The Interactions of Low Oxidation State Transition Metal Clusters with DNA: Potential Applications in Cancer Therapy

A series of ruthenium and platinum clusters have been examined for DNA binding activity in methanol-water and water solutions. The clusters [H₄Ru₄(C₆H₆)₄]²⁺and Ru₃(CO)₉(PTA)₃(PTA=1,3,5-triaza-7-phosphatricyclo[3.3.1.1] decane) proved to be most effective; the former is believed to cross link DNA and the latter possibly intercalates. These clusters are highly water soluble and combined with their DNA damaging activity and size represent potential anticancer drugs.     

DNA binding,cleavage, and cytotoxicity of binuclear phenolate nickel(II) complexes

Three binuclear phenolate complexes, [Ni₂(L¹)₂(OAc)](BPh₄)·DMF (1), [Ni₂(L²)₂(OAc)](BPh₄) (2), and [Ni₂(L³)₂(OAc)](OH)·3H₂O (3), where L¹ = 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-methyl-phenol, L² = 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-methoxy-phenol, and L³ = 2-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-4-tert-butyl-phenol), have been synthesized. Single-crystal diffraction reveals that all the metal atoms are in a distorted octahedral geometry. The interactions of the complexes with calf thymus DNA (CT-DNA) have been investigated by UV–vis absorption, fluorescence emission, and circular dichroism spectroscopy and viscosity measurements. Furthermore, DNA cleavage mechanism shows that the complexes may be capable to promote DNA cleavage through oxidative DNA damage pathway, which is indicative of the involvement of hydroxyl radical, singlet oxygen, or singlet oxygen-like entity in the cleavage process. Cytotoxicity studies on the Hela and MCF-7 cancer cell lines show that complexes 1–3 exhibit excellent activity toward the tested tumor cell lines with respect to the standard drug carboplatin, revealing that they have the potential to act as effective metal-based anticancer drugs.     

Synthesis, spectroscopic, powder X-ray diffraction and DNA binding studies on copper(II) complexes of 4,4′-diaminodiphenyl sulfone

Four new Cu(II) complexes of 4,4??-diaminodiphenyl sulfone (DDS) with different anions (chloride, sulfate, nitrate or acetate) were synthesized and characterized by elemental analysis, electronic absorption, IR, magnetic moment, thermal analysis and powder X-ray diffraction studies. It was found that the pure DDS and complex [Cu₂(DDS)₂(NO₃)₂].(NO₃)₂ (3) crystallize in orthorhombic system while the complexes [Cu₂(DDS)₂].Cl₄ (1), [Cu₂(DDS)₂].(SO₄)₂ (2), and [Cu₂(DDS)₂].(CH₃COO)₄ (4) crystallize in monoclinic system. The crystallite sizes of complexes have smaller values as compared to pure DDS. Infrared studies suggest that the coordination of NH₂ of DDS with Cu(II) ion. The binding of the complexes with calf thymus (CT) DNA was investigated by electronic absorption titration, fluorescence measurements and DNA thermal denaturation. The spectroscopic studies together with the DNA melting studies indicated that the complexes may bind to CT-DNA in a non-intercalative mode.     

Quantum chemical and spectroscopic analysis of calcium hydroxyapatite and related materials

Amorphous calcium hydroxyapatite was examined by vibrational spectroscopy (Raman and infra-red (IR)) and quantum chemical simulation techniques. The structures and vibrational (IR, Raman and inelastic neutron scattering) spectra of PO₄³⁻ ion, Ca₃(PO₄)₂, [Ca₃(PO₄)₂]₃, Ca₅(PO₄)₃OH, CaHPO₄, [CaHPO₄]₂, Ca₃(PO₄)₂·H₂O, Ca₃(PO₄)₂·2H₂O and Ca₃(PO₄)₂·3H₂O clusters were quantum chemically simulated at ab initio and semiempirical levels of approximation. A complete coordinate analysis of the vibrational spectra was performed. The comparison of the theoretically simulated spectra with the experimental ones allows to identify correctly the phase composition of the amorphous calcium hydroxyapatite and related materials. The shape of the bands in the IR spectra of the hydroxoapatite can be used in order to characterize the structural properties of the material, e.g., the PO₄³⁻ ion status, the degree of hydrolysis of the material and the presence of hydrolysis products.     

Solvent and Concentration-Dependent Aggregation Study of C 60 Dyads and Multiads on Nonlinear Photonic Properties

We have studied the molecular self-assembly tendency of C₆₀(> DPAF-C₉) dyad, C₆₀(> DPAF-C₉)₂ triad, and C₆₀(> DPAF-C₉)₄ pentads in a solvent-dependent and concentration-dependent manner. The evaluation was performed by the particle-size measurements on molecular assemblies in either toluene or CS₂ using the dynamic light scattering technique. As a result, we observed a strong bimodal particle size distribution in most cases of the samples in both nonpolar solvents. In the instance of C₆₀(> DPAF-C₉) dyad, the first group of small nanoparticles exhibited a particle diameter size of 3.0–4.0 nm in good agreement with the estimated long axis length of C₆₀(> DPAF-C₉) (～ 2.7 nm), using 3D molecular modeling technique. Similar observation of a bimodal particle size distribution was detected on C₆₀(> DPAF-C₉)₄ pentads in toluene with a small nanoparticle diameter size of ～ 8.0 nm fitting well with the estimated dimension length of ～ 9.8 nm for loosely packed 3–6 C₆₀(> DPAF-C₉)₄ molecular assemblies. Furthermore, the tendency of forming large aggregation particles in a particle diameter of more than 4.0 μ m was significantly enhanced at a concentration of 1.0 × 10^–2 M.     

Quasielastic scattering of neutrons from freely jointed polymer chains in dilute solutions

Starting with Kirkwood's Fokker–Planck equation for the polymer configuration-space distribution function and using the Zwanzig–Mori projection operator technique we have calculated the scattering law S_(q,w) for a freely jointed model polymer chain in a dilute solution. When memory effects are neglected, the theory predicts a Lorentzian for S_(q,w) with a halfwidth Ω_(q), which we have determined as a function of the momentum transfer q for all values of q. The results are compared with recent neutron scattering experiments on deuterated polytetrahydrofuran and polystyrene in dilute solution in CS₂. It is found that the observed q dependence of Ω(q) is represented satisfactorily by the present theory with a bond length b of about 6.3 Å for polystyrene and 3.8 Å for polytetrahydrofuran, and a friction coefficient ζ = 4πη0b where η₀ is the viscosity of the solvent.     

Synthesis of dinitroxylcis-diaminoplatinum(ii) complexes and their interaction with DNA

Dinitroxyl complexes of platinum,cis-Pt^II(APO)₂X₂, where APO is 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, were obtained by either a direct reaction of APO with K₂PtX₄ (X=Cl or I) or a replacement of iodide ligands incis-Pt^II(APO)₂I₂ by nitrate and oxalate ligands. The interation of water-solublecis-Pt^II(APO)₂(NO₃)₂ with, ox spleen DNA resulted in platinated DNA with a degree of modification (r)-7 times lower than that obtained withcis-Pt^II(NH₃)₂Cl₂ (cisplatin). Melting pointT _m, melting range ΔT, and the degree of hyperchromicity ΔH for platinated DNA showed that for equalr values, thecis-Pt^II(APO)₂—DNA adducts increase heterogeneity in the DNA structure much more effectively than thecis-Pt^II(NH₃)₂—DNA adducts. Poor platinating activity, substantial disturbance of the DNA structure, as well as low toxicity and moderate antitumor activity ofcis-Pt^II(APO)₂X₂ complexes are probably explained by steric hindrances caused by two bulky APO ligands. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1640–1644, August, 1998.     

Cytotoxicity of tantalum(V) and niobium(V) small carborane complexes and mode of action in P388 lymphocytic leukemia cells

The metallacarboranes (Et₂C₂B₄H₄)‐­TaCl₂(C₅H₅) ( 1 ), (Et₂C₂B₄H₄)NbCl₂(C₅H₅) ( 2 ), (Et₂C₂B₄H₄)TaCl₂(C₅Me₅) ( 3 ), [(Me₃Si)₂­C₂B₄H₄]TaCl₂(C₅H₅) ( 4 ) and (Me₂C₂B₄H₄)‐­TaCl₂(C₅H₅) ( 5 ) are potent cytotoxic agents against suspended tumors, producing cell death in several tissue culture lines; for example, all were effective against murine L1210 lymphoid leukemia, and all except 5 against murine P388 lymphocytic growth. Human leukemic growth is also retarded since 1–4 were effective against Tmolt₃ cell leukemia, all except 4 against Tmolt₄ leukemia, and 1, 2 , and 5 against HI‐60 leukemia. Cytotoxicity was found towards HuT‐8 lymphoma, THP‐1 acute monocytic leukemia and suspended HeLa‐S³ uterine carcinoma. Some but not all of the complexes were active against Sk‐2 melanoma and Mcf‐7 breast effusion growth. Mode‐of‐action studies in P388 lymphocytic leukemia cells showed that de novo purine synthesis was inhibited; this inhibition reduces DNA and RNA syntheses. Purine synthesis was reduced by compounds 3 and 4 at the regulatory enzymes, i.e. phosphoribosyl pyrophosphate (PRPP) amidotransferase and dihydrofolate reductase. The agents lowered d[ATP] and d[CTP] pools, further reducing DNA synthesis. The complexes afforded DNA fragmentation leading to apoptosis, but this was not by a mechanism of nucleoside alkylation, intercalation between base‐pairs or cross‐linking of the DNA strands. Copyright © 2000 John Wiley & Sons, Ltd.     

