Copper(II), cobalt(II) and nickel(II) complexes of alkyl-substituted tris(2-benzimidazolylmethyl)amines and their ternary copper(II) systems containing several thiolates

Copper(II), cobalt and nickel(II) complexes of tris(benzimidazolylmethyl)amine(1) and of its methyl(2), isobutyl(3) or isopropyl(4)-substituted derivatives of one of the backbone methylene groups were prepared and characterized. The ligands (1)–(3) afforded trigonal bipyramidal copper(II) complexes, whereas ligand (4) gave a tetrahedrally distorted tetragonal one because of the steric hindrance arising from the isopropyl group. All the cobalt(II) complexes prepared were supposed to be tetrahedral or pseudotrigonal bipyramidal, and all the nickel(II) complexes to be slightly tetrahedrally distorted octahedral. Ternary copper(II) systems containing several thiolates as the third component exhibited intense blue, brown or green color under a reduced temperature by virtue of the charge transfer bands, S^? → Cu.     

Synthesis,characterization and DNA binding studies of platinum(II) complexes with benzimidazole derivative ligands

The aim of this study was to synthesize and evaluate plasmid DNA interaction of new platinum(II) complexes with some 2-substituted benzimidazole derivatives as carrier ligands which may have potent anticancer activity and low toxicity. Twelve benzimidazole derivatives carrying indole, 2-/or 3-/or 4-methoxyphenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-methoxybenzyl, 3,4,5-trimethoxybenzyl, 3,4,5-trimethoxystyryl, 3,4,5-trimethoxybenzylthio or dimethylamino ethyl groups in their position 2 and twelve platinum(II) complexes with these carrier ligands were synthesized. The chemical structure of the platinum complexes have been characterized by their elemental analysis and FIR, ¹H NMR and mass spectra and their ¹H NMR and FIR spectra were interpreted by comparison with those of the ligands. The interaction of all the ligands and their complexes with plasmid DNA and their restriction endonuclease reactions by BamHI and HindIII enzymes were studied by agarose gel electrophoresis. It was determined that complex 1 [dichloro-di(2-(1H-indole-3-yl)benzimidazole)platinum(II)·2H₂O] has stronger interaction than carboplatin and complex 10 [dichloro-di(2-(3,4,5-trimethoxystyryl)benzimidazole)platinum(II)·2H₂O] has stronger interaction than both carboplatin and cisplatin with plasmid DNA.     

Improving anti-trypanosomal activity of 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives by complexation with vanadium

New vanadium complexes of the type [V(IV)O(L)(2)], where L are 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, were prepared as an effort to obtain new anti-trypanosomal agents improving the bioactivity of the free ligands. Complexation to vanadium of the quinoxaline ligands leads to excellent antiprotozoal activity, similar to that of the reference drugs nifurtimox and benznidazole and in all cases higher than that of the corresponding free ligands. In addition, it is for the first time that the V((IV))O-quinoxaline complexes are reported as a family of anti-Trypanosoma cruzi agents. Finally, the anti-trypanosomal activity of these vanadium complexes could be explained on the basis of their lipophilicity and the electronic characteristics of the quinoxaline substituents.     

Evaluation of insulin-mimetic activities of vanadyl and zinc(II) complexes from the viewpoint of heterocyclic bidentate ligands

