1,3- or 1,2-diaminopropane chelates through with an O-glycoside bond. All the carbohydrate moieties reduced the toxicity inherent with platinum(II) complexes.     

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.     

Synthesis and antiproliferative activity of benzocyclobutacarbazol derivatives. A new class of potential antitumor agents

Several benzocyclobutacarbazol derivatives were synthesized and evaluated for their potential cytotoxic properties. A number of these compounds exhibited significant antiproliferative activity with concomitant interaction with the cell cycle and represent a new class of potential anticancer agents.     

Antiproliferative activity of Pt(II) and Pd(II) phosphine complexes with thymine and thymidine

Oxidative addition reactions between [M(PPh(3))(4)] (M=Pt and Pd) and N1-methylthymine (t)/3',5'-di-O-acetylthymidine (T) were carried out to give [M(II)(PPh(3))(2)Cl t (or T)] complexes, in which the metal is coordinated to the N3 of the base. All complexes were characterized by spectroscopic analyses (IR, NMR) and Fast Atom Bombardment mass spectrometry (FAB-MS); X-ray data for the thymine complexes and elemental analysis for the thymidine complexes are reported. The antiproliferative activity of the complexes was tested on human chronic myelogenous leukaemia K562 cells. Arrested polymerase-chain reaction analysis was carried on to correlate antiproliferative activity and inhibition of DNA replication. All Pd and Pt complexes exhibit antiproliferative activity, Pd complexes resulting always more active than Pt complexes. Arrested PCR data are strongly in agreement with the effects on cell growth, suggesting that inhibition of the DNA replication by the synthesized compounds is the major basis for their in vitro antiproliferative activity.     

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.     

Metal complexes with the ligand derived from 6-acetyl-1,3,7-trimethyllumazine and benzohydrazide. Molecular structures of two new Co(II) and Rh(III) complexes and analysis of in vitro antitumor activity

The structures and spectroscopic properties of new Mn(II), Co(II), Cd(II), Hg(II), Ag(I), Rh(III), and Ir(I) complexes with the ligand BZLMH derived from 6-acetyl-1,3,7-trimethyllumazine (lumazine = pteridine-2,4(1H,3H)-dione) and benzohydrazide are reported. Complexes have been characterized by elemental analyses, spectroscopic studies (IR, UV-vis, ¹H, ¹³C and ¹⁵N NMR) and magnetic measurements. In all the complexes, the lumazine-derived ligand appears to be coordinated in either tridentate (N5, N61 and O63) or tetradentate forms (O4, N5, N61 and O63). The molecular structures of the [Co(BZLMH)(H₂O)(CH₃CN)₂](ClO₄)₂ · CH₃CN and [RhCl₂(BZLM)(CH₃CN)] · CH₃CN complexes, determined by single crystal X-ray diffraction, have allowed to corroborate both coordination behaviours.The cytotoxic activity of the free ligand and complexes against human neuroblastoma NB69 cell line is also described. The differential analysis of the initial cytotoxic screening data has shown good activity only for the [RhCl₂(BZLM)(CH₃CN)] · CH₃CN compound at concentrations at around 2 μM; for the other complexes, a modulation of the cell growth was not found upon complexation, this non-specific effect strongly suggesting an apoptotic behaviour.     

Ethylenediamine-palladium(II) complexes with pyridine and its derivatives: synthesis, molecular structure and initial antitumor studies.

The synthesis of four mononuclear palladium complexes of general formula [Pd(en)Cl(L)]NO3 (en = ethylenediamine; L = pyridine (I), 4-methylpyridine (II), 4-hydroxypyridine (III) or 4-aminopyridine (IV) has been achieved. The structure of these compounds was studied by elemental analysis, IR, far-IR and 1H NMR; complex I was analyzed by X-ray diffraction. The crystal of [Pd(en)(pyridine)Cl]NO3 is monoclinic, space group P21/c (a = 7.990(2), b = 16.058(3), c = 9.846(2) A, beta = 103.81(3) degrees, Z = 4, R = 0.067, Rw = 0.066). The Pd(II) atom exhibits an approximately square planar coordination with bond lengths in the range 2.017-2.042 A for Pd-N and 2.320 A for Pd-Cl. In order to determine the donor strength of the aromatic pyridine ligands, the stability constants of binary complex ML2+ (M = [Pd(en) (H2O)2]2+; L = pyridine, 4-Me-pyridine, 4-OH-pyridine and 4-NH2-pyridine) were determined by potentiometric pH titration in aqueous solution (T = 25 degrees C, I = 0.1 mol l-1 NaNO3). The results show that the stability constants of the binary complexes systematically increase with increasing pKa of the pyridines. The above four palladium complexes, [Pt(en)(pyridine)Cl]NO3 and cis-diamminedichloroplatinum (II) (cis-DDP) were assayed for cytotoxicity in vitro against the human leukemia cell line HL-60, and compounds I, II, III and cis-DDP show significant cytotoxic activity against HL-60.     

