Coordination behaviour of biologically active benzothiazolines towards silicon(IV)

The synthesis and structural features of some trigonal bipyramidal and octahedral complexes of silicon(IV) with biologically active benzothiazolines are described. These were derived by the condensation of pyridine-2-aldehyde, furfuraldehyde, thiophene-2-aldehyde and indole-3-carbaldehyde with 2-mercaptoaniline. The newly synthesized complexes have been characterized by elemental analyses, conductance measurements, molecular weight determinations and electronic, infrared, ¹H and ¹³C NMR spectral studies. The ligand and its complexes of Si(IV) have been tested for their antifungal activity against Helmenthosporeum gramineum and Rhizopus oryzae. The growth inhibition percentage was calculated on the basis of the average diameter of the fungal colony.     

Synthesis, characterization and antiamoebic activity of benzimidazole derivatives and their vanadium and molybdenum complexes

Reaction of [MoO(2)(acac)(2)] (where, acac=acetyl acetone) and KVO(3) with 2-(salicylidieneimine) benzimidazole lead to form new complexes [MoO(2)(sal-BMZ)(2)] and K [VO(2)(sal-BMZ)(2)] [where, sal-BMZ=2-(salicylidieneimine) benzimidazole], which showed the monobasic bidentate nature of the ligand in which the phenolic oxygen and the imine nitrogen of the ligand are coordinated to the metal ion. These complexes were characterized along with nine other complexes of oxoperoxovanadium (V), molybdenum (Vl) and tungsten (Vl) with benzimidazole derivatives and screened in vitro by micro dilution technique for their amoebicidal activity with a view to search for a more effective agent against Entamoeba histolytica suggests that compound 2 and 3 might be endowed with important antiamoebic properties since they showed IC(50 )values in a microM range.     

Spectroscopic differences between heterocyclic benzothiazoline, -thiazole and imine containing ligands and comparison of the Co and Cu pyridine benzothiazole and imine complexes

Five heterocyclic benzothiazoline and -thiazole analogs have been synthesized and characterized by ¹H NMR and IR spectroscopy. The analogs fall into two different classes, (a) those which contain one benzothiazoline group adjacent to the heterocyclic ring system (starting with 2-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde or 2-furaldehyde), and (b) those which have two benzothiazoline substituents (starting with 2,6-pyridinecarboxaldehyde and 2,5-thiohenecarboxaldehyde). In addition, the imine containing ligands, bis-2-[(pyridin-2-ylmethylene)-imino]-benzenethiol disulfide (PyIS)₂ and bis-2-[(thiophen-2-ylmethylene)-imino]-benzenethiol disulfide(ThIS)₂, were prepared starting with the disulfide of 2-aminothiophenol. Each species has been characterized by ¹H NMR and IR spectroscopies. Ligation reactions with 2-(2-pyridyl)benzothiazoline (Py(Bt)) and Cu(OAc)₂·1H₂O resulted in the formation of a dinuclear species containing two copper ions, two ligand frames and two acetate groups, [Cu(PyAS)(OAc)]₂ (1). Both copper ions are five-coordinate and bonded to one monodentate acetate, one ligand frame (NNS) and one bridging thiolate. Ligation reaction with 2-(2-pyridyl)benzothiazole (Py(oBt)) and CoCl₂·xH₂O or Cu(BF₄)₂·xH₂O resulted in the formation of a six-coordinate, octahedral Co(II) complex, cis-[Co(Py(oBt)₂Cl₂] (2) and a five coordinate Cu(II) complex, [Cu(Py(oBt))₂(OH₂)](BF₄) (3), respectively. All complexes have been characterized by X-ray crystallography as well as UV-Vis and IR spectroscopy.     

