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1.
This paper reports the separation and preliminary characterization of the products formed by the reaction of the antitumor compound cis-Pt(NH3)2Cl2 with DNA. Electrophoresis of the acid hydrolysed platinum-DNA complex gave a profile of platinum concentration which contained 5 peaks whose relative intensities varied with the amount of cis-Pt(NH3)2Cl2 fixed on the DNA. Similar analysis of the products formed between DNA and trans-Pt(NH3)2Cl2 or [Pt(dien)Cl]Cl, which are not active antitumor agents, indicated that these compounds bound to DNA in a different manner than cis-Pt(NH3)2Cl2. DNA isolated from Escherichia coli which had been treated with cis-Pt(NH3)2Cl2 or [Pt(dien)Cl]Cl did not give the same electrophoresis profiles as the corresponding platinum-DNA complexes formed in vitro.  相似文献   

2.
用生物微量热技术及DNATm测量研究了手性不同的三种环方铂络合物与小牛胸腺DNA(200bp)作用中的特异性,发现R,R构型的与DNA作用最强,这与癌细胞的体外筛选结果相一致.而且通过HPLC及13C-NMR研究为环方铂络合物与DNA作用的分子机理分析找到了直接的证据.  相似文献   

3.
Porphyrin platinum conjugates - new aims   总被引:1,自引:0,他引:1  
Forty porphyrin platinum conjugates were synthesized, which exhibited a photodynamic effect due to the porphyrin system and a cytostatic effect due to the platinum fragment present in the same molecule. The porphyrin ligands for the platinum complexes were synthesized starting from hematoporphyrin and deuteroporphyrin. The platinum complexes are of the (diamine)PtCl2, (diamine)Pt(phthalato), (NH3)2Pt(dicarboxylato) and (diamine)Pt(dicarboxylato) type. Their antitumor activity was tested with the MDA-MB-231 mammary carcinoma cell line with and without irradiation.  相似文献   

4.
Linear double-stranded DNA molecules interact with positively charged polyconidine molecules in aqueous salt solutions to yield liquid-crystalline dispersions (LCDs) with a mean particle diameter of ~6000 Å. The packing density of (DNA-polycation) complexes differs among LCD particles formed at different ionic strengths. X-ray data on the liquid-crystalline phases of (DNA-polyconidine) complexes formed under different conditions were compared with a phase diagram, reflecting polymorphism of liquid crystals of linear double-stranded DNA. It was shown that LCD was hexagonal at 0.15 M ≤ C NaCl < 0.4 M and cholesteric at 0.4 M ≤ C NaCl < 0.55 M. Cholesteric LCD displayed abnormal optical activity in the circular dichroism spectrum. A similar situation was observed with poly(2,5-ionene), another polycation differing in chemical structure from polyconidine. The results demonstrated structural polymorphism of (DNA-polycation) LCDs. It was assumed that the packing mode of (DNA-polycation) complexes in LCD particles can be regulated by changing NaCl concentration. The mechanism generating the cholesteric liquid-crystalline state of DNA in a narrow range of NaCl concentrations is discussed.  相似文献   

5.
To evaluate the biological preference of chiral drug candidates for molecular target DNA, new potential metal‐based chemotherapeutic agents 1 , 1a , 1b , 2 , 2a , 2b , 3 , 3a , 3b of late 3d transition metals Ni(II), Cu(II), and Zn(II), respectively, derived from (R)‐ and (S)‐2‐amino‐2‐phenylethanol with  CH2 CH2 linker were synthesized and thoroughly characterized. Interaction studies of 1 , 1a , 1b , 2 , 2a , 2b , 3 , 3a , 3b with calf thymus DNA in Tris buffer were studied by electronic absorption titrations, luminescence titrations, cyclic voltammetry, and circular dichroism. The results reveal that the extent of DNA binding of R‐enantiomer of copper 1a was highest in comparison to rest of the complexes via electrostatic interaction mode. The nuclease activity of 1a , 1b with supercoiled pBR322 DNA was further examined by gel electrophoresis, which reveals that complex 1a exhibits a remarkable DNA cleavage activity (concentration dependent) with pBR322DNA, and the cleavage activity of both enantiomers of complex 1 was significantly enhanced in the presence of activators. The activating efficiency follows the order Asc > H2O2 > MPA for 1a , and reverse order was observed for 1b , because of the differences in enantioselectivity and conformation. Further, it was observed that cleavage reaction involves singlet oxygen species and superoxide radicals via oxidative cleavage mechanism. In addition, complex 1a exhibits significant inhibitory effects on the topoisomerase II (topo II) activity at a very low concentration ∼24 μM, which suggest that complex 1a is indeed catalytic inhibitor or (poison) of human topo II. Chirality 2011 © 2011 Wiley‐Liss, Inc.  相似文献   