Vanadyl sulfate (VOSO₄) has been clinically tested in diabetic patients since 1995. Oral administrations of VOSO₄ improved the type 2 diabetic state with respect to plasma glucose, HbA_1c, and fructosamine levels. The development of toxicity by increasing the administration of VOSO₄ should be avoided. One method was the utilization of vanadyl complexes with coordination compounds that are low-toxic and low-molecular-weight ligands to enhance the permeation of the metal ion to lipid bilayer membrane. Over a decade we have focused on a variety of heterocyclic compounds as bidentate ligands for metal ions. Vanadyl and zinc(II) complexes of 1-substituted 3-hydroxy-2-methyl-4(1H)-pyridinethiones, 4,5,6-substituted 1-hydroxy-2(1H)-pyrimidinones, 4-(p-substituted)phenyl-3-hydroxythiazole-2(3H)-thiones, 3-hydroxypyrone, 1-alkyl- or 1-phenylalkyl-3-hydroxy-2(1H)-pyridinethiones, optically active 1-substituted 3-hydroxy-4(1H)-pyridinethiones, and 5-dialkylsulfonamido- or 5,7-bis(dialkylsulfonamido)-8-hydroxyquinolines were prepared, and their insulin-mimetic activities were evaluated in terms of IC₅₀ values which stand for a 50% inhibitory concentration of the free fatty acid release from isolated rat adipocytes. In this article, the relationship between the insulin-mimetic activity and the partition coefficient, the chirality, the substituent effect, molecular weight, the pK_a value, and the coordination mode was discussed. In vivo blood glucose-lowering effects of the vanadyl complex with 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone in streptozotocin (STZ)-induced diabetic rats and the zinc(II) complexes with 4-(p-chlorophenyl)thiazole- and 4-methylthiazole-2(3H)-thione in KK-A^y mice were also discussed.     

Selective hypoxia-cytotoxins based on vanadyl complexes with 3-aminoquinoxaline-2-carbonitrile-N1,N4-dioxide derivatives

A new vanadyl complex with the formula VO(L1)2, where L1=3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1), N(4)-dioxide, has been synthesized and characterized by elemental analyses, conductometry, fast atom bombardment mass spectroscopy (FAB-MS) and electronic, Fourier transform infrared (FTIR), Raman, nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopies. Results were compared with those previously reported for analogous vanadium complexes with other 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands. As an effort to develop novel metal-based selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of aminoquinoxaline carbonitrile N-dioxides bioreductive prodrugs, the new complex and VO(L)2 complexes, with L=3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide (L2) and 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide (L3), were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes resulted in vitro more potent cytotoxins than the free ligands (i.e. potencies P(VO(L1)2)=3.0, P(L1)=9.0 microM) and Tirapazamine (P=30.0 microM) and showed excellent selective cytotoxicity in hypoxia, being no cytotoxic in oxia. In addition, the solubility in hydrophilic solvents resulted significantly higher for the vanadyl complexes than for the free ligands. These results could be indicative that complexation of the quinoxaline-2-carbonitrile N1,N4-dioxide derivatives with vanadium could improve their bioavailability. In addition, a new aspect of the series has been investigated. A detailed comparison of the electrochemical behavior of the free ligands and the complexes has been performed searching for a correlation between reduction potentials of the complexes and their activities and hypoxia selectivities.     

Synthesis, X-ray crystal structures and biomimetic and anticancer activities of novel copper(II)benzoate complexes incorporating 2-(4'-thiazolyl)benzimidazole (thiabendazole), 2-(2-pyridyl)benzimidazole and 1,10-phenanthroline as chelating nitrogen donor ligands