Transition metal complexes with N, S donor ligands as synthetic antioxidants: synthesis, characterization and antioxidant activity

Transition metal complexes containing bidentate N, S donor ligands i.e., carvone thiosemicarbazone [(RS)-5-isopropenyl-2-methylcyclohex-2-en-1-one thiosemicarbazone (IPMCHTSC)] and carvone N(1)-phenylthiosemicarbazone [(RS)-5-isopropenyl-2-methylcyclohex-2-en-1-one phenylthiosemicarbazone (IPMCHPhTSC)] have been synthesized. All the metal complexes (1-8) have been characterized by elemental analysis, molar conductance measurement and various spectral studies [infrared (IR), electronic, fast-atom bombardment (FAB) mass and NMR (for ligands)] and thermogravimetric analysis. FAB mass spectroscopic studies of (1), (3), (4), (5), (6) (7), and (8) suggest their monomeric nature. Metal complexes are [M(LH)Cl(2)] and [M(LH)(2)Cl(2)] type, where M?=?Fe(III), Co(II), and Cu(II) and LH?=?IPMCHTSC and IPMCHPhTSC. The proposed geometries of the complexes were octahedral for 1:2 complexes, square planar for 1:1 complexes and distorted octahedral for Cu(II) complexes (1:2). The free radical scavenging activity of ligands (IPMCHTSC and IPMCHPhTSC) and their metal complexes have been determined at the concentration range of 10-400 μg/mL by means of their interaction with the stable free radical 2,2'-diphenyl-1-picrylhydrazyl and 5-200 μg/mL by 2,2'-Azinobis-3-ethylbenzothiazoline-6-sulphonic acid. All the compounds have shown encouraging antioxidant activities.     

Solution equilibrium studies on metal complexes of 2,3-dihydroxy-phenylalanine-hydroxamic acid (Dopaha) and models: catecholate versus hydroxamate coordination in iron(III)-, aluminium(III)- and molybdenum(VI)-Dopaha complexes

Equilibrium results based on pH potentiometric, spectrophotometric and (1)H NMR measurements for the complexes of Fe(III), Al(III) and Mo(VI) with 2,3-dihydroxy-phenylalanine-hydroxamic acid (Dopaha) as well as for binary model systems Fe(III)-, Al(III)-, Mo(VI)-acetohydroxamic acid (Aha), -alpha-alaninehydroxamic acid (alpha-Alaha) and -1,2-dihydroxy-3,5-benzene-disulphonate (Tiron) and ternary model systems Fe(III)-, Al(III)-, Mo(VI)-Tiron-Aha, are summarized in this paper. The amine-type coordination mode is not detectable with these metal ions at all. Precipitation occurs at pH <5.5 with Fe(III) and Al(III) even at a Dopaha-to-metal ion ratio of 10:1. Hydroxamate-type coordination was demonstrated with both metals below the pH range of precipitation but, after dissolution, catecholate-type coordination was exclusively found. The hydroxamate-type coordination mode occurs only in the very acidic pH range for Mo(VI) complexes and the crossover from hydroxamate to catecholate binding occurs at pH >3. A ligand-bridged dinuclear species, [(MoO(2))(2)(Dopaha)(2)](2+), involving mixed-type (catecholate and hydroxamate) coordination modes is formed in the pH range 2.5-5.5. [MoO(2)A(2)H(2)], with catecholate-type coordination, forms above pH 3. On increasing the pH further, deprotonation of the coordinated Dopaha and hydrolytic processes result in the formation of catecholate-coordinated [MoO(3)AH] and [MoO(3)A]. MoO(4)(2-) and free Dopaha exist above pH 10.     

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.     

Syntheses, crystal structures and biological relevance of glycolato and S-lactato molybdates

Glycolato and S-lactato complexes containing the dioxomolybdenum(VI) moiety have been synthesized for studies on the role of the alpha-hydroxycarboxylato anion in the iron molybdenum cofactor of nitrogenase. The ligands in these complexes, vis K2[MoO2(glyc)2].H2O (H2glyc=glycolic acid, C2H4O3) (1) and (Na2[MoO2(S-lact)2])3.13H2O (H2lact=lactic acid, C3H6O3) (2) chelate through their alpha-alkoxyl and alpha-carboxyl oxygen atoms. In contrast, octanuclear K6[(MoO2)8(glyc)6(Hglyc)2].10H2O (3) formed by the reduction of the glycolato complex (1), features three different ligand binding modes: (i) non-bridging and bridging bidentate coordination of alpha-alkoxyl and alpha-carboxyl groups, and (ii) bidentate bridging using alpha-carboxyl group, leaving the alpha-alkoxyl group free. The octanuclear skeleton shows strong metal-metal interactions. The coordination modes in (1) and (2) mimic that of homocitrate to the iron molybdenum cofactor (FeMo-co) of nitrogenase. The bidentate coordination of alpha-alkoxyl and alpha-carboxyl groups shows that bond of alpha-carboxyl group to Mo is less susceptible to the oxidation state of molybdenum compared with the Mo-alpha-alkoxyl bond. This is supported by the dinuclear coordination of alpha-carboxyl group with free alpha-alkoxyl group in glycolato molybdate(V) (3).     

Spectroscopic and biological properties of palladium(II) complexes of ethyl 2-quinolylmethylphosphonate

Spectroscopic (1H NMR, UV-visible) and biological (cytostatic, antiviral activity) studies of palladium(II) complexes of monoethyl 2-quinolymethylphosphonate (2-Hmqmp): dihalide adducts trans-Pd(2-Hmqmp)2X2, chelate Pd(2-mqmp)2.2H2O and ion-pair salt complexes [2-H2mqmp]+[Pd(2-Hmqmp)X3]- (X = Cl, Br), have been carried out in order to determine structural and biological properties of these biologically interesting complex compounds. The complexes were evaluated in vitro for their cytostatic activity against murine L1210 and human KB and T-lymphoblast Molt4/C8 and CEM/0 cell lines, and the results obtained were compared with those obtained for the complexes of diethyl 2-quinolylmethylphosphonate (2-dqmp). The L1210 cell was the most responsive line and complexes of diester 2-dqmp were more active than complexes of monoester 2-Hmqmp. A good relationship was observed between the cytostatic activity of the complexes and their lypophilicity or solubility. Some complexes exhibited significant cell growth inhibitory effects, but none of the them was more cytostatic than cisplatin. Both 2-dqmp and 2-Hmqmp complexes were also evaluated in vitro for their antiviral activity in different assay systems, comprising a broad spectrum of DNA and RNA viruses, but no specific antiviral effects were noted. In addition, the complexes did not show any specific anti-HIV activity.     

Synthesis, spectral study and cytotoxicity of platinum(II) complexes with 2,9-disubstituted-6-benzylaminopurines

A series of platinum(II) complexes with 2,9-disubstituted-6-benzylaminopurines has been prepared. The complexes have the following composition: cis-[Pt(Boh)(2)Cl(2)] (1), cis-[Pt(Oc)(2)Cl(2)] (2), cis-[Pt(Ros)(2)Cl(2)] (3), cis-[Pt(i-PrOc)(2)Cl(2)] (4), cis-[Pt(BohH(+))(2)Cl(2)]Cl(2) (5), cis-[Pt(OcH(+))(2)Cl(2)]Cl(2) (6), cis-[Pt(RosH(+))(2)Cl(2)]Cl(2) (7) and cis-[Pt(i-PrOcH(+))(2)Cl(2)]Cl(2) (8), where Boh=2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine, Oc=2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, Ros=2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine and i-PrOc=2-(2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine. The complexes have been characterized by elemental analyses, conductivity measurements and their infrared, ES+mass (electrospray mass spectra in the positive ion mode) and NMR ((1)H, (13)C, (15)N and (195)Pt) spectra. The results obtained from the physical studies, particularly from multinuclear NMR spectroscopy, show that in all the investigated complexes (1-8), two molecules of purine derivative are coordinated to platinum via the N(7) atom of the imidazole ring in a cis-configuration. The prepared compounds have been screened for their in vitro cytotoxicity against G-361 (human malignant melanoma), HOS (human osteogenic sarcoma), K-562 (human chronic myelogenous leukemia) and MCF-7 (human breast adenocarcinoma) cell lines. All complexes are significantly more active than the initial 2,9-disubstituted-6-benzylaminopurine derivatives. In the case of some tumour cell lines, IC(50) values for the complexes (1, 3, 4, 5, 8) are significantly lower than those obtained for cisplatin and oxaliplatin. The best cytotoxicity was achieved for the complex (3) for which IC(50) values range from 1 to 2 microM.     