6.
We are reporting the synthesis, characterization, and calf thymus DNA binding studies of novel chiral macrocyclic Mn(III) salen complexes S‐1 , R‐1 , S‐2 , and R‐2 . These chiral complexes showed ability to bind with DNA, where complex S‐1 exhibits the highest DNA binding constant 1.20 × 106 M?1. All the compounds were screened for superoxide and hydroxyl radical scavenging activities; among them, complex S‐1 exhibited significant activity with IC50 1.36 and 2.37 μM, respectively. Further, comet assay was used to evaluate the DNA damage protection in white blood cells against the reactive oxygen species wherein complex S‐1 was found effective in protecting the hydroxyl radicals mediated plasmid and white blood cells DNA damage. Chirality 24:1063–1073, 2012.© 2012 Wiley Periodicals, Inc.  相似文献   

7.
Some amino acid derivatives, such as R-glycine, have been synthesized together with their full spectroscopic characterization. The sodium salts of these bidentate amino acid ligands have been interacted with [M(bpy)(H2O)2](NO3)2 giving the corresponding some new complexes with formula [M(bpy)(R-gly)]NO3 (where M is Pt(II) or Pd(II), bpy is 2,2′-bipyridine and R-gly is butyl-, hexyl- and octyl-glycine). Due to less solubility of octyl derivatives, the biological activities of butyl and hexyl derivatives have been tested against chronic myelogenous leukemia cell line, K562. The interaction of these complexes with highly polymerized calf thymus DNA has been extensively studied by means of electronic absorption, fluorescence and other measurements. The experimental results suggest that these complexes positive cooperatively bind to DNA presumably via groove binding. Molecular dynamic results show that the DNA structure is largely maintained its native structure in hexylglycine derivative–water mixtures and at lower temperatures. The simulation data indicates that the more destabilizing effect of butylglycine is induced by preferential accumulation of these molecules around the DNA and due to their more negative free energy of binding via groove binding.  相似文献   

8.
A pair of chiral binuclear ruthenium(II) complexes were prepared and their binding affinities towards double stranded native DNA were assessed by observing isotropic absorption, polarized light spectra - circular and linear dichroism (CD and LD), fluorescence quenching and DNA thermal denaturation. Upon binding to DNA, the complexes produced LD signals consisting of positive and negative signals in the absorption region, although they exhibited red shift and hypochromism in the absorption spectrum. These contrasting observations indicated that the binding modes of the complexes are largely deviated from classical intercalative binding. Groove binding of the complexes to DNA was found to be more likely than intercalative binding. The small increase of DNA melting temperature in the presence of the complexes indicated a predominance of DNA groove binding. The absence of “molecular light switch effect” further supported non-intercalative binding. The groove binding propensity of complexes was also supported by comparison of the resulting data with the [Ru(phen)2(dppz)]2+.  相似文献   

9.
A series of Pt(II) complexes containing 1,2-diphenylethylenediamine (stien) isomers were synthesized and tested for their antitumor activity against leukemia L1210. Among the Pt(II) complexes examined water-soluble Pt(II) complexes with sulfate, nitrate and D-glucuronate ions as leaving groups exhibited relatively high antitumor activity. Furthermore, the interactions between calf-thymus DNA and Pt(SO4) (stein) complexes were investigated by means of circular dichroism spectrometry. Dichroism enhancements observed in the interaction between DNA and Pt(SO4) (stien) complexes were analysed to be contributable to two factors: (1) vicinal effects of DNA on the d-d transitions of Pt(II) ions and (2) conformational changes of DNA caused by the coordination of cis-configurational Pt(II) complexes.  相似文献   