Cu(BZA)(2)(EtOH)(0.5) (1) was generated by the reaction of copper(II) hydroxide with benzoic acid (BZAH). [Cu(TBZH)(2)(BZA)](BZA).0.5TBZH.H(2)O (2) and [Cu(2-PyBZIMH)(2-PyBZIM)(BZA)].1.66EtOH (3) were obtained when 1 reacted with Thiabendazole (TBZH) and 2-(2-pyridyl)benzimidazole (2-PyBZIMH), respectively. [Cu(BZA)(2)(phen)(H(2)O)] (4) was isolated from the reaction of benzoic acid and 1,10-phenanthroline (phen) with copper(II)acetate dihydrate. Molecular structures of 2, 3 and 4 were determined crystallographically. 2 and 3 are hydrogen bonded dimers and trimers, respectively. The copper centres in complexes 2 and 3 are bis-chelate derivatives that have N(4)O ligation and their geometry is very similar being approximately square-pyramidal. However whereas in complex 2 both TBZH ligands are neutral in 3 one of the 2-PyBZIMH chelators is deprotonated on each copper. The structural results for 4 represent a re-examination of this crystallographically known compound for which no hydrogen atom coordinates have been previously reported. It crystallises as a hydrogen bonded dimmer and is a mono-chelate of phen with each copper centre possessing N(2)O(3) ligation and square pyramidal geometry. The catalase and superoxide dismutase (SOD) activities of the four complexes along with those of the known phenanthroline complexes [Cu(mal)(phen)(2)] and [Cu(phendione)(3)](ClO(4))(2) (malH(2)=malonic acid and phendione=1,10-phenanthroline-5,6-dione) were investigated. Complexes 1-4, the metal free ligands and a simple copper(II) salt were assessed for their cancer chemotherapeutic potential against the hepatocellular carcinoma (Hep-G(2)) and kidney adenocarcinoma (A-498) cell lines. TBZH, 2-PyBZIMH and benzoic acid when uncoordinated to a metal centre offer poor chemotherapeutic potential. copper(II) benzoate is significantly more active than the free acid. The bis-chelate derivatives [Cu(TBZH)(2)(BZA)](BZA).0.5TBZH.H(2)O (2) and [Cu(2-PyBZIMH)(2-PyBZIM)(BZA)].1.66EtOH (3) elicit a significant cytotoxic response to the cancer cell lines tested. Replacing TBZH and 2-PyBZIMH with phen to give [Cu(BZA)(2)(phen)(H(2)O)] (4) does not significantly increase the anti-cancer activity.     

Ligand specificity of human plasminogen kringle 4.

The ligand specificity of the human plasminogen kringle 4 was characterized in terms of ligand size, aromatic/aliphatic character, and ionic charge distribution. The binding of the following ligands was investigated via 1H NMR spectroscopy, and their equilibrium association constants (Ka) were determined: (1) p-aminomethylbenzoic acid (Ka approximately 4.8 mM-1), (2) benzylamine (Ka approximately 0.2 mM-1), (3) l-aminohexane (Ka approximately 0.07 mM-1), (4) 7-aminoheptanoic acid (Ka approximately 6.6 mM-1), (5) 5-aminopentanoic acid (Ka approximately 16 mM-1), (6) N alpha-acetyl-L-arginine (Ka approximately 0.3 mM-1), and (7) N alpha-acetyl-L-arginine methyl ester (Ka approximately 0.08 mM-1). Benzamidine and L-arginine do not bind measurably to kringle 4. We have also established that 1-hexanoic acid and 4-methylbenzoic acid do not interact significantly with kringle 4 (Ka less than 0.05 mM-1). The Trp62 resonances were found to be quite sensitive to aromatic ligands as well as to aliphatic ligand length. Phe64 is similarly sensitive to the ligand aromatic/aliphatic character and chain length and to the identity of the ligand anionic group. His31 and His33 do not respond significantly to variations in ligand structure, although they are perturbed by aromatic and aliphatic effectors. The perturbations induced by the arginine derivatives on these residues show that these compounds interact with the lysine-binding site (LBS) of kringle 4. The LBS was further characterized using 2D NMR studies of a kringle 4/trans-(aminomethyl)cyclohexanecarboxylic acid (AMCHA) complex. A complete assignment of the AMCHA spectrum in the bound state was achieved. This enabled the unambiguous identification of intermolecular contact points between the central AMCHA protons and Trp62 and Trp72. A model based on the X-ray crystallographic structure of kringle 4, incorporating these constraints, has been derived.     

Binding of adenosine 3',5'-monophosphate dependent protein kinase regulatory subunit to immobilized cyclic nucleotide derivatives.