Synthesis, characterization, antibacterial and cytotoxic study of platinum (IV) complexes

Platinum (IV) complexes [Pt (L)2Cl2] [where, L= benzyl-N-thiohydrazide (L1), (benzyl-N-thio)-1,3-propanediamine (L2), benzaldehyde-benzyl-N-thiohydrazone (L3) and salicylaldehyde-benzyl-N-thiohydrazone (L4)] have been synthesized. The thiohydrazide, thiodiamine and thiohydrazones can exist as thione-thiol tautomer and coordinate as a bidentate N-S ligand. The ligands were found to act in monobasic bidentate fashion. Analytical data reveal that metal to ligand stoichiometry is 1:2. The complexes have been characterized by elemental analysis, IR, mass, electronic and 1H NMR spectroscopic studies. In vitro antibacterial and cytotoxic studies have been carried out for some complexes. Various kinetic and thermodynamic parameters like order of reaction (n), activation energy (Ea), apparent activation entropy (S#) and heat of reaction (DeltaH) have also been carried out for some complexes.     

Synthesis, spectroscopic, cytotoxic, and DNA binding studies of binuclear 2,2'-bipyridine-platinum(II) and -palladium(II) complexes of meso-alpha,alpha'-diaminoadipic and meso-alpha,alpha'-diaminosuberic acids.

Four new binuclear complexes of formula [M2(bipy)2(BAA)]Cl2 (where M is Pt(II) or Pd(II), bipy is 2,2'-bipyridine, and BAA is a dianion of meso-alpha-alpha'-diaminoadipic acid (DAA) or meso-alpha,alpha'-diaminosuberic acid (DSA) have been synthesized. These complexes have been characterized by chemical analysis and ultraviolet-visible, infrared, and 1H NMR spectroscopy. The mode of binding of ligands in these complexes has been ascertained by infrared and detailed 1H NMR spectroscopy. These complexes are 1:2 electrolyte in conductivity water. They have also been tested against P388 lymphocytic leukemia cells and their target is DNA molecules. [Pt2(bipy)2(DSA)]Cl2, [Pd2(bipy)2(DSA)Cl2, and [Pd2(bipy)2(DAA)]Cl2 show I.D.50 values comparable or lower than cis-diamminedichloroplatinum(II) and [Pt(bipy)(Ala)]Cl. In addition, binding studies of [Pt2(bipy)2(DSA)]Cl2 and [Pd2(bipy)2(DAA)]Cl2 to calf thymus DNA have been carried out and the mode of binding seems to be hydrogen bonding, as suggested earlier for analogous mononuclear amino acid-DNA complexes.     

Comparison of anti-hyperglycemic effect amongst vanadium, molybdenum and other metal maltol complexes

A wide variety of vanadium-containing complexes have been tested, both in vivo and in vitro, as possible therapeutic agents for the oral treatment of type 2 diabetes mellitus. None so far has surpassed bis(maltolato)oxovanadium(IV) (BMOV) for glucose- and lipid-lowering in an orally available formulation. Ligand choice is clearly an important factor in pharmacological efficacy of vanadium compounds as insulin enhancing agents. In this study, we kept the ligand and dose the same, varying instead the metal ion bound to the maltolato ligand in a series of binary complexes of neutral charge. A requirement for vanadyl ion as the metal ion of choice was apparent; no other metal ion tested served as a suitable substitute. Amongst [MoO(2)](2+), Co(II), Cu(II), Cr(III), and Zn(II), only [MoO(2)](2+) and Co(II) showed any hypoglycemic activity at the ED(50) dose for bis(maltolato)oxovanadium(IV), 0.6 mmolkg(-1) by oral gavage in streptozotocin (STZ)-diabetic rats within 72 h of administration of compound.     

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.     

Spectroscopic, biological, and antitumor studies on N-ethyl- and N-propylimidazole platinum(II) complexes

Platinum(II) halide complexes with N-ethylimidazole (N-EtIm) and N-propylimidazole (N-PropIm) of the Pt(L)2X2 and Pt(L)4X2 types (X = Cl, Br, I) were prepared and characterized by far infrared spectra, electronic spectra, and conductivity measurements. The inhibitorial activity of some complexes on the Ca,Mg-dependent ATPase and the antitumor studies of the Pt(L)4Cl2 derivatives have been investigated. Pt complexes are not inhibitory active in comparison to the same Pd complexes (if c = 10(-4) M). The LD50 in physiological solution for [Pt(N-EtIm)4]Cl2 X 2H2O and [Pt(N-PropIm)4]Cl2 are higher enough with respect to the cis platinum.     