10.
The amine substituent effect in compounds [Pt(diamine)Cl2] on inhibition of maize and cucumber root growth and branching has been investigated. The diamines used were ethylenediamine (en),N-methylethylenediamine (men),N,N-dimethylethylenediamine (N,N-dmen),N,N-dimethylethylenediamine (N,N-dmen),N,N,N,N-tetramethylethylenediamine (tmen), 1,2-propanediamine (1,2-pn), 2-methyl-1,2-propanediamine (ibn), 2,3 dimethyl-2,3-butanediamine (C-tmen), 1,3-propanediamine (1,3-pn), 2,2-dimethyl-1,3-propanediamine (C2-dm-1,3 pn),N,N-dimethyl-1,3-propanediamine (N,N-dm-1,3-pn). Increased substitution of hydrogen atoms of the amine part with CH3 groups reduces the cytostatic activity of complexes. The substitution of hydrogen atoms of NH2 and vicinal CH2 groups displays similar results. C-2 dimethylation (C-dm-1,3-pn) does not change the activity of the complex compared with (1,3-pn). It was observed that maize and cucumber roots differ in their relative sensitivity to various complexes. All complexes containing pn and their substituted analogs inhibited cucumber root growth weaker than that in maize. A comparison of obtained data with earlier published results concerning antitumor activity of complexes shows that they correlate in a similar manner with increased substitution of amino groups. Therefore, roots may be used as cheap test objects for primary screening of cytostatics. The general tendency of a decrease in cytostatic activity goes parallel with the number of Nor vicinal C-methyl groups and seems to arise from a decrease in hydrogen-bonding potential; however, some other possible reasons are also discussed. The activity discrimination by different species in our experiments and clearly different results forN,N-dimethylation depending on the chelate ring size (en and pn derivatives) on maize cannot be attributed to slower ligand-exchange kinetics from methylation. It is possible to assume that the major role in cytostatic activity of platinum complexes belongs to a cell repair system, i.e. the ability to eliminate platinum diamine fragments from DNA, depending on the number and strength of hydrogen bonds formed by thecis-diamine fragment.  相似文献   

11.
Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.  相似文献   

12.
The enantiomers of the Sm (III), Eu (III) and Yb (III) complexes [LnL(NO3)2](NO3) of a chiral hexaazamacrocycle were tested as catalysts for the hydrolytic cleavage of supercoiled plasmid DNA. The catalytic activity was remarkably enantioselective; while the [LnLSSSS(NO3)2](NO3) enantiomers promoted the cleavage of plasmid pBR322 from the supercoiled form (SC) to the nicked form (NC), the [LnLRRRR(NO3)2](NO3) enantiomers were inactive. Kinetics of plasmid DNA hydrolysis was also investigated by agarose electrophoresis and it indicated typical single-exponential cleavage reaction. The hydrolytic mechanism of DNA cleavage was confirmed by the successful ligation of hydrolysis product by T4 ligase. The NMR study of the solutions of the complexes in various buffers indicated that the complexes exist as monomeric cationic complexes [LnL(H2O)3]3 + in slightly acidic solutions and as dimeric cationic complexes [Ln2L2(μ-OH)2(H2O)2]4 + in slightly basic 8 mM solutions, with the latter form being a possible catalyst for hydrolysis of phosphodiester bonds.  相似文献   

13.
A series of novel platinum(II) complexes involving an asymmetric chelating diamine 2-morpholinoethylamine (MPEA) as the carrier, cis-[Pt(MPEA)X2] (X2 = 2Cl, oxalate, malonate, 1,1-cyclobutanedicarboxylate (CBDCA), 3-hydroxy-1,1-cyclobutanedicarboxylate (HO-CBDCA)), have been synthesized and characterized by elemental analysis and spectroscopic data along with X-ray crystal structure for a representative complex cis-[Pt(MPEA) (CBDCA)]. The Pt(II) is in a square planar environment and is coordinated by a chelating CBDCA and MPEA in cis position. The complexes with dicarboxylate are quite soluble (>25 mg/ml) and stable in water. The cytotoxicity of the complexes has been assessed in the human lung cancer cell lines A549 and A549/ATCC. One complex, cis-[Pt(MPEA)Cl2], is more active than carboplatin against both the sensitive and resistant cells, and has less cross-resistance with cisplatin.  相似文献   

14.
The square planar Pt(II) complexes of the type [Pt(Ln)(Cl2)] (where Ln = L1?3 = thiophene-2-carboxamide derivatives and L4?6 = thiophene-2-carbothioamide derivatives) have been synthesized and characterized by physicochemical and various spectroscopic studies. MIC method was employed to inference the antibacterial potency of complexes in reference to free ligands and metal salt. Characteristic binding constant (Kb) and binding mode of complexes with calf thymus DNA (CT-DNA) were determined using absorption titration (0.76–1.61 × 105 M?1), hydrodynamic chain length assay and fluorescence quenching analysis, deducing the partial intercalative mode of binding. Molecular docking calculation displayed free energy of binding in the range of –260.06 to –219.63 kJmol?1. The nuclease profile of complexes towards pUC19 DNA shows that the complexes cleave DNA more efficiently compared to their respective metal salt. Cytotoxicity profile of the complexes on the brine shrimp shows that all the complex exhibit noteworthy cytotoxic activity with LC50 values ranging from 7.87 to 15.94 μg/mL. The complexes have been evaluated for cell proliferation potential in human colon carcinoma cells (HCT 116) and IC50 value of complexes by MTT assay (IC50 = 125–1000 μg/mL).  相似文献   

