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1.
Stefan Wirth Christoph J. Rohbogner Marcin Cieslak Julia Kazmierczak-Baranska Stefan Donevski Barbara Nawrot Ingo-Peter Lorenz 《Journal of biological inorganic chemistry》2010,15(3):429-440
The synthesis and characterization of three novel iridium(III) complexes and one rhodium(III) complex with 1-nitroso-2-naphthol
(3) chelating as a 1,2-naphthoquinone-1-oximato ligand are described. The reaction of μ2-halogenido-bridged dimers [(η5-C5Me5)IrX2]2 [X is Cl (1a), Br (1b), I (1c)] and [(η5-C5Me5)RhCl2]2 (2a) with 3 in CH2Cl2 yields the mononuclear complexes (η5-C5Me5)IrX(η2-C10H6N2O) (4a, 4b, 4c) and (η5-C5Me5)RhCl(η2-C10H6N2O) (5a). All compounds were characterized by their 1H and 13C NMR, IR, and mass spectra, UV/vis spectra were recorded for 4a and 5a. The X-ray structure analyses revealed a pseudo-octahedral “piano-stool” configuration for the metals with bidentate coordination
through oximato-N and naphthoquinone-O, forming a nearly planar five-membered metallacycle. The metal complexes 4a and 5a were evaluated in respect to their cytotoxicity and binding affinity toward double-stranded DNA. As determined in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide assay, both exerted a much stronger cytotoxic effect toward HeLa and HL60 cancer cell lines than did cisplatin. The
remarkable cytotoxicity of the compounds tested may be attributed to necrosis, rather than to apoptosis, as it is evidenced
by the caspase-3/7 activation assay. No clear evidence was found for interaction with double-stranded DNA. The melting experiments
showed no significant differences between thermodynamic parameters of intact DNA and DNA incubated with 3, 4a, or 5a, although these derivatives altered DNA recognition by the BamHI restriction enzyme. Therefore, the screened iridium and rhodium complexes 4a and 5a may still be interesting as potential anticancer drugs owing to their high cytotoxicity toward cancer cell lines, whereas
they do not modify DNA in a way similar to that of cisplatin. 相似文献
2.
The building blocks fac-[99mTc{κ3-HB(timMe)3}(CO)3] and fac-[99mTc{κ3-R(μ-H)B(timMe)2}(CO)3] [R is H (4a), Ph (5a); timMe is 2-mercapto-1-methylimidazolyl] were obtained almost quantitatively by reacting fac-[99mTc(CO)3(H2O)3]+ with the corresponding scorpionate. These compounds cross the intact blood–brain barrier in mice, with significant retention in the case of 4a and 5a. Using 4a as the lead structure, we have synthesized the functionalized complexes fac-[M{κ3-H(μ-H)B(timBu-pip)2}(CO)3] [M is Re (8), 99mTc (8a); timBu-pip is methyl[4-((2-methoxyphenyl)-1-piperazinyl)butyl](2-mercapto-1-methylimidazol-5-yl)methanamide] and fac-[M{κ
3-H(μ-H)B(timMe)(timBu-pip)}(CO)3] [M is Re (9), 99mTc (9a)] and evaluated their potential as radioactive probes for the targeting of brain 5-HT1A serotonergic receptors. The Re complexes exhibit excellent affinity [IC50=0.172 ± 0.003 nM (8); IC50=0.65 ± 0.01 nM (9)] for the 5-HT1A receptor. The radioactive congeners (99mTc) have shown an initial brain uptake of 1.38 ± 0.46%ID g−1 (8a) and 0.43 ± 0.12%ID g−1 (9a), but suffer from a relatively fast washout. 相似文献
3.
