A shotgun approach for the identification of platinum–protein complexes

A shotgun approach including peptide-based OFFGEL-isoelectric focusing (IEF) fractionation has been developed with the aim of improving the identification of platinum-binding proteins in biological samples. The method is based on a filter-aided sample preparation (FASP) tryptic digestion under denaturing and reducing conditions of cisplatin–, oxaliplatin–, and carboplatin–protein complexes, followed by OFFGEL-IEF separation of the peptides. Any risk of platinum loss is minimized throughout the procedure due to the removal of the reagents used after each stage of the FASP method and the absence of thiol-based reagents in the focusing buffer employed in the IEF separation. The platinum–peptide complexes stability after the FASP digestion and the IEF separation was confirmed by size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS). The suitability of peptide-based OFFGEL-IEF fractionation for reducing the sample complexity for further nano-liquid chromatography-electrospray ionization-tandem mass spectrometry (nLC-ESI-MS/MS) analysis has been demonstrated, allowing the detection of platinum-containing peptides, with significantly lower abundance and ionization efficiency than unmodified peptides. nLC-MS/MS analysis of selected OFFGEL-IEF fractions from tryptic digests with different complexity degrees: standard human serum albumin (HSA), a mixture of five proteins (albumin, transferrin, carbonic anhydrase, myoglobin, and cytochrome-c) and human blood serum allowed the identification of several platinum–peptides from cisplatin–HSA. Cisplatin-binding sites in HSA were elucidated from the MS/MS spectra and assessed considering the protein three-dimensional structure. Most of the potential superficial binding sites available on HSA were identified for all the samples, including a biologically relevant cisplatin-cross-link of two protein domains, demonstrating the capabilities of the methodology.

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Graphical Abstract Graphical abstract shows the several steps involved in the identification of platinum-protein complexes: FASP digestion of proteins, peptide fractionation by OFFGEL-IEF and identification of Pt-complexes by nLC-ESIMS/MS

     

Spectroscopic study of hydrogen bonding in the enol form of β-diketones—II. Symmetry of the hydrogen bond

The effects of proton potential on the i.r. and Raman spectra of β-diketones are discussed. The spectroscopic behaviour of the asymmetric hydrogen bond stretching mode and of the out-of-plane hydrogen bond bending modes indicates a relatively high barrier double minimum potential.From the observed O…O distances and these predicted from the spectroscopic results for intermolecular H-bonds, a bent hydrogen bond was concluded. The spectroscopic data show a great change in the internal modes of β-diketones upon deuteration. This was attributed to the lengthening of the O…O distance which is a known characteristic of a double minimum potential.     

A perturbation theoretical method for determination of the dependence of the intramolecular X–H(D) potential on the hydrogen bond strength

A perturbation theoretical method is proposed that allows determination of the function describing the dependence of the intramolecular XH(D) potential on the hydrogen bond strength. Treating the XH(D) oscillators as mixed cubic–quartic oscillators in which the stretch–stretch couplings of the ν(X–H(D)) mode with the internal modes of the radical X may be neglected, and introducing the hydrogen bonding influence through the changes in the harmonic diagonal force constants (as proposed by Sceats and Rice [41]), it is possible to extract the analytical form of the function ) from the experimental versus correlations. The other parameters obtained by the empirical correlations, within this model, also have an exact physical meaning. The method is applicable to weak hydrogen bonds as well as to hydrogen bonds of intermediate strength, and, strictly speaking, to linear X– systems. However, extension to arbitrary geometry may be easily done. This revised version was published online in July 2006 with corrections to the Cover Date.     

A supramolecular polymerisation model for the structurisation of DNA–lipid complexes

Complexes formed by DNA and lipid mixtures have great interest for the assessment of self-assembling mechanisms in open biological systems. X-ray diffraction has revealed that minor alterations of the cationic/neutral lipid composition produced major alterations to the liquid crystalline structure and the hydration of the complexes. We have extended to these systems by an approach based on the identification of a fundamental repeating unit that grows according to the general principles of supramolecular polymerisation and liquid crystallinity. Structural reorganisations that optimise the electrostatic and hydrophobic compensation are enhanced by competition between the rigidity of the polyelectrolyte and the cohesion of the lipid assembly. The non-hydrated hexagonal structure revealed by X-ray examination is represented by a dendritic-type supramolecular polymerisation of DNA units decorated by the aliphatic tails of dissociated liposomes. An increase in the cationic/neutral lipid component ratio enhances the stability of planar bilayers, favouring the formation of the partly hydrated lamellar structure revealed by X-ray diffraction.     

