Di-, tri-, and tetranuclear zinc hydroxamate complexes as structural models for the inhibition of zinc hydrolases by hydroxamic acids

Attempts to produce Zn analogues of the structural model complexes [M2(mu-O2CR)2(O2CR)2(mu-H2O)(tmen)2] (M = Ni, Co, Mn; R = CH(3), C(CH3)3, CF3) by the reaction of a series of zinc carboxylates with N,N,N',N'-tetramethylethylenediamine (tmen), resulted in the mononuclear complexes [Zn(OAc)(2)(tmen)] (1) and [Zn(crot)2(tmen)].(0.5)H2O (2) for R = CH3 and (CH)2CH3, respectively, and the dinuclear complexes [Zn(2)(mu-piv)(2)(piv)(2)(mu-H2O)(tmen)2] (3) and [Zn2(mu-OAc(F))2(OAc(F))2(mu-H2O)(tmen)2] (4) for R = C(CH3)3 and CF3, respectively. In contrast to the analogous imidazole series, i.e., [M2(mu-O2CR)2(O2CR)2(mu-H2O)(Im)4] (M = Ni, Co, Mn; R = CH3, C(CH3)3, CF3), zinc carboxylates react with imidazole to give only the mononuclear complexes [Zn(OAc)2(Im)2] (5), [Zn(crot)2(Im)2].H2O (6), [Zn(piv)2(Im)2].(0.5)H2O (7), and [Zn(OAc(F))2(Im)2] (8). Reaction of 1, 2, and 3 with either acetohydroxamic acid (AHA) or benzohydroxamic acid (BHA) gives the dinuclear complexes [Zn2(O2CR)3(R'A)(tmen)], where R'A = acetohydroxamate (AA) (9, 10, 11) or benzohydroxamate (BA) (13, 14, 15). In these complexes, the zinc atoms are bridged by a single hydroxamate and two carboxylates, with a capping tmen ligand on one zinc and a monodentate carboxylate bonded to the second zinc atom. This composition models closely the observed structure of the active site of the p-iodo-d-phenylalanine hydroxamic acid inhibited Aeromonas proteolyticaaminopeptidase enzyme. In contrast, 4 reacts with AHA to give [Zn2(OAc(F))3(tmen)2(AA)] (12) with an additional tmen ligand so that both Zn atoms are 6-coordinate, whereas reaction with BHA gives the trinuclear complex [Zn3(OAc(F))4(tmen)2(BA)2] (16). Reactions of 3 and 4 with glutarodihydroxamic acid (GluH2A2) produce the tetranuclear complexes [Zn4(piv)6(tmen)4(GluA2)] (18) and [Zn4(OAc(F))6(tmen)4(GluA2)] (19).     

A novel dizinc bridged hydroxamate model for hydroxamate inhibited zinc hydrolases

Reaction of Zn(OAc)(2).2H2O with tmen leads to the formation of [Zn(tmen)(OAc)2] (I) which reacts with benzohydroxamic acid to form Zn(BA)2.H2O (II) and the novel dizinc hydroxamate bridged complex [Zn2(mu-OAc)2(OAc)(mu-BA)(tmen)] (III), which may also be prepared by self-assembly and whose structure closely mimics that of the native hydroxamate inhibited Aeromonas proteolytica aminopeptidase.     

A vibrational and DFT study of M(diimine)(dithiolate) complexes and their complexation route

A complete vibrational spectra analysis of the Pd(phen)(bdt), the free ligands, where phen=1,10-phenanthroline and bdt=1,2-benzenedithiolate and the starting material of its synthesis, Pd(phen)Cl(2), is performed in this paper. The molecular geometry, binding and spectroscopic properties for the aforementioned compounds are studied in detail by FT-IR, Raman and DFT methods using B3LYP functional together with basis sets of valence triple-zeta quality. Further, changes in FT-IR and Raman spectra during complexation are monitored revealing the electron delocalization over ligands. They are also consistent with pi-back donation theory.     