Several cyclic nucleotide derivatives with aminoalkyl side chains attached to the purine ring were synthesized and their interactions with adenosine 3',5'-monophosphate (cAMP) dependent protein kinase were studied before and after immobilization to CNBr-activated Sepharose 4B. The soluble N6-substituted derivatives were as effective as cAMP itself in activating protein kinase and were more effective than 8-substituted cAMP derivatives, whereas the 2-substituted cAMP derivatives and the cGMP derivatives were the least effective. All of the synthetic derivatives tested were poor substrates for beef heart phosphodiesterase being hydrolyzed at rates less than 2% for that of cAMP itself. Utilizing methodology developed to evaluate the affinity of protein kinase for immogilized cyclic nucleotides it was found that all of the immobilized cyclic nucleotides interacted with protein kinase in a biospecific manner as judged by the following criteria: (1) the immobilized cyclic nucleotides competed with cAMP for the binding sites on protein kinase; (2) the analogous spacer-arm did not compete; and (3) the effects of enzyme concentration, MgATP, and cleavage of the cyclic phosphate ring on the interactions of protein kinase with the immobilized cyclic nucleotides were the same as previously shown for free cAMP. In addition, the immobilized ligands were bound with the same order of effectiveness as the analogous soluble ligand. The observed Ka for the activation of 0.005 muM protein kinase by N6-H2N(CH2)2-cAMP was increased from 0.23 to 3 muM by the process of immobilization. This increase was unaffected by the coupling density and spacer-arm length. The observed Kb for 0.10 muM protein kinase binding to immobilized N6-H2N(CH2)2-cAMP was increased as the molecular sieving exclusion limit of the matrix used was decreased indicating that at least part of this decrease in apparent affinity upon immobilization is due to exclusion of the enzyme from a portion of the matrix and therefore of the immobilized ligand molecules.     

Copper(II) complexes of some N-substituted bis(aminomethyl)phosphinate ligands. An integrated EPR study of microspeciation and coordination modes by the two-dimensional simulation method

Copper(II) complexes of bis(aminomethyl)phosphinic acid (L1), bis(N-glycino-N-methyl)phosphinic acid (L2), bis(N-benzylglycino-N-methyl)phosphinic acid (L3), bis(l-prolino-N-methyl)phosphinic acid (L4) and bis(iminodicarboxymethyl-N-methyl)phosphinic acid (L5) were studied in aqueous solution by pH-potentiometric and electron paramagnetic resonance (EPR) spectroscopic methods. The EPR spectrum packages recorded at various ligand-to-metal concentration ratios and pH's were analyzed (after matrix rank analysis by the method of residual intensities as a complementary method) by the two-dimensional computer simulation method, which simultaneously determines the formation constants and the EPR parameters of the various (micro)species. L1 forms mono and bis complexes in different protonation states; for the other ligands, the mono complexes are always prevalent. For steric reasons, the formation of CuL is shifted to increasingly higher pH regions in the sequence L2, L3 and L4. CuLH was identified for L3, L4 and L5, and also CuLH(2) for L4 and L5. Cu(2)L(2) was found in small amounts for L3 and L4, while it predominates at pH>4 for L5. For L5, Cu(2)L(2)H(2) was also detected. For the ligands that form dimeric metal complexes in equimolar solution or at a ligand excess, Cu(2)L is formed at a metal ion excess. Ligation of the phosphinate O was suggested by indirect proofs in the protonated complexes of L1. For the ligands L2, L3 and L4, the copper(II) coordination in various species in different protonation states is reminiscent of that in the mono and bis complexes of simple amino acids. For the bis(aminomethyl)phosphinates, however, the cis positions of the amino groups in CuL are ensured by the structure of the ligand, and the isomers differ from each other in the (equatorial or axial) position of the second carboxylate group.     

8-Substituted derivatives of adenosine 3',5'-cyclic phosphate require an unsubstituted 2'-hydroxyl group in the ribo configuration for biological activity.