Yun-Jun Liu Zhen-Hua Liang Zheng-Zheng Li Cheng-Hui Zeng Jun-Hua Yao Hong-Liang Huang Fu-Hai Wu 《Biometals》2010,23(4):739-752
A new ligand DBHIP and its two ruthenium(II) complexes [Ru(dmb)2(DBHIP)](ClO4)2 (1) and [Ru(dmp)2(DBHIP)](ClO4)2 (2) have been synthesized and characterized. The cytotoxicity of DBHIP and complexes 1 and 2 has been assessed by MTT assay. The apoptosis studies were carried out with acridine orange/ethidium bromide (AO/EB) staining
methods. The binding behaviors of these complexes to calf thymus DNA (CT-DNA) were studied by absorption titration, viscosity
measurements, thermal denaturation and photoactivated cleavage. The DNA-binding constants of complexes 1 and 2 were determined to be 8.64 ± 0.16 × 104 (s = 1.34) and 2.79 ± 0.21 × 104 (s = 2.17) M−1. The results suggest that these complexes interact with DNA through intercalative mode. The studies on the mechanism of photocleavage
demonstrate that superoxide anion radical (O2
•–) and singlet oxygen (1O2) may play an important role in the DNA cleavage. The experiments on antioxidant activity show that these compounds also exhibit
good antioxidant activity against hydroxyl radical (OH•). 相似文献
4.
Two zinc(II) terpyridine complexes Zn(atpy)2(PF6)2 (1) (atpy = 4′-p-N9′-adeninylmethylphenyl-2,2′:6,2′′-terpyridine) and Zn(ttpy)2(PF6)2 (2) (ttpy = 4′-p-tolyl-2,2′:6,2′′-terpyridine) have been synthesized and characterized by elemental analysis, 1H NMR and electrospray mass spectroscopy. The structure of complex 2 was also determined by X-ray crystallography, which revealed a ZnN6 coordination in an octahedral geometry with two terpyridine acting as equatorial ligands. The circular dichroism data showed
that complex 1 exhibited an ICD signal at around 300 nm and induced more evident disturbances on DNA base stacking than complex 2, reflecting the impact of the adenine moiety on DNA binding modes. Complex 1 exhibited higher cleavage activity to supercoiled pUC 19 DNA than complex 2 under aerobic conditions, suggesting a promotional effect of adenine moiety in DNA nuclease ability. Interestingly, both
complexes demonstrated potent in vitro cytotoxicity against a series human tumor cell lines such as human cervix carcinoma
cell line (HeLa), human liver carcinoma cell line (HepG2), human galactophore carcinoma cell line (MCF-7) and human prostate
carcinoma cell line (pc-3). The cytotoxicity is averagely 10 times more active than the anticancer drug cisplatin.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
5.
Alessandra de Santana Braga Barbosa Ribeiro Cláudio Carlos da Silva Flávia de Castro Pereira Aliny Pereira de Lima Cesar Augusto Sam Tiago Vilanova-Costa Simone Santos Aguiar Luiz Alfredo Pavanin Aparecido Divino da Cruz Elisângela de Paula Silveira-Lacerda 《Biological trace element research》2009,130(3):249-261
Chemotherapeutic agents play an important role in cancer treatment mostly due their systemic action on human organism allowing
access to liquid tumors and even metastases. Among these drugs, ruthenium compounds have been showing promising results to
treat tumors and represent an important development of new antitumor therapy. This study presents the evaluation of cis-(dichloro)tetraammineruthenium(III) chloride, cis-[RuCl2(NH3)4]Cl, genotoxic effects using human peripheral blood lymphocytes cultured in vitro. Mitotic index (MI), chromosome aberrations
(CA), and DNA damage using the comet assay were analyzed. MI in human peripheral blood lymphocyte cultures treated with 1,
10, 100, and 1,000 μg mL−1
cis-[RuCl2(NH3)4]Cl were 5.9%, 4.6%, 3.9%, and 0%, respectively. Doxorubicin chloridate was used as the positive control. CA derived from
1, 10, and 100 μg mL−1 concentrations were defined as spontaneous when compared with the negative control, and at the concentration of 1,000 μg
mL−1, the cell cycle was inhibited (IM = 0%). Results obtained for the comet assay using cis-[RuCl2(NH3)4]Cl suggest that this compound has no genotoxic activity against cultured human peripheral blood lymphocytes. 相似文献
6.