Metal complexes with the quinolone antibacterial agent N-propyl-norfloxacin: synthesis, structure and bioactivity

Nine new metal complexes of the quinolone antibacterial agent N-propyl-norfloxacin, pr-norfloxacin, with VO(2+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Zn(2+), MoO(2)(2+), Cd(2+) and UO(2)(2+) have been prepared and characterized with physicochemical and spectroscopic techniques while molecular mechanics calculations for Fe(3+), VO(2+) and MoO(2)(2+) complexes have been performed. In all complexes, pr-norfloxacin acts as a bidentate deprotonated ligand bound to the metal through the pyridone and one carboxylate oxygen atoms. All complexes are six-coordinate with slightly distorted octahedral geometry. For the complex VO(N-propyl-norfloxacinato)(2)(H(2)O) the axial position, trans to the vanadyl oxygen, is occupied by one pyridone oxygen atom. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA resulting to a B-->A DNA transition. The antimicrobial activity of the complexes has been tested on three different microorganisms. The complexes show equal or decreased biological activity in comparison to the free pr-norfloxacin except UO(2)(pr-norf)(2) which shows better inhibition against S. aureus.     

Metal based isatin-derived sulfonamides: their synthesis, characterization, coordination behavior and biological activity

Some isatin derived sulfonamides and their transition metal [Co(II), Cu(II), Ni(II), Zn(II)] complexes have been synthesized and characterized. The structure of synthesized compounds and their nature of bonding have been inferred on the basis of their physical (magnetic susceptibility and conductivity measurements), analytical (elemental analyses) and spectral (IR, (1)H NMR and (13)C NMR) properties. An octahedral geometry has been suggested for Co(II), Ni(II) and Zn(II) and square-planar for Cu(II) complexes. In order to assess the antibacterial and antifungal behavior, the ligands and their metal(II) complexes were screened for their in vitro antibacterial activity against four Gram-negative species, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa and Salmonella typhi and two Gram-positive species, Staphylococcus aureus and Bacillus subtilis and, for in vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. In vitro cytotoxic properties of all the compounds were also studied against Artemia salina by brine shrimp bioassay. The results of average antibacterial/antifungal activity showed that zinc(II) complexes were found to be the most active against one or more bacterial/fungal strains as compared to the other metal complexes.     

Synthetic, spectral, thermal and antimicrobial studies on some mixed 1,3-dithia-2-stannacyclopentane derivatives with dialkyldithiocarbamates

1,3-dithia-2-stannacyclopentane derivatives with dialkyldithiocarbamates of the types SCH(2)CH(2)SSn[S(2)CNR(2)]Cl (I) and SCH(2)CH(2)SSn[S(2)CNR(2)](2) (II) (where R = CH(3), C(2)H(5) and -CH(2)-CH(2)-) have been synthesized by the reaction of 2,2-dichloro-1,3-dithia-2-stannacyclopentane and sodium/ammonium salts of dialkyldithiocarbamates in 1:1 and 1:2 molar ratios, respectively, in anhydrous benzene. These newly synthesized derivatives have been characterized by elemental analyses (C, H, N, S and Sn), thermal [thermogravimetry (TG) and differential thermal analyses (DTA)] as well as spectral [UV, IR and multinuclear NMR ((1)H, (13)C and (119)Sn)] studies. The monodentate behaviour of the dialkyldithiocarbamate ligands was confirmed by IR and (119)Sn NMR spectral data and distorted tetrahedral structures have been suggested for both type (I) and (II) compounds. The free ligands and their tin complexes have also been screened for their antibacterial and antifungal activities. These results made it desirable to delineate a comparison between free ligands and their tin complexes. These exhibit higher antibacterial effect than some of the previously investigated antibiotics.     

Structural elucidation and biological significance of 2-hydroxy-1-naphthaldehyde derived sulfonamides and their first row d-transition metal chelates

2-Hydroxy-1-naphthaldehyde derived sulfonamides and their first row d-transition metal chelates [cobalt (II), copper (II), nickel (II) and zinc (II)] have been synthesized and characterized. The nature of bonding and structure of all the compounds have been deduced from elemental analyses, infrared, 1H NMR, 13C NMR, mass spectrometry, electronic spectra, magnetic susceptibility and conductivity measurements. An octahedral geometry has been suggested for all the complexes. The metal complexes were screened for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi and their biopotency has been discussed. The results of these studies revealed that all compounds showed moderate to significant antibacterial activity against all bacterial strains and good antifungal activity against various fungal strains. In-vitro cytotoxic properties of all the compounds against Artemia salina was also studies by brine shrimp bioassay.     

X-Ray crystallographic, NMR and antimicrobial activity studies of magnesium complexes of fluoroquinolones - racemic ofloxacin and its S-form, levofloxacin

The magnesium complexes of racemic ofloxacin (oflo) and its pure S-form levofloxacin (S-oflo) have been studied by X-ray crystallography and NMR spectroscopy. Two compounds, [Mg(R-oflo)(S-oflo)(H(2)O)(2)].2H(2)O (1) and [Mg(S-oflo)(2)(H(2)O)(2)].2H(2)O (2), respectively, have been prepared by hydrothermal reactions and their crystal structures have been determined. In both structures the anionic fluoroquinolone ligands are coordinated through the keto and carboxylate oxygens forming 1:2 Mg:oflo complexes. The two structures are practically identical except for the orientation of one of the oxazine methyl groups at the chiral center of 2 which was found in equatorial position, the other oxazine methyl groups in 1 and 2 being axial. This difference affects the stacking pattern of quinolone molecules in the cell. (1)H NMR chemical shift data and Mn(II) paramagnetic line broadening measurements on the free ofloxacin suggest that the coordination of the ligands in solution involves the keto and carboxylate oxygens. However, it is not possible to decide whether the complexes in aqueous solution have 1:1 or 1:2 stoichiometry. The methylated piperazine nitrogen does not interact with the metal ion. Magnesium-quinolone interaction is discussed in relation to the biological activity of quinolones. The antimicrobial activity of the complexes against various microorganisms was tested and it was established that their activity is similar to that of free quinolone drugs.     

Thermal activation of the purified rat hepatic glucocorticoid receptor. Evidence for a two-step mechanism

Thermal "activation" or "transformation" of rat hepatic [6,7-3H]triamcinolone acetonide (TA)-receptor complexes purified in the unactivated state to near homogeneity (Grandics, P., Miller, A., Schmidt, T. J., Mittman, D., and Litwack, G. (1984) J. Biol. Chem. 259, 3173-3180) has been further investigated. The data generated in reconstitution experiments demonstrate that warming (25 degrees C for 30 min) of the purified unactivated complexes promotes their activation as judged by an increase in DNA-cellulose binding, but to a lower extent than that observed after warming of glucocorticoid-receptor complexes in crude cytosols. However, maximal DNA-cellulose binding capacity can be detected in reconstituted systems (also heated at 25 degrees C for 30 min) consisting of purified unactivated [3H]TA-receptor complexes and a cytoplasmic "stimulator(s)." This cytoplasmic factor(s), which does not copurify with the receptor, is heat-stable (90 degrees C for 30 min), excluded from Sephadex G-25, and trypsin-sensitive and stimulates DNA-cellulose binding in a dose-dependent manner. The ability of Na2MoO4 to block thermal activation of the highly purified receptor complexes suggests that this transition metal anion interacts directly with the receptor protein itself. The fact that the cytoplasmic stimulator(s) enhances DNA-cellulose binding of the [3H]TA-receptor complexes without increasing the proportion of those complexes eluted in the activated (low salt) position from DEAE-cellulose is consistent with a proposed two-step model of in vitro activation. During the Na2MoO4-sensitive Step 1, elevated temperature (25 degrees C for 30 min) may directly alter the conformation of the purified receptor complexes (i.e. subunit dissociation or disaggregation), resulting in the appropriate shift in the elution profile of the [3H]TA-receptor complexes on DEAE-cellulose but only in a minimal (approximately 2-3-fold) increase in the binding of these complexes to DNA-cellulose. During the Na2MoO4-insensitive and temperature-independent Step 2, a heat-stable cytoplasmic protein(s) may interact with these thermally activated [3H]TA-receptor complexes and enhance their ability to bind to DNA-cellulose without further increasing the percentage of those complexes which elute from DEAE-cellulose in the activated position. In crude cytosols these two steps would presumably occur simultaneously, and addition of Na2MoO4 prior to warming would block Step 1 and hence Step 2 would not occur.