A new approach for the study of cationic lipid–DNA complexes by energy dispersive X-ray diffraction

X-ray diffraction (XRD) studies on the cationic liposomes (CL)–DNA complexes currently used in gene delivery have provided detailed structural informations on these compact, ordered self-assemblies sheding light on the poorly understood structure–activity relationship. Among these, the experiments carried out by using a synchrotron radiation source have showed an experimental resolution remarkably better than that achieved one by traditional in house apparatuses. Here we show a new experimental approach for the study of CL–DNA complexes, based on the employment of silicon wafers as substrates, which allows to obtain high-resolution structural informations by energy dispersive X-ray diffraction (EDXD).     

A bond-valence approach to the semicoordination of copper-oxygen and copper–nitrogen complexes

Bond valence as the function of inter-nuclear distance for Cu–O and Cu–N bonds were estimated. Based on the developed bond-valence theory a mutual dependence between the bond length in copper coordination sphere with chromophores CuO₆, CuO₅, CuN₆ and CuN₄O₂ has been derived and compared with the experimental structural correlations. The discontinued transition from chemical bonding to the nonbonding state in the direction of the elongated bond was estimated. The shortest bond lengths are dependent on the copper atom valence. The supreme manifestation of coordination sphere plasticity is estimated as semicoordination. The semicoordinative Cu–O and Cu–N bonds are 3.07 and 2.78 Å long.     

A new insight on hydrogen bond donor property of bridged B–H–B protons in the interaction of diborane with some hydrogen bond acceptor molecules

Structural Chemistry - Ab initio calculations at the MP2/6-311++G(d,p) computational level were used to analyze the interactions between a molecule of B2H6 with some small molecules which often...     

A new approach to the synthesis of N-monosubstituted aniline and its derivatives via β-cyclodextrin host-guest complexes

A novel method for the synthesis of N-monosubstituted aniline and its derivatives β-cyclodextrin(CD)host-guest complexes has been presented.The mild reaction gives the title compounds with high selectivity in good yields of 90-98%.     

A new approach to the synthesis of N-monosubstituted aniline and its derivatives via β-cyclodextrin host-guest complexes

A novel method for the synthesis of N-monosubstituted aniline and its derivatives via β-cyclodextrin （CD） host-guest complexes has been presented. The mild reaction gives the title compounds with high selectivity in good yields of 90-98%.     

Variationally determined electronic states for the theoretical analysis of intramolecular interaction: I. Resonance energy and rotational barrier of the C–N bond in formamide and its analogs

We present a new method that produces a variationally determined zeroth-order wave function for the analysis of intramolecular interactions between the fragments of a molecule. In our method, called the space-restricted wave function (SRW) method, this wave function is defined with nonorthogonal orbitals, which are obtained using the appropriately restricted variational spaces. The wave function thus obtained represents the electronic state with the target interactions deactivated, and it is constructed without unnecessarily breaking bonds, in contrast to some of the existing methods. Furthermore, we can perform energy decomposition analysis of intramolecular interactions using the zeroth-order functions that the SRW method yields. The validity of the SRW method is demonstrated in the analysis of the resonance energy and the rotational barrier of the C–N bond in formamide and its analogs. This method gives energy components that are different from those given by existing methods. With these components, we elucidate the origin of the rotational barrier from another point of view. Our SRW method gives meaningful results for the investigation of electron behavior and the nature of the molecular system.     

A synthetic approach to palmerolides via Negishi cross coupling. The challenge of the C15–C16 bond formation

The esterification of fragment C1–C8 (2) with fragment C16–C23 (3) to give iodo derivative 4, followed by a Pd-catalysed coupling with a C9–C15 fragment (7 or 8), may provide a common precursor of most palmerolides. Ligands and reaction conditions were exhaustively examined to perform the C15–C16 bond formation via Negishi reaction. With simple models, pre-activated Pd–Xantphos and Pd–DPEphos complexes were the most efficient catalysts at RT. Zincation of the C9–C15 fragment (8) and cross coupling with 4 required 3 equiv of t-BuLi, 10 mol % of Pd–Xantphos and 60 °C.     

Correlation of volumes and entropies of activation for oxidation of coordinated sulfur in bis-ethylenediaminecobalt(III) complexes by peroxodisulphate,hydrogen peroxide and periodate and for peroxodisulphate oxidation of diimine-cyanide–iron(II) complexes

Activation parameters H , S and V and correlations between S and V are reported for peroxodisulphate oxidation of [Fe(CN)₆]^4–, [Fe(bipy)₃]²⁺ (bipy = (2, 2-bipyridyl), [Fe(phen)₃]²⁺ (phen = 1,10-phenanthroline), cis-[Fe(bipy)₂(CN)₂], [Fe(bipy)(CN)₄]^2–, [Fe(phen)(CN)₄]^2–, [Co(en)₂(glyS)]⁺ (glyS = mercaptoacetate, SCH₂COO^2–), [Co(en)₂(cyS)]⁺ (cyS = cysteinate, SOCH₂CH(COO)NH₂ ^2–) and [Co(en)₂(amS)]²⁺ (amS = ethanesulphenaminate, SCH₂CH₂NH₂ ^–) and for periodate and hydrogen peroxide oxidation of the three last-named complexes. Activation parameters are discussed in terms of electrostriction, solvation and ligand size contributions. Opposite trends for S /V correlations were found for oxidations of Fe^II complexes in comparison with oxidations of coordinated sulphur in the Co^III complexes.     

A new proposed mechanism for the cathodic reduction of a carbon–chlorine bond in 2-acetylphenyltrichloroacetate

The cathodic reduction of 2-acetylphenyltrichloroacetate at a controlled potential of −0.5 V (vs SCE) yields 3,3-dichloro-4-hydroxy-4-methyl-3,4-dihydrocoumarin. The charge consumption is 1e⁻/substrate molecule, which is in agreement with a non-conventional R–X→R⁻+X mechanism.     

A new approach to the bicyclo[3.3.1]nonane framework of huperzine A-like molecules via palladium-catalyzed intramolecular γ-arylation

In our synthetic studies toward huperzine A, a diastereoselective α′-alkylation of the α-amido-γ-methyl hexenone 4 was realized through a dianion intermediate which significantly enhanced the reactivity. Under the attempted Heck reaction conditions, an unexpected and unprecedented palladium-catalyzed intramolecular γ-arylation of 3 was observed, which generated 18 with bicyclo[3.3.1]nonane framework in satisfactory yield.     

Variationally determined electronic states for the theoretical analysis of intramolecular interaction. II. Qualitative nature of the P?O bond in phosphine oxides

We have developed a space‐restricted wave function (SRW) method for the analysis of various types of intramolecular interactions. In this study, we demonstrate the applicability of our SRW method to the analysis of the nature of the P? O bond in phosphine oxide (R₃PO), one of the hypervalent molecules. An interesting character of this bond has been extensively studied by focusing on the negative hyperconjugation of the O lone pair (n_O) with the R₃P group. We reinvestigated the nature of the bond in terms of a change in total energy to produce evidence for the validity of our method. The electronic states without the interaction involving three n_O orbitals (R₃P⁺?O^?) produced by the method were used as reference states in the assessment of the effects of this n_O–R₃P interaction. The result confirms that this interaction plays an essential role in the nature of the bond and occurs between the n_O orbitals and the P? R antibonding orbitals, in agreement with previous studies. A molecular orbital (MO)‐pair analysis technique shows that the n_O–R₃P interaction is decomposed into the negative hyperconjugation and the Pauli repulsion. Considering a reference state where the P? O bond is completely broken (R₃P²⁺···O^2?) at an interacting distance, P? O bond formation is attributed to one σ bond plus two 0.5 π bonds. This is equivalent to three banana bonds highly polarized to the O atom. Consequently, the SRW method suggested improved explanations of the nature of the P? O bond. © 2012 Wiley Periodicals, Inc.     

A vibrational study of the metal—olefin bond in norbornadiene complexes of Rh(I), Pd(II) and Pt(II)

Vibrational assignments of the complexes [RhClC₇H₈]₂, PtCl₂C₇H₈, and PdCl₂C₇H₈ have been undertaken. A reinvestigation of the norbornadiene spectrum was necessary and a new set of assignments is given. The shift in energy of bands I and II and the out-of-plane olefinic CH wagging modes, as well as the relative energies of the bands associated with the metal—olefin motions are consistent with the total metal—norbornadiene interaction following the order Rh>Pt>Pd and the extent of the π component being ordered as Rh⋍Pt>Pd.     

Palladium-catalyzed oxidative C–H bond coupling of indoles and benzaldehydes: a new approach to the synthesis of 3-benzoylindoles

A palladium-catalyzed dehydrogenative acylation of indoles using easily accessible aldehydes as the acyl source is described. This reaction provides a new approach for the synthesis of 3-acylindoles.     

A comparative study of interplay effects between the cation-π and intramolecular hydrogen bond interactions in the various complexes of methyl salicylate with Mn+, Fe2+, Co+, Ni2+, Cu+, and Zn2+ cations

Structural Chemistry - The interplay among two important noncovalent interactions involving aromatic ring is studied by means of density functional theory (DFT) calculations on complexes of methyl...