Modeling the inhibition of peptide deformylase by hydroxamic acids: influence of the sulfur donor

The first complexes containing both a sulfur atom and a hydroxamate moiety coordinated to a biologically relevant transition metal were synthesized as models for the structure of inhibited peptide deformylases. Two of these [(N(2)S)Zn(hydroxamate)] complexes were characterized by X-ray crystallography. The first contains a thioether and a simple hydroxamate, the second a thiolate and a N-substituted hydroxamate. Isolation of a complex with a thiolate and a simple hydroxamate group was not possible.     

A DFT study on the mechanism of phosphodiester cleavage mediated by monozinc complexes

Density functional theory (DFT), Tao-Perdew-Staroverov-Scuseria (TPSS), is employed to study the reaction mechanism for the zinc-mediated phosphodiester cleavage reaction. The calculations indicate a general base catalysis mechanism. The flexibility of Zn(II) ion's coordination number (5 and 6) as well as the formation of hydrogen bonds between the coordinating water and the ester are responsible for the trapping (namely, coordinating to the Zn complexes) of the phosphodiester. The hydrogen bonds, between the water, the ester, and the nitrogen-ligand, tris(6-amino-2-pyridylmethyl)amine, not only stabilize the key five-coordinated phosphorus intermediates with a trigonal pyramidal PO5 unit but also lower the energy barriers for the proton transfer within the complexes by gaining stronger solvation energies.     

Acidity of hydroxamic acids and amides

The relatively strong acidity of hydroxamic acids was analyzed by means of isodesmic reactions in which this acid or its anion is formed from simpler precursors. Acidity of amides was analyzed in the same way. Energies of all compounds involved in the reactions were calculated at the B3LYP/AUG-cc-pVTZ//B3LYP/6-311 + G(d,p) level; at this level a good agreement was reached with the sparse experimental data. Interpretation of the results was the same as in the recent discussion of the acidity of carboxylic acids, and the conclusions were similar: both amides and hydroxamic acids are stabilized with respect to simpler reference molecules of amines or N-alkylhydroxylamines, respectively. However, their anions are stabilized still more and are responsible for the acidity. This effect is stronger in hydroxamic acids or amides than in carboxylic acids. The problem of whether it is due to resonance depends on the definition of this term. Semiquantitative comparison suggests that resonance in hydroxamic acids is more important than in amides and still more than in carboxylic acids. The stronger acidity of hydroxamic acids compared to amides is due to the destabilizing inductive effect of the hydroxyl group in the acid molecule, not to any effect in the anion.     

A DFT computational study of the bis-silylation reaction of acetylene catalyzed by palladium complexes

In this paper we have investigated at the DFT(B3LYP) level the catalytic cycle for the bis-silylation reaction of alkynes promoted by palladium complexes. A model-system formed by an acetylene molecule, a disilane molecule, and the Pd(PH(3))(2) complex has been used. The most relevant features of this catalytic cycle can be summarized as follows: (i) The first step of the cycle is an oxidative addition involving H(3)Si-SiH(3) and Pd(PH(3))(2). It occurs easily and leads to the cis (SiH(3))(2)Pd(PH(3))(2) complex that is 5.39 kcal mol(-1) lower in energy than reactants. (ii) The transfer of the two silyl groups to the C-C triple bond does not occur in a concerted way, but involves many steps. (iii) The cis (SiH(3))(2)Pd(PH(3))(2) complex, obtained from the oxidative addition, is involved in the formation of the first C-Si bond (activation barrier of 18.34 kcal mol(-1)). The two intermediates that form in this step cannot lead directly to the formation of the final bis(silyl)ethene product. However, they can isomerize rather easily (the two possible isomerizations have a barrier of 16.79 and 7.17 kcal mol(-1)) to new more stable species. In both these new intermediates the second silyl group is adjacent to the acetylene moiety and the formation of the second C-Si bond can occur rapidly leading to the (Z)-bis(silyl)ethene, as experimentally observed. (iv) The whole catalytic process is exothermic by 41.54 kcal mol(-1), in quite good agreement with the experimental estimate of this quantity (about 40 kcal mol(-1)).     