Topography of Nucleic Acid Helices in Solutions

A number of reporter molecules of the structure R-(CH₂)_n-N⁺(CH₃)₂(CH₂)_mN⁺(CH₃)₃·2Br^?, where R is a chromophore absorbing in the 300–500 mp region, have been synthesized. The effect of DNA and RNA on the absorption, induced circular dichroism, and proton magnetic resonance spectra is reported. A red shift and a hypochromic effect on the absorption spectra of the bound chromophore is observed. In all cases where R is an “unsymmetrical” 4-nitroaniline chromophore, it is found that DNA and RNA induce an opposite CD in the absorption band of the bound reporter molecules. These results together with PMR studies are interpreted in terms of the structure of the nucleic acid systems in solutions.     

Characterization, Crystal Structure and Initial DNA Binding Interaction of Two Cu（Ⅱ） Complexes with 4,5-Diazafluoren-9-one

Two new complexes [Cu（dafo）2（en）]（ClO4）2·2H2O （en=NH2CH2CH2NH2） 1 and [Cu（dafo）2（dap）]（ClO4）2·2H2O [dap=NH2CH2CH（CH3）NH2] 2 （dafo=4,5-diazafluoren-9-one） have been synthesized and characterized by elemental analysis, IR and UV spectra. Meanwhile, the complex 1 has been characterized by single crystal X-ray diffraction analysis. The initial DNA binding interactions of the complexes 1 and 2 have been investigated by UV spectra, emission spectra and cyclic voltammogram. Concluding the results of three methods used to measure the interaction of complexes 1 and 2 with DNA, the action mode of the two complexes with DNA is intercalation, and character of ligands and steric effect may affect the interaction of the complexes with DNA.     

Exploring the Symmetry,Structure, and Self‐Assembly Mechanism of a Gigantic Seven‐Fold Symmetric {Pd84} Wheel

The symmetry, structure and formation mechanism of the structurally self‐complementary { Pd₈₄ } = [Pd₈₄O₄₂(PO₄)₄₂(CH₃CO₂)₂₈]^70? wheel is explored. Not only does the symmetry give rise to a non‐closest packed structure, the mechanism of the wheel formation is proposed to depend on the delicate balance between reaction conditions. We achieve the resolution of gigantic polyoxopalladate species through electrophoresis and size‐exclusion chromatography, the latter has been used in conjunction with electrospray mass spectrometry to probe the formation of the ring, which was found to proceed by the stepwise aggregation of {Pd₆}^? = [Pd₆O₄(CH₃CO₂)₂(PO₄)₃Na_6?nH_n]^? building blocks. Furthermore, the higher‐order assembly of these clusters into hollow blackberry structures of around 50 nm has been observed using dynamic and static light scattering.     

Exploring the Symmetry,Structure, and Self‐Assembly Mechanism of a Gigantic Seven‐Fold Symmetric {Pd84} Wheel

The symmetry, structure and formation mechanism of the structurally self‐complementary { Pd₈₄ } = [Pd₈₄O₄₂(PO₄)₄₂(CH₃CO₂)₂₈]⁷⁰⁻ wheel is explored. Not only does the symmetry give rise to a non‐closest packed structure, the mechanism of the wheel formation is proposed to depend on the delicate balance between reaction conditions. We achieve the resolution of gigantic polyoxopalladate species through electrophoresis and size‐exclusion chromatography, the latter has been used in conjunction with electrospray mass spectrometry to probe the formation of the ring, which was found to proceed by the stepwise aggregation of {Pd₆}⁻ = [Pd₆O₄(CH₃CO₂)₂(PO₄)₃Na_6−nH_n]⁻ building blocks. Furthermore, the higher‐order assembly of these clusters into hollow blackberry structures of around 50 nm has been observed using dynamic and static light scattering.     