Lukas K. Filak Gerhard Mühlgassner Michael A. Jakupec Petra Heffeter Walter Berger Vladimir B. Arion Bernhard K. Keppler 《Journal of biological inorganic chemistry》2010,15(6):903-918
The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L
1
) and N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L
2
) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L
3
) and N′-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L
4
) of the general formulas [(η6-p-cymene)MII(L
1
)Cl]Cl, where M is Ru (4) and Os (6), [(η6-p-cymene)MII(L
2
)Cl]Cl, where M is Ru (5) and Os (7), [(η6-p-cymene)MII(L
3
)Cl]Cl, where M is Ru (8) and Os (10), and [(η6-p-cymene)MII(L
4
)Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass
spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography (L
1
·HCl, 4·H2O, 5, and 9·2.5H2O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent
kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC50 values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of
cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L
1
and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L
4
and 11, arguing for additional targets and molecular effects, such as intercalation into DNA. 相似文献
7.
In order to systematically perform an experimental and theoretical study on DNA binding and photocleavage properties of transition
metal complexes of the type [M(L)2(L1)](PF6)n · xH2O (where M = Co(III) or Ni(II), L = 1,10-phenanthroline or 2.2′ bipryidine, L1 = Thiophene [2,3-b] quinoline (qt), n = 3 or 2 and x = 5 or 2) have been synthesized and characterized by elemental analysis, IR, 1H NMR, UV and magnetic susceptibility data. The DNA-binding properties of these complexes have been investigated with UV-Vis,
viscosity measurements, thermal denaturation and cyclic voltametric studies. It is experimentally found that all the complexes
are bound to DNA via intercalation in the order [Co(bpy)2(qt)](PF6)3 > [Co(phen)2(qt)](PF6)3 > [Ni(phen)2(qt)](PF6)2 > [Ni(bpy)2(qt)](PF6)2. The photocleavage studies with pUC19 DNA shows that all these complexes promoted the conversion of SC form to NC form in
absence of ‘inhibitors’. 相似文献
8.
Spectral and the X-ray diffraction studies of the title compound [H(2-picNO)2] [AuCl4] (2-picNO = alpha-picoline N-oxide) were done to investigate the short hydrogen bond in the dimeric cation [H(2-picNO)2]+. The compound exhibits several narrow transmission bands overlaid on a broad continuous absorption characteristic of a short hydrogen bond; it crystallizes with four molecules in a monoclinic unit cell of space group P21/n with lattice parameters a = 22.376(9), b = 9.874(6), c = 7.957(5) Å and β = 94.98(6)°. The structure was solved using 2623 data points collected on a CAD4 to the final value for R(Fo) = 0.039. The structure consists of discrete [AuCl4]? and [H(2-picNO)2]+ ions. Contrary to all known examples, the dimeric cation in this compound has a short hydrogen bond having no symmetry constraints making the present structural analysis unique in this series of compounds. The O—O distance is 2.393(6) Å and the dihedral angle between the two planar 2-picNO moieties in the cation is 44.1°. The [AuCl4]? anion is planar with an average AuCl distance of 2.268(2) Å. The infrared spectrum and the structure of the compound is compared with the related structures. 相似文献
9.
Gao E Guan F Gao X Zhu M Liu L Wang C Zhang W Sun Y 《Journal of biological inorganic chemistry》2012,17(2):263-274
Two novel palladium(II) complexes with a thiosalicylic acid (HSC6H4CO2H) ligand, with the formulas [Pd(TSA)(L)]·mH2O (TSA is thiosalicylic acid; in complex 1, L is 1,10-phenanthroline and m = 1; in complex 2, L is 2,2′-bipyridine and m = 2), have been synthesized and characterized. The coordination geometry of both palladium atoms is square planar; they are
four-coordinated and each is coordinated in an N,N,O−,S− mode. There is a sigmoid oxygen chain in complex 1, but an oxygen ring in complex 2. The competitive binding of the complexes to HeLa cell DNA (HL-DNA) has been investigated by fluorescence spectroscopy. The
results show that the two complexes have the ability to bind with HL-DNA. Viscosity studies suggest that the complexes bind
to DNA by intercalation. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the HL-DNA. The two
complexes exhibit cytotoxic specificity and a significant cancer cell inhibitory rate. The apoptosis tests indicated that
the complexes have an apoptotic effect. Furthermore, complex 1 exhibits more biological activity than complex 2, which is mainly because the area of the aromatic ring of 1,10-phenanthroline is larger than that of 2,2′-bipyridine. 相似文献
10.
11.
Olga A. Akimova Johanne Tremblay James W. Van Huysse Pavel Hamet Sergei N. Orlov 《Apoptosis : an international journal on programmed cell death》2010,15(1):55-62
Mechanisms underlying the tissue-specific impact of cardiotonic steroids (CTS) on cell survival and death remain poorly understood.
This study examines the role of Na+,K+-ATPase α subunits in death of Madin-Darby canine kidney (MDCK) cells evoked by 24-h exposure to ouabain. MDCK cells expressing
a variant of the α1 isoform, CTS-sensitive α1S, were stably transfected with a cDNA encoding CTS-resistant α1R-Na+,K+-ATPase, whose expression was confirmed by RT–PCR. In mock-transfected and α1R-cells, maximal inhibition of 86Rb influx was observed at 10 and 1000 μM ouabain, respectively, thus confirming high abundance of α1R-Na+,K+-ATPase in these cells. Six-hour treatment of α1R-cells with 1000 μM ouabain led to the same elevation of the [Na+]i/[K+]i ratio that was detected in mock-transfected cells treated with 3 μM ouabain. However, in contrast to the massive death of
mock-transfected cells exposed to 3 μM ouabain, α1R-cells survived after 24-h incubation with 1000 μM ouabain. Inversion of
the [Na+]i/[K+]i ratio evoked by Na+,K+-ATPase inhibition in K+-free medium did not affect survival of α1R-cells but increased their sensitivity to ouabain. Our results show that the α1R
subunit rescues MDCK cells from the cytotoxic action of CTS independently of inhibition of Na+,K+-ATPase-mediated Na+ and K+ fluxes and inversion of the [Na+]i/[K+]i ratio. 相似文献
12.
Marija Milovanovi? Vladislav Volarevi? Nebojša Arsenijevi? 《Journal of inorganic biochemistry》2010,104(9):944-1312
We have studied the kinetics of the complex formation of gold(III) complexes, [AuCl2(en)]+ (dichlorido(ethylenediamine)aurate(III)-ion) and [AuCl2(SMC)] (dichlorido (S-methyl-l-cysteine)aurate(III)) with four biologically N-donor nucleophiles. It was shown that studied ligands have a high affinity for gold(III) complex, which may have important biological implications, since the interactions of Au(III) with DNA is thought to be responsible for the anti-tumour activity. The [AuCl2(SMC)] complex is more reactive than [AuCl2(en)]+. L-His reacts faster than the other N-donor nucleophiles in the reaction with [AuCl2(en)]+, but in the reaction with [AuCl2(SMC)] 5′-GMP is the best nucleophile. Gold(III) complexes are much more reactive than Pt(II) complexes with the same nucleophiles. The activation parameters for all studied reactions suggest an associative substitution mechanism. The cytotoxicity of gold(III) complexes, [AuCl2(en)]+, [AuCl2(SMC)] and [AuCl2(DMSO)2]+ was evaluated in vitro against chronic lymphocytic leukemia cells, obtained from blood of patients with chronic lymphocytic leukemia (CLL). The [AuCl2(en)]+ complex show comparable cytotoxicity profiles compared to cisplatin. 相似文献
13.
In this work, the effects of iron ion intercalations on lead–tellurate glasses were investigated via FTIR, Raman and UV-Vis
spectroscopies. This homogeneous glass system has compositions xFe2O3·(100−x)[4TeO2·PbO2], where x = 0–60 mol%. The presented observations in these mechanisms show that the lead ions have a pronounced affinity towards [TeO3] structural units, resulting in the deformation of the Te–O–Te linkages, and leading to the intercalation of [PbO
n
] (n = 3, 4) and [FeO
n
] (n = 4, 6) entities in the [TeO4] chain network. The formation of negatively charged [FeO4]1− structural units implies the attraction of Pb2+ ions in order to compensate for this electrical charge. Upon increasing the Fe2O3 content to 60 mol%, the network can accommodate an excess of oxygen through the formation of [FeO6] structural units and the conversion of [TeO4] into [TeO3] structural units. For even higher Fe2O3 contents, Raman spectra indicate a greater degree of depolymerization of the vitreous network than FTIR spectra do. The bands
due to the Pb–O bond vibrations are very strongly polarized and the [TeO4] structural units convert into [TeO3] units via an intermediate coordination stage termed “[TeO3+1]” structural units. Our UV-Vis spectroscopic data show two mechanisms: (i) the conversion of the Fe3+ to Fe2+ at the same time as the oxidation of Pb2+ to Pb+4 ions for samples with low Fe2O3 contents; (ii) when the Fe2O3 content is high (x ≥ 50 mol%), the Fe2+ ions capture positive holes and are transferred to Fe3+ ions through a photochemical reaction, while the Pb2+ ions are formed by the reduction of Pb4+ ions. DFT calculations show that the addition of Fe2O3 to lead–tellurate glasses seems to break the axial Te–O bonds, and the [TeO4] structural units are gradually transformed into [TeO3+1]- and [TeO3]-type polyhedra. Analyzing these data further indicates a gradual conversion of the lead ions from covalent to ionic environment.
There is then a charge transfer between the tri- and tetracoordinated tellurium atoms due to the capacity of the lead–tellurate
network to form the appropriate coordination environments containing structural units of opposite charge, such as iron ions,
[FeO4]1−. 相似文献
14.
Frédéric Schmitt Padavattan Govindaswamy Olivier Zava Georg Süss-Fink Lucienne Juillerat-Jeanneret Bruno Therrien 《Journal of biological inorganic chemistry》2009,14(1):101-109
Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear
5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II)
derivatives (arene is C6H5Me or p-Pr
i
C6H4Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In
the absence of light, all tetranuclear complexes were cytotoxic (IC50 ≤ 20 μM), while the mononuclear derivatives were not (IC50 ≥ 100 μM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration
(5 μM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting
arene ruthenium–DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma
cells when exposed to laser light of 652 nm. At low concentration (5 μM), LD50 of the mononuclear derivatives was between 5 and 10 J/cm2, while for the tetranuclear derivatives LD50 was approximately 2.5 J/cm2 for the [Ru4(η6-arene)4(tetra-4-pp)Cl8] complexes and less than 0.5 J/cm2 for the [Ru4(η6-arene)4(tetra-3-pp)Cl8] complexes. Examination of cells under a fluorescence microscope revealed the [Ru4(η6-arene)4(tetra-4-pp)Cl8] complexes as cytoplasmic aggregates, whereas the [Ru4(η6-arene)4(tetra-3-pp)Cl8] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good
properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer. 相似文献
15.
Novel 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (4′-methylbenzoyl) hydrazone (H2L) (1) and its two copper(II) complexes have been synthesized. Single-crystal X-ray diffraction studies revealed that the structure
of the new copper(II) chloride complex, [Cu(H2L)Cl2]·2H2O (2), is square pyramidal and that of the copper(II) nitrate complex, [Cu(HL)NO3]·DMF (3), is square planar. In 2, the copper atom is coordinated by the ligand with ONO donor atoms, one chloride ion in the apical position, and the other
chloride in the basal plane. In 3, the ligand coordinates as a uninegative tridentate ONO− species and with one nitrate ion in the basal plane. DNA binding experiments indicated that the ligand and copper(II) complexes
can interact with DNA through intercalation. Bovine serum albumin binding studies revealed that the compounds strongly quench
the intrinsic fluorescence of bovine serum albumin through a static quenching process. Antioxidative activity tests showed
that 1 and its copper(II) complexes have significant radical scavenging activity against free radicals. Cytotoxic activities of
the ligand and copper(II) complexes showed that the two copper(II) complexes exhibited more effective cytotoxic activity against
HeLa and HEp-2 cells than the corresponding ligand. The entire biological activity results showed that the activity order
was 1 < 2 < 3. 相似文献
16.
Seil M El Ouaaliti M Fontanils U Etxebarria IG Pochet S Dal Moro G Marino A Dehaye JP 《Purinergic signalling》2010,6(4):405-416
The response to ATP of peritoneal macrophages from wild-type (WT) and P2X7-invalidated (KO) mice was tested. Low concentrations (1–100 μM) of ATP transiently increased the intracellular concentration
of calcium ([Ca2+]i) in cells from both mice. The inhibition of the polyphosphoinositide-specific phospholipase C with U73122 inhibited this
response especially in WT mice suggesting that the responses coupled to P2Y receptors were potentiated by the expression of
P2X7 receptors. One millimolar ATP provoked a sustained increase in the [Ca2+]i only in WT mice. The response to 10 μM ATP was potentiated and prolonged by ivermectin in both mice. One millimolar ATP increased
the influx of extracellular calcium, decreased the intracellular concentration of potassium ([K+]i) and stimulated the secretion of interleukin-1β (IL-1β) only in cells from WT mice. Ten micromolar ATP in combination with
3 μM ivermectin reproduced these responses both in WT and KO mice. The secretion of IL-1β was also increased by nigericin
in WT mice and the secretory effect of a combination of ivermectin with ATP in KO mice was suppressed in a medium containing
a high concentration of potassium. In WT mice, 150 μM BzATP stimulated the uptake of YOPRO-1. Incubation of macrophages from
WT and KO mice with 10 μM ATP resulted in a small increase of YOPRO-1 uptake, which was potentiated by addition of 3 μM ivermectin.
The uptake of this dye was unaffected by pannexin-1 blockers. In conclusion, prolonged stimulation of P2X4 receptors by a combination of low concentrations of ATP plus ivermectin produced a sustained activation of the non-selective
cation channel coupled to this receptor. The ensuing variations of the [K+]i triggered the secretion of IL-1β. Pore formation was also triggered by activation of P2X4 receptors. Higher concentrations of ATP elicited similar responses after binding to P2X7 receptors. The expression of the P2X7 receptors was also coupled to a better response to P2Y receptors. 相似文献
17.
trans -[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha =cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigatedat 25 °C in a 1.0 M aqueous medium at pH 2.0–5.0 (1) and 4.5–6.8 (2–4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law , where k is a pH-dependent rate constant and [GSH]tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes
and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of
these protolytic equilibria. The thiolate species GS− is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1–4 by GS− are (1.43±0.01)×107, (3.86±0.03)×106, (1.83±0.01)×106, and (1.18±0.01)×106 M−1 s−1, respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination
reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results
together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity
profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction
within 1 s of the platinum(IV) compounds with a trans Cl-Pt-Cl axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter
to increase anticancer activity, at least for this class of compounds.
Received: 8 December 1999 / Accepted: 15 February 2000 相似文献
18.