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.     

Nickel(II) and cobalt(II) complexes of hydroxyl-substituted triazamacrocyclic ligand as potential antitumor agents

The stability constants for the formation of nickel(II) and cobalt(II) complexes of the ligand [1,4,7]triazecan-9-ol (L) were presented. Antitumor activity of two complexes was reported. Nuclei of [NiL]-stimulated BEL-7402 cells clearly exhibited condensation and break down into chromatin clumps typical of apoptosis. Also it exhibited perturbation effects to cell cycle, and optimal induction of apoptosis was found by Flow-Cytometric analysis. But CoL complex did not exhibit introduction effects to BEL-7402 cells apoptosis; and could not perturb cell cycle. NiL and CuL complexes could cleave supercoiled DNA (pBR 322 DNA) to nicked and linear DNA, and DNA of cells treated with NiL or CuL complex was obviously damaged; while CoL complex only could cleave supercoiled DNA (pBR 322 DNA) to nicked DNA, and DNA of cells treated with CoL complex had no significant difference with control.     

Synthesis, characterization and antibacterial activity of new sulfonamide derivatives and their nickel(II), cobalt(II) complexes

Methanesulfonicacid hydrazide (a sulfonamide compound, msh: CH₃SO₂NHNH₂) derivatives: methylsalicylaldehydemethanesulfonylhydrazone (5msalmsh), 5-methyl-2-hydroxyaceto-phenonemethanesulfonylhydrazone (5mafmsh) and their Ni(II), Co(II) complexes have been synthesized for the first time. The structure of these sulfonamide compounds has been investigated by using elemental analyses; FT-IR, ¹H NMR, ¹³C NMR, LC-MS, and UV-Vis spectrometric methods; magnetic susceptibility; conductivity measurements; thermal studies. The crystal structure of 5msalmsh has been investigated by X-ray analysis. The antibacterial activities of synthesized compounds were studied against gram positive bacteria: Staphylococcus aureus, Bacillus subtilis, and Bacillus magaterium; and gram negative bacteria: Salmonella enteritidis, and Escherichia coli by using the microdilution broth method. The biological activity screening showed that ligands have more activity than complexes against the tested bacteria.     

Cis-platinum(II) complexes of carboxymethyl-dextran as potential antitumor agents. I. Preparation and characterization

Cis-diamminedichloro platinum (II) (cis-DDP) and cis-diamminediaquo platinum (II) nitrate (cis-aq) were demonstrated to form complexes with dextran (dex) substituted with carboxymethyl (CM) groups at an average substitution ratio of 1 mole CM per 2 mole glucose units of dextran. The complexes were formed by reacting each of the two platinum (II) derivatives with carboxymethyl-dextran (CM-dex) at room temperature (RT) or at 37 degrees C in an aqueous solution. The complexing rate depended on temperature, ratio of platinum (II) compounds to CM-dex in the reaction mixture, and time of reaction. Experiments were performed with two CM-dex preparations, derived from dex T-10 (Mr-10,000) and from dex T-40 (Mr-40,000). Soluble cis-DDP and cis-aq complexes formed with CM-dex T-10 and CM-dex T-40 could carry up to 15 mole or 60 mole of the platinum (II) compounds per 1 mole CM-dex, respectively but higher complexing ratios resulted in complex precipitation. Reactivity of cis-aq with CM-dex was higher than that of cis-DDP. NaCl interfered with complex formation, but did not cause dissociation of already formed complexes. The binding of cis-DDP and cis-aq to CM-dex is, however, reversible since the drugs could be exchanged by other acceptors of higher affinity to platinum (II) such as O-phyenlenediamine, or DNA.     

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.