NMR studies of thioureas and their zinc complexes

The NMR spectra of thiourea, a number of N substituted thioureas and of the zinc(II) complexes of these ligands are reported. Two rate processes occur. The first arises from rotation about the CN bond of the thiourea and requires activation energies in the range of 7–12 kcal/mole for the free ligands. The activation energy for rotation in the complexed ligand is substantially higher. The second rate process involves ligand exchange. The rate for this process is slightly greater than that for analogous Co(II) and Ni(II) compounds. Approximate enthalphies and entropies of activation are reported.     

Ring-closing olefin metathesis on ruthenium carbene complexes: model DFT study of stereochemistry

Ring-closing metathesis (RCM) is the key step in a recently reported synthesis of salicylihalamide and related model compounds. Experimentally, the stereochemistry of the resulting cycloolefin (cis/trans) depends strongly on the substituents that are present in the diene substrate. To gain insight into the factors that govern the observed stereochemistry, density functional theory (DFT) calculations have been carried out for a simplified dichloro(2-propylidene)(imidazole-2-ylidene)ruthenium catalyst I, as well as for the real catalyst II with two mesityl substituents on the imidazole ring. Four model substrates are considered, which are closely related to the systems studied experimentally, and in each case, two pathways A and B are possible since the RCM reaction can be initiated by coordination of either of the two diene double bonds to the metal center. The first metathesis yields a carbene intermediate, which can then undergo a second metathesis by ring closure, metallacycle formation, and metallacycle cleavage to give the final cycloolefin complex. According to the DFT calculations, the stereochemistry is always determined in the second metathesis reaction, but the rate-determining step may be different for different catalysts, substrates, and pathways. The ancillary N-heterocyclic carbene ligand lies in the Ru-Cl-Cl plane in the simplified catalyst I, but is perpendicular to it in the real catalyst II, and this affects the relative energies of the relevant intermediates and transition states. Likewise, the introduction of methyl substituents in the diene substrates influences these relative energies appreciably. Good agreement with the experimentally observed stereochemistry is only found when using the real catalyst II and the largest model substrates in the DFT calculations.     

Stability of nonplanar N-methylporphyrins and their zinc complexes

Resistance of N-methyl-substituted porphyrins and their Zn(II) complexes to thermooxidative degradation and to the action of a DMSO-AcOH proton-donor solvent was studied by thermogravimetry and chemical kinetics. The fairly low stability of the complexes is caused by decreased planarity and, as a consequence, aromaticity of the macrorings and also by the tendency of the complexes to demethylation. The stability of the zinc complexes in AcOH varies in parallel with the degree of nonplanarity and resistance to thermooxidative degradation of their ligands.     

Synthesis,characterization, structures,and DFT study of zinc(II) complexes with tributylphosphine chalcogenides

Four new zinc(II) complexes of the type [ZnCl₂(n-Bu₃PE)₂] (E=O (1), S (2), Se (3), or Te (4)) have been synthesized from zinc(II) chloride and the ligands n-Bu₃PE giving yields of 56–88%. The adducts were characterized by multinuclear (³¹P, ¹³C, and ⁷⁷Se) NMR, conductivity, IR spectroscopy and by X-ray analyses. Zinc complexes 1–4 are compriseS of two ligands coordinated to the metal center in a distorted tetrahedral arrangement. The P=E bond lengths of 1.497(7) (E=O), 2.000(4) (E=S), and 2.178(2) Å (E=Se) in these complexes are slightly elongated compared to those in the free ligand. In addition, a DFT/B3LYP theoretical study on the geometry optimization of the title ligands and their zinc complexes has been carried out in order to support and complement the experimental data and to further investigate the nature of the chalcogenide-metal interaction. The results show good agreement between the experimental and theoretical data.     

Models of hypoxia activated prodrugs: Co(III) complexes of hydroxamic acids

Co(III) complexes of simple hydroxamic acids have been evaluated as models of hypoxia activated prodrugs containing MMP inhibitors. The complexes are based upon a proposed carrier system comprising the tripodal tetradentate ligand tris(2-methylpyridyl)amine (tpa) with the hydroxamate functionality occupying the remaining coordination sites of the Co centre. Acetohydroxamato (aha), propionhydroxamato (pha), and benzohydroxamato (bha) complexes were synthesised and characterised by single crystal X-ray diffraction. For aha and pha both the hydroxamato and hydroