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1.
Chem Commun (Camb) ; 48(61): 7607-9, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22728887

ABSTRACT

Two new Pt(II) squares with quinoxaline-bridges selectively stabilize human telomeric G-quadruplexes with high binding constants (10(7)-10(9) M(-1)) and an unprecedented binding stoichiometric ratio of Pt(II) square/G-quadruplex (6 : 1). This selectivity is likely due to the Pt(II) squares' cube-like shape. Both Pt(II) squares also show significant telomerase inhibition and anticancer efficacy.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , G-Quadruplexes/drug effects , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Telomerase/antagonists & inhibitors , Cell Line, Tumor , Circular Dichroism , Crystallography, X-Ray , DNA/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Neoplasms/drug therapy
2.
J Inorg Biochem ; 105(2): 149-54, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21194612

ABSTRACT

In this work, the interaction between the guanine-rich single-strand oligomer AG(3)(T(2)AG(3))(3) quadruplex and two Ru(II) complexes, [Ru(L(1))(dppz)(2)](PF(6))(4) (1) and [Ru(L(2))(dppz)(2)](PF(6))(4) (2) (L(1) = 5,5'-di(1-(trimethylammonio)methyl)-2,2'-dipyridyl cation, L(2) = 5,5'-di(1-(triethylammonio)methyl)-2,2'-dipyridyl cation, dppz = dipyrido[3,2-a:2',3'-c] phenazine), has been studied by UV-Visible, fluorescence, DNA melting, and circular dichroism in K(+) buffer. The two complexes after binding to G-quadruplex have shown different DNA stability and fluorescence enhancement. The results show that both complexes can induce the stabilization of quadruplex DNA. ΔT(m) values of complexes 1 and 2 at [Ru]/[DNA] ratio of 1:1 were 9.4 and 7.0, respectively. Binding stoichiometry along with the quadruplex was investigated through a luminescence-based Job plot. The major inflection points for complexes 1 and 2 were 0.49 and 0.46, respectively. The data were consistent with the binding mode at a [quadruplex]/[complex] ratio of 1:1. In addition, the conformation of G-quadruplex was not changed by the complexes at the high ionic strength of K(+) buffer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemistry , G-Quadruplexes , Phenazines/chemistry , Ruthenium , Antineoplastic Agents/chemistry , Circular Dichroism , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , Humans , Molecular Conformation , Transition Temperature
3.
Chem Commun (Camb) ; 46(35): 6497-9, 2010 Sep 21.
Article in English | MEDLINE | ID: mdl-20697618

ABSTRACT

The novel dinuclear Zn(ii) complex (1) containing a beta-CD dimer could accelerate BNPP (a DNA substitute) hydrolysis more efficiently than catalyze HPNP (a RNA substitute) transesterification with different mechanisms involved; the beta-CDs played remarkably different roles.


Subject(s)
Acids/chemistry , Zinc/chemistry , Catalysis , Coordination Complexes/chemistry , Hydrolysis , Hydrophobic and Hydrophilic Interactions , Kinetics , Organophosphates , Organophosphorus Compounds/chemistry , Phosphoric Diester Hydrolases/chemistry , Phosphoric Diester Hydrolases/metabolism , beta-Cyclodextrins/chemistry
4.
Dalton Trans ; 39(8): 2128-36, 2010 Feb 28.
Article in English | MEDLINE | ID: mdl-20148233

ABSTRACT

Novel copper(ii) complexes bearing 2,2'-bipyridine (bpy) derivatives with adenine, thymine and uracil nucleobases [Cu(L(1))Cl(2)].2H(2)O (1), [Cu(L(2))Cl(2)] (2) and [Cu(L(3))Cl(2)].H(2)O (3) (L(1) = 5,5'-Di[N9-adenylmethyl]-2,2'-bipyridine, L(2) = 5,5'-Di[N1-thyminylmethyl]-2,2'-bipyridine and L(3) = 5,5'-Di[N1-uracilmethyl]-2,2'-bipyridine) were synthesized and characterized. Structure simulation was performed for these complexes. Circular dichroism (CD) spectra revealed the interactions between these ligands and pBR322 DNA and showed that the local DNA structure was perturbed by these ligands. Cleavage of pBR322 DNA by these complexes was carried out in 20 mM HEPES (pH 7.5) at 37 degrees C. The calculated pseudo-Michaelis-Menten kinetic parameters (k(cat)) were 14.7 +/- 0.6 and 40.4 +/- 1.3 h(-1) for and . The cleavage efficiency of was 80-fold higher than that of its simple analogue [Cu(bpy)Cl(2)] (k(cat) = 0.50 h(-1)) and very close to the catalytic rate constant of natural EcoRI endonuclease (k(cat) = 43.2 h(-1)) at similar conditions. Thus, complex might be one of the most effective artificial nucleases that could catalyze double-stranded DNA hydrolytic cleavage so far. Hydrolytic mechanisms involved in DNA cleavage were explored using radical scavengers and T4 ligase. Competitive experiments with special binding agents showed that complexes could preferentially bind to the minor groove of double-stranded DNA, suggesting specific DNA binding characteristics. Molecular docking calculations also indicated that complexes could bind to the minor groove of targeted DNA much more strongly than their simple analogues and preferentially bind at the AT region of the dodecamer. Such high DNA cleavage ability and selectivity of these copper(ii) complexes could be attributed to the synergic effects of the metal center and the pendant nucleobases.


Subject(s)
Coordination Complexes/chemistry , Copper/chemistry , Nucleosides/chemistry , Circular Dichroism , DNA/chemistry , DNA Cleavage , Deoxyribonucleases/chemistry , Deoxyribonucleases/metabolism
5.
Chem Asian J ; 4(8): 1354-60, 2009 Aug 03.
Article in English | MEDLINE | ID: mdl-19579255

ABSTRACT

A new beta-cyclodextrin dimer, 2,6-dimethylpyridine-bridged-bis(6-monoammonio-beta-cyclodextrin) (pyridyl BisCD, L), is synthesized. Its zinc complex (ZnL) is prepared, characterized, and applied as a catalyst for diester hydrolysis. The formation constant (log K(ML)=7.31+/-0.04) of the complex and deprotonation constant (pK(a1)=8.14+/-0.03, pK(a2)=9.24+/-0.01) of the coordinated water molecule were determined by a potentiometric pH titration at (25+/-0.1) degrees C, indicating a tridentate N,N',N''-zinc coordination. Hydrolysis kinetics of carboxylic acid esters were determined with bis(4-nitrophenyl)carbonate (BNPC) and 4-nitrophenyl acetate (NA) as the substrates. The resulting hydrolysis rate constants show that ZnL has a very high rate of catalysis for BNPC hydrolysis, yielding an 8.98x10(3)-fold rate enhancement over uncatalyzed hydrolysis at pH 7.00, compared to only a 71.76-fold rate enhancement for NA hydrolysis. Hydrolysis kinetics of phosphate esters catalyzed by ZnL are also investigated using bis(4-nitrophenyl)phosphate (BNPP) and disodium 4-nitrophenyl phosphate (NPP) as the substrates. The initial first-order rate constant of catalytic hydrolysis for BNPP was 1.29x10(-7) s(-1) at pH 8.5, 35 degrees C and 0.1 mM catalyst concentration, about 1600-fold acceleration over uncatalyzed hydrolysis. The pH dependence of the BNPP cleavage in aqueous buffer was shown as a sigmoidal curve with an inflection point around pH 8.25, which is nearly identical to the pK(a) value of the catalyst from the potentiometric titration. The k(BNPP) of BNPP hydrolysis promoted by ZnL is found to be 1.68x10(-3) M(-1) s(-1), higher than that of NPP, and comparatively higher than those promoted by its other tridentate N,N',N''-zinc analogues.


Subject(s)
Organometallic Compounds/chemistry , Zinc/chemistry , beta-Cyclodextrins/chemistry , Catalysis , Dimerization , Esters , Hydrolysis , Hydrophobic and Hydrophilic Interactions , Kinetics , beta-Cyclodextrins/chemical synthesis
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