Copper (II) complex of formulation [Cu–Phen–Tyr](H2O)](ClO4) (Phen = 1,10-phenanthroline, l-Tyr = l-tyrosine), has been prepared, and their induced DNA oxidative cleavage activity studied. The complex binds to DNA by intercalation,
as deduced from the absorption and fluorescence spectral data. Scatchard plots constructed from the absorption titration data
gave binding constant 2.44 × 104 M−1 of base pairs. Extensive hypochromism, broadening, and red shifts in the absorption spectra were observed. Upon binding to
DNA, the fluorescence from the DNA–ethidium bromide system was efficiently quenched by the copper (II) complex. Stern–Volmer
quenching constant 0.61 × 103 M−1 obtained from the linear quenching plots. [Cu–Phen–Tyr] complex efficiently cleave the supercoiled DNA to its nicked circular
form with gallic acid as biological reductant at appropriate complex concentration. The gallic acid as reductant could observably
improve copper (II) complex to DNA damage. The pseudo-Michaelis–Menten kinetic parameters (k
cat, K
M) were calculated to be 1.32 h−1 and 5.46 × 10−5 M for [Cu–Phen–Tyr] complex. Mechanistic studies reveal the involvement of superoxide anions and hydroxyl radical (HO·) as the reactive species under an aerobic medium. 相似文献
19.
Catarina Xavier Clelia Giannini Sergio Dall’Angelo Lurdes Gano Stefano Maiorana Roger Alberto Isabel Santos 《Journal of biological inorganic chemistry》2008,13(8):1345-1344
The 16-mer peptide nucleic acid sequence H-A GAT CAT GCC CGG CAT-Lys-NH2 (1), which is complementary to the translation start region of the N-myc oncogene messenger RNA, was synthesized and conjugated to a pyrazolyl diamine bifunctional chelator (pz). The novel conjugate
pz-A GAT CAT GCC CGG CAT-Lys-NH2 (2) was labeled with technetium tricarbonyl, yielding quantitatively the complex fac-[99mTc(CO)3(κ3-pz-A GAT CAT GCC CGG CAT-Lys-NH2)]2+ (4). Complex 4 was obtained with high radiochemical purity and high specific activity, revealing high stability in human serum and in cell
culture medium. The identity of 4 was confirmed by comparing its reversed-phase high performance liquid chromatography profile with that of the rhenium analog
fac-[Re(CO)3(κ3-pz-A GAT CAT GCC CGG CAT-Lys-NH2)]2+ (3), prepared by conjugation of fac-[Re(CO)3(3,5-Me2pz(CH2)2N((CH2)3COOH)(CH2)2NH2)]+ to 1, using solid-phase techniques. UV melting experiments of 1 and 3 with the complementary DNA sequence led to the formation of stable duplexes, indicating that the conjugation of 1 to the pyrazolyl chelator and to the metal fragment fac-[M(CO)3]+ did not affect the recognition of the complementary sequence as well as the duplex stability. For a first screening, SH-SY5Y
human neuroblastoma cells, which express N-myc, were treated with 4. The results show that 4 internalizes (7% of the activity goes into the cells, after 4 h at 37 °C), presenting also a relatively high cellular retention
(only 40% of internalized activity is released from the cells after 5 h).
An erratum to this article can be found at 相似文献
20.
Ceyda Icsel Veysel T. Yilmaz Aysegul Golcu Engin Ulukaya Orhan Buyukgungor 《Bioorganic & medicinal chemistry letters》2013,23(7):2117-2122
Two new platinum(II) complexes, trans-[Pt(2-mpy)2]·4H2O (1) and [PtCl(2-pyc)(2-hmpy)]·H2O (2), where 2-hmpy = 2-(hydroxymethyl)pyridine, 2-mpy = deprotonated 2-hmpy and 2-pyc = pyridine-2-carboxylate, have been synthesized and characterized by elemental analysis, IR, NMR, and X-ray crystallography. The DNA binding affinities of these complexes for Fish Sperm DNA (FS-DNA) were investigated using fluorescence, viscosity, thermal denaturation and gel electrophoresis measurements. Fluorescence analysis indicates that complex 1 binds to DNA by a single intercalative mechanism, while complex 2 exhibits two types of interactions such as intercalation and covalent binding. Gel electrophoresis assay demonstrates ability of the complexes to cleavage the supercoiled pBR322 plasmid DNA. The in vitro cytotoxicities of both complexes were preliminarily evaluated and the cytotoxicity of complex 1 against the human lung cancer cells (H1299) is similar to oxaliplatin, but higher than transplatin and carboplatin. 相似文献