15.
The interaction of newly synthesised water-soluble planar complexes of general structure [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- with DNA was investigated by means of DNA melting studies, CD spectroscopy, and DNA gel mobility studies. Addition of stoichometric amounts of [Pt(diimine)H2L-S,O]Cl complexes to polynucleotides caused a significant increase in the melting temperature of poly(dA-dT) and calf-thymus DNA, respectively, indicating that these complexes interacted with DNA and stabilised the double helical structure. The CD spectra confirmed the relatively strong binding of three related Pt(II) complexes ([Pt(2,2'-bipyridine)H2L-S,O]Cl, [Pt(4,4'-dimethyl-2,2'-bipyridine)H2L-S,O]Cl, and [Pt(1,10-phenanthroline)H2L-S,O]Cl), to DNA. Comparison with the published CD spectra of ethidium bromide/DNA complex suggests a similar intercalation mode of binding. cis-[(4,4'-di-tert-butyl-2,2'-bipyridyl)N,N-di(2-hydroxyethyl)-N'-benzoylthioureatoplatinum(II)] chloride, with its very bulky tert-butyl groups, did not intercalate into the polynucleotide double helix. In DNA mobility studies in the presence of the four [Pt(diimine)H2L-S,O]Cl complexes, only [Pt(2,2'-bipyridine)H2L-S,O]Cl affected the DNA mobility to any detectable extent. Finally, in vivo studies on the biological activity of the complexes, using an Escherichia coli DNA excision repair deficient uvrA mutant strain, indicated that only the [Pt(2,2'-bipyridine)H2L-S,O]Cl complex showed significant cellular toxicity and that this was, in part, linked to DNA damage.  相似文献   

16.
A series of twelve novel diamminetetrakis(carboxylato)platinum(IV) and 18 novel bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) complexes with mixed axial carboxylato ligands was synthesized and characterized by multinuclear 1H‐, 13C‐, 15N‐, and 195Pt‐NMR spectroscopy. Their cytotoxic potential was evaluated (by MTT assay) against three human cancer cell lines derived from ovarian teratocarcinoma (CH1/PA‐1), lung (A549), and colon carcinoma (SW480). In the cisplatin‐sensitive CH1/PA‐1 cancer cell line, diamminetetrakis(carboxylato)platinum(IV) complexes showed IC50 values in the low micromolar range, whereas, for the most lipophilic compounds of the bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) series, IC50 values in the nanomolar range were found.  相似文献   

17.
Two couples of enantiomeric platinum(II) complexes: Pt(L1a)Cl ( 1a ), Pt(L1b)Cl ( 1b ) and Pt(L1a)(C ≡ C ? Ph) ( 2a ), Pt(L1b)(C ≡ C ? Ph) ( 2b ) (L1a = (+)‐1,3‐di‐(2‐(4,5‐pinene)pyridyl)benzene, L1b = (?)‐1,3‐di‐(2‐(4,5‐pinene)pyridyl)benzene) were synthesized and characterized. Their absolute configurations were determined by single crystal X‐ray diffraction and further verified by circular dichroism (CD) spectra (including electronic circular dichroism [ECD] and vibrational circular dichroism [VCD]). These complexes show interesting mechanoluminescence and/or vapoluminescence due to crystalline‐to‐amorphous transformation. The crystalline solids, grinding‐induced amorphous powders, and vapor‐induced amorphous powders of complexes 2a and 2b were comparatively investigated by solid‐state ECD and VCD spectra. The transformation from crystalline solids to amorphous powders was accompanied by significant variances of the spectral feature in both ECD and VCD spectra. Chirality 25:384–392, 2013. © 2013 Wiley Periodicals, Inc.  相似文献   

18.
Two new chiral mononuclear Mn(III) complexes, [Mn L ( R )Cl (C2H5OH)]?C2H5OH ( 1 ) and [Mn L ( S ) (CH3OH)2]Cl?CH3OH ( 2 ), {H2 L = (R,R)‐or (S,S)‐N,N’‐bis‐(2‐hydroxy‐1‐naphthalidehydene)‐cyclohexanediamine} were synthesized and characterized by various physicochemical techniques. Bond valence sum (BVS) calculations and the Jahn‐Teller effect indicate that the Mn centers are in a +3 oxidation state. The statuses of the two complexes in the solution were confirmed as a pair of enantiomers by electrospray ionization, mass spectrometry (ESI‐MS) spectrum. The binding ability of the complexes with calf thymus CT‐DNA was investigated by spectroscopic and viscosity measurements. Both of the complexes could interact with CT‐DNA via an intercalative mode with the order of 1 ( R ‐enantiomer) > 2 ( S ‐enantiomer). Under the physiological conditions, the two compounds exhibit efficient DNA cleavage activities without any external agent, which also follows the order of R ‐enantiomer > S ‐enantiomer. Interestingly, the concentration‐dependent DNA cleavage experiments indicate an optimal concentration of 17.5 μM. In addition, the interaction of the compounds with bovine serum albumin (BSA) was also investigated, which indicated that the complexes could quench the intrinsic fluorescence of BSA by a static quenching mechanism. Chirality 27:142‐150, 2015. © 2014 Wiley Periodicals, Inc.  相似文献   

19.
In this study, two Pt(II) and three Pt(IV) complexes with the structures of [PtL2Cl2] (1), [PtL2I2] (2), [PtL2Cl2(OH)2] (3), [PtL2Cl2(OCOCH3)2] (4), and [PtL2Cl4] (5) (L = benzimidazole as carrier ligand) were synthesized and evaluated for their in vitro antiproliferative activities against the human MCF-7, HeLa, and HEp-2 cancer cell lines. The influence of compounds 1–5 on the tertiary structure of DNA was determined by their ability to modify the electrophoretic mobility of the form I and II bands of pBR322 plasmid DNA. The inhibition of BamH1 restriction enzyme activity of compounds 1–5 was also determined. In general, it was found that compounds 1–5 were less active than cisplatin and carboplatin against MCF-7 and HeLa cell lines (except for 1, which was found to be more active than carboplatin against the MCF-7 cell line). Compounds 1 and 3 were found to be significantly more active than cisplatin and carboplatin against the HEp-2 cell line.  相似文献   

20.
The macrocyclic symmetrical and a series of unsymmetrical binuclear copper(II) complexes have been synthesized by using mononuclear complex [CuL] [3,3′-((1E,7E)-3,6-dioxa-2,7-diazaocta-1,7-diene-1,8-diyl)bis(3-formyl-5-methyl-2-diolato)copper(II)]. Another compartment of the [CuL] have been condensed with various diamines like 1,2-bis(aminooxy)ethane (L1), 1,2-diamino ethane(L2a), 1,3-diamino propane(L2b), 1,4-diamino butane(L2c), 1,2-diamino benzene(L2d), 1,8-diamino naphthalene(L2e) and characterized by elemental, spectroscopic, and X-ray crystallographic methods. The influence of the coordination geometry and the ring size of the binucleating ligands on the electronic, redox, magnetic, catecholase activity, DNA binding and cleavage properties have been studied. The molecular structures of the symmetrical binuclear complex [Cu2L1(H2O)2](ClO4)2 (1) and unsymmetrical binuclear complex [Cu2L2b(ClO4)(H2O)]ClO4 (2b) were determined by X-ray crystallography. Both of them were discrete binuclear species in which each Cu(II) ions are in distorted square pyramid. The Cu?Cu distances vary from 3.0308 (2b) to 3.0361 Å (1). Electrochemical studies evidenced that two quasi-reversible one electron-transfer reduction waves −0.91 to −1.01 V, −1.26 to −1.55 V) for binuclear complexes are obtained in the cathodic region. Cryomagnetic investigation of the binuclear complexes reveals a weak antiferromagnetic spin exchange interaction between the Cu(II) ions within the complexes (−2J = 104.4-127.5 cm−1). The initial rate (Vin) for the oxidation of 3,5-di-tert-butylcatechol to o-quinone by the binuclear Cu(II)complexes are in the range 3.6 × 10−5 to 7.3 × 10−5 Ms−1. The binuclear Cu(II) complexes are avid binders to calf thymus DNA. The complexes display significant oxidative cleavage of circular plasmid pBR322 DNA in the presence of mercaptoethanol using the singlet oxygen as a reactive species. The aromatic diamine condensed macrocyclic ligands of copper(II) complexes display better DNA interaction and significant chemical nuclease activity than the aliphatic diamine condensed macrocyclic Cu(II) complexes.  相似文献   

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