Derivatives of adenosine 3',5'-cyclic phosphate (cAMP) with modifications in both the 2' and the 8 positions were synthesized and their enzymic activities as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterases were determined. Three types of derivatives were investigated: 8-substituted derivatives of O2'-Bt-cAMP, 8-substituted derivatives of 9-beta-D-arabinofuranosyladenine 3',5'-cyclic phosphate (ara-cAMP), and 8-substituted derivatives of 8,2'-anhydro-9-beta-D-arabinofuranosyladenine 3,'5'-cyclic phosphate (8,2'-anhydro-cAMP). The 8-substituted O2'-Bt-cAMP derivatives were synthesized by acylation of the preformed 8-substituted cAMP (8-HS-cAMP, 8-MeS-cAMP, and 8-PhCH2S-cAMP). 8-Br-O2'-tosyl-cAMP was sued as an intermediate for the preparation of 8,2'-anhydro-cAMP derivatives (8-HO-, 8-SH-, 8-H2N-, and 8-H3 CHN derivatives of 8,2'-anhydro-cAMP). 8-Substituted ara-cAMP derivatives were obtained by ring opening of 8-HO-8,2'-anhydro-cAMP with H+/H2O, NH3/MeOH, or MeONa/MeOH (to yield the 8-HO-, 8-H2N-, and 8-MeO-ara-cAMP derivatives). All of these doubly modified derivatives of cAMP are less than one-hundredth as active as cAMP at activating protein kinase and did not serve as substrates for the phosphodiesterase. These data show that the general inactivity of 2' derivatives of cAMP with kinase was not overcome by addition of an 8-substituent, even though many 8-substituted derivatives of cAMP activate the kinase more efficiently than does cAMP itself. In addition they show that while 2'-modification were tolerated by the phosphodiesterase, addition of an 8-substituent countermanded the allowable 2'-modification. The 8-substituted derivates of 02'-Bt-cAMP were found in general to be slightly better inhibitors of phosphodiesterase than the parent compounds containing no o2'-Bt substitution. As a group, the 8-substituted ara-cAMP derivatives were poorer inhibitors of phosphodiesterase than 8-substituted cAMP derivatives while the 8,2'-anhydro-cAMP derivatives were much poorer inhibitors than the 8-substituted ara-cAMP derivatives.     

Synthesis and stability studies of 2',3',5'-tri-O-acetyl-2-amino(-N6-cyclopentyl)-1-deazaadenosines

In this article, we report on the synthesis of 2',3',5'-tri-O-acetyl-2-amino-1-deazaadenosine and of 2',3',5'-tri-O-acetyl-2-amino-N(6)-cyclopentyl-1-deazaadenosine, which are very versatile intermediates for the preparation of 2-substituted 1-deazaadenosine derivatives. The two synthesized compounds showed to be quite unstable, with the N(6)-substituted derivatives being less stable than the N(6)-unsubstituted counterpart, according to the calculated HOMO-LUMO energy gap. Stability studies were performed through HPLC-MS analysis.     

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.     

DNA, protein binding, cytotoxicity, cellular uptake and antibacterial activities of new palladium(II) complexes of thiosemicarbazone ligands: effects of substitution on biological activity

The coordination propensities of 4(N,N')-diethylaminosalicylaldehyde-4(N)-substituted thiosemicarbazones (H(2)L(1-4)) were investigated by reacting with an equimolar amount of [PdCl(2)(PPh(3))(2)]. The new complexes were characterized by various spectroscopic techniques. The structure determination of the complexes [Pd(DeaSal-tsc)(PPh(3))] (1), [Pd(DeaSal-mtsc)(PPh(3))] (2) and [Pd(DeaSal-etsc)(PPh(3))] (3) by X-ray crystallography showed that ligands are coordinated in a dibasic tridentate ONS donor fashion forming stable five and six membered chelate rings. The binding ability of complexes (1-4) to calf-thymus DNA (CT DNA) has been explored by absorption and emission titration methods. Based on the observations, an electrostatic and an intercalative binding mode have been proposed. The protein binding studies have been monitored by quenching of tryptophan and tyrosine residues in the presence of complexes using lysozyme as a model protein. As determined by MTT assays, complex 3 exhibited a higher cytotoxic effect towards human lung cancer cell line (A549) and liver cancer cells (HepG2). LDH, NO assay and cellular uptake of the complexes have been studied. Further, antibacterial activity studies of the complexes have been screened against the pathogenic bacteria such as Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, MIC50 values of the complexes showed that the complexes exhibited significant activity against the pathogens and among the complexes, 3 exhibited higher activity.     