Phase behaviour and molecular dynamics in the binary system of sodium perchlorate and 1,2-propanediamine

The phase and glass transition behaviour in a binary mixture of sodium perchlorate and 1,2-propanediamine {(NaClO₄)_x(12PDA)_1?x, x < 0.40} was investigated by differential scanning calorimetry and Raman scattering measurements. A eutectic point and a peritectic point were found at x = 0.17 and 0.19, respectively. The phase diagram indicates the existence of solvated compounds of (NaClO₄)₁(12PDA)₄ and (NaClO₄)₂(12PDA)₅. The concentration dependence of the glass transition point shows a sigmoid curve implying an underlying anomaly.     

High-pressure Raman study of Al2(WO4)3

A high-pressure Raman scattering study of the tungstate Al₂(WO₄)₃ is presented. This study showed the onset of two reversible phase transitions at 0.28±0.07 and 2.8±0.1 GPa. The pressure evolution of Raman bands provides strong evidences that both the transitions involve rotations/tilts of nearly rigid tungstate tetrahedra and that the structure of the stable phase in the 0.28-2.8 GPa range may be the same as the structure of the ambient pressure, low-temperature monoclinic (C_2h⁵) ferroelastic phase of Al₂(WO₄)₃.     

Two heptadentate Co(III) and Mn(III) complexes with partially deprotonated cyclen derivative bearing four hydroxypropyl pendants: structure,DNA binding and DNA cleavage

Two new complexes, (Co^III)₂(H₃L^?)₂(0.5H₂O)₂(ClO₄)₄ (I) and (Mn^III)₂(H₃L^?)₂(0.5H₂O)₂ (ClO₄)₄ (II), were synthesized and crystallographically characterized [H₄L = 1,4,7,10‐tetra‐(2‐hydroxypropyl)‐l,4,7,10‐tetraazacyclododecane] using electrospray ionization mass spectrometry and X‐ray photoelectron spectrometery. The characterizations confirmed that the valences of the metal ions increased from divalent to trivalent due to deprotonation of one OH group (H₄L was in the form of H₃L^?). Owing to the instability of Co(III) and Mn(III) in both air and in solution, they preferred to exist in divalent form. The two heptadentate complexes are extraordinary in that the chiral pendants of the complexes are different in configuration. Spectroscopic studies, viscosity measurements, thermal denaturation experiments and circular dichroism spectra demonstrated that the complexes were prone to interact with DNA by groove binding. At micromolar concentrations and under physiological conditions, the two complexes were able to oxidatively cleave the supercoiled pUC19 plasmid DNA into its nicked and linear forms. Mechanistic studies using various additives suggest the complexes had structures different from those of other inorganic complexes. These are the first reported inorganic complexes not containing planar aromatic ligands and yet binding at the major groove. Copyright © 2012 John Wiley & Sons, Ltd.     

Oxidation of cis-Diamminediacetato PtII with Hydrogen Peroxide Can Give Rise to Two Isomeric PtIV Products

The oxidation of cis-[Pt(NH₃)₂(OAc)₂] with H₂O₂ yields a mixture of two isomers: ctc-[Pt(NH₃)₂(OH)₂(OAc)₂] and ctc-[Pt(NH₃)₂(OH)(OAc)(OH)(OAc)]. Following modification with 4-phenylbutyric (PhB) anhydride, two isomers were separated and characterized; the symmetric ctc-[Pt(NH₃)₂(PhB)₂(OAc)₂] ( 1 ) and the nonsymmetric ctc-[Pt(NH₃)₂(PhB)(OAc)(PhB)(OAc)] ( 2 ). They differ in their log P values and despite having similar cellular uptake and similar DNA platination levels, the symmetric ctc-[Pt(NH₃)₂(OH)₂(OAc)₂] is more than 4-fold more potent than the nonsymmetric isomer in a panel of 4 cancer cell lines.     

Molecular structure of Pt(PF3)4 by gas-phase electron diffraction

The structure of Pt(PF₃)₄ was reinvestigated making use of a new theory of intramolecular dynamic scattering. Derived molecular parameters were insensitive to the dynamic corrections. Refinements for this tetrahedral molecule yielded r_g(Pt-P) = 2.229(5) Å, r_g(P-F) = 1.550(4) Å, and ∠PtPF = 118.9°(0.4), with the indicated uncertainties representing 2.5σ. Amplitudes of vibration were also determined. Diffraction patterns were consistent with freely rotating PF₃ groups.