Synthesis and solution studies of Cu(II) complexes with pyridine derivatives of iminobisphosphonic acids

New 2-pyridyl, 3-pyridyl and 4-pyridyl derivatives of iminobisphosphonic acid were prepared by addition of tris(trimethylsilyl)phosphite to the corresponding derivatives of pyridineimine-methylphosphonates 3 and subsequent methanolysis of the silylated products 4. Solution studies on the coordination abilities of the ligands have shown that these compounds bind copper(II) ion through the tridentate {N,O,O} mode, where Cu(II) is stabilized by two five-membered chelate rings. The complexes obtained are very stable, with the pCu(II) value above 12, and therefore the ligands can be used as powerful chelating agents for copper ion.     

Self-assembly and cytotoxicity study of waterwheel-like dinuclear metal complexes: the first metal complexes appended with multiple free hydroxamic acid groups

Two waterwheel-like dinuclear complexes [M(2)(PHA)(4)(H(2)O)(2)] (M = Cu(II) (1), Zn(II) (2); HPHA = phthal-hydroxamic acid) appended with four free hydroxamic acid groups, namely, free hydroxamic acid metal complexes (FHAMCs) have been synthesized and characterized. The crystal structure of complex 1 was determined by single crystal X-ray diffraction, which adopts the paddlewheel motif with four bidentate carboxylate ligands joining two Cu(II) ions. The relative cytotoxicities of compounds 1 and 2 against SMMC-7721 and HO-8910 cell lines are similar and more predominant than HPHA (IC(50): Cu(II)>Zn(II)>HPHA). The synergic effect of the bound water molecules, multiple free hydroxamic acid groups and dimetal active sites with bridging carboxylate may have significant impacts on their pharmacological activity. As the prototype for a new class of hydroxamic acid derivatives, the self-assembly of FHAMCs presents a promising new strategy in designing multiple hydroxamic acids with remarkable bioactivities.     

Relatively stable N-ligated [2Fe2S](2+) clusters with dipyrromethane capping ligands

[2Fe2S] clusters with terminal N-ligation (His, Arg) and unique functions are increasingly recognized in biological systems. In this work three new [2Fe2S] clusters 1-3 with different 1,1'-dipyrrolmethane derivatives as chelating terminal ligands have been prepared and fully characterized, including by X-ray crystallography: (NEt(4))(2)[L(2)Fe(2)(mu-S)(2)] with L=Me(2)C(C(4)H(3)N)(2) (1), Ph(2)C(C(4)H(3)N)(2) (2), (CH(2))(5)C(C(4)H(3)N)(2) (3). These systems represent rare examples of synthetic [2Fe2S] complexes with N-donor capping ligands. While geometric parameters as well as spectroscopic and electrochemical characteristics of the new complexes are as anticipated, the chelating nature of the terminal ligands in 1-3 imparts a relatively high stability that will be advantageous for reactivity studies of the [2Fe2S] core.     

Synthesis and characterization of new copper- and zinc-chloroquine complexes and their activities on respiratory burst of polymorphonuclear leukocytes

The metal-chloroquine (CQ) complexes, Cu(CQ)2Cl (1), Cu(CQ)(PPh3)(NO3) (2), [Cu(OAc)2(CQ)]2 (3) ZnCl2(CQ)(H2O)2 (4), [Zn(OAc)2(CQ)(H2O)]2 (5), were synthesized and characterized by NMR, FAB-mass, elemental analysis, and UV-Vis, EPR and IR spectroscopies. The effects of these compounds on the generation of reactive oxygen species (ROS) from human neutrophils (PMNs) were tested in the concentration range 1-100 microM and compared to that of chloroquine. The data show that the copper-chloroquine complexes 1-3 inhibit neutrophil release of ROS in PMNs activated either by a phorbol ester or by phagocytosable particles. Both effects were dose-dependent, with an IC50 of approximately 10 microM. With the same stimulants, there was only modest inhibition of ROS generation by any of the zinc-chloroquine complexes 4-5 at 10-100 microM. All complexes did not show significant in vitro toxicity as assayed by the trypan blue exclusion method. Our results reinforce previous observations that many metal derivatives of anti-inflammatory drugs affect neutrophil functions with higher potency than their parent ligands.     

Design of 1-substituted 2-arylmethyl-4,5-methylenedioxybenzene derivatives as antiseizure agents

A series of 1-substituted 2-[(4-aryl)-methyl]-4,5-methylenedioxybenzene derivatives (13-25), structurally related to model compound 5 (2-[(4-aminophenyl)-(4-methylsemicarbazono)-methyl]-4,5-methylenedioxyphenylacetic acid methyl ester), were synthesized and tested as anticonvulsant agents in DBA/2 mice against sound-induced seizures. The new compounds possess anticonvulsant properties lower than those of prototype 5 but, in some instances, comparable to that of GYKI 52466, a well-known noncompetitive AMPA receptor antagonist.     

Phosphatidylcholine-fatty acid membranes. I. Effects of protonation, salt concentration, temperature and chain-length on the colloidal and phase properties of mixed vesicles, bilayers and nonlamellar structures

The phase and colloidal properties of phosphatidylcholine/fatty acid (PC/FA) mixed vesicles have been investigated by optical methods, acid-base titration, and theoretically as a function of temperature (5-80 degrees C), molar lipid ratio (0-1), lipid chain length (C14-C18), headgroup ionization (1.5 less than or equal to pH less than or equal to 10), vesicle concentration (0.05-32 mumol vesicle.dm-3, and ionic strength (0.005 less than or equal to J less than or equal to 0.25). Increasing the fatty acid concentration in PC bilayers causes the phase transition temperatures (at 4 less than or equal to pH less than or equal to 5) to rise until, for more than 2 FA molecules per PC molecule, the sample turbidity exhibits only two transitions corresponding to the chain-melting of the 1:2 stoichiometric complexes of PC/FA, and pure fatty acid. The former transition is into a nonlamellar phase and is accompanied by extremely rapid vesicle aggregation (with association rates on the order of Ca approximately 10(7) dm3.mol-1.s-1) and massive lipid precipitation. Fluid-phase vesicles with less than 2 FA per PC associate much more slowly (Ca approximately 10(3) dm3.mol-1.s-1), their aggregation being comparable to that of the ordered-phase liposomes. Under no conditions was the relation between the fatty acid concentration and the vesicle association rate for the fluid-phase vesicles linear. In contrast to the X-ray diffraction data, optical measurements reveal a 'pretransitional region' between the chain-melting temperature of the PC component and the temperature at which the gross transformation into a nonlamellar phase sets in. This is seen for all lipid mixtures investigated. On the relative temperature scale, lipids with different chain lengths behave qualitatively similarly; however, the effective association constants determined for samples of constant lipid concentration seem to decrease somewhat with the number of CH2 groups per chain. Fatty acid protonation, which yields electrically neutral bilayers, invariably increases the rate of vesicle association; we have measured, for example, Ca approximately 10(2) at pH approximately 7 and Ca approximately 10(7) dm3.mol-1.s-1 at pH approximately 4). Protonation of the phosphatidylcholine phosphate groups, which causes a net positive charge to accumulate on the lipid vesicles, initially increases (Ca approximately 10(8) dm3.mol-1.s-1) but ultimately decreases (Ca approximately 10(7) dm3.mol-1.s-1) the rate of association between PC/FA (1:2) mixed vesicles.(ABSTRACT TRUNCATED AT 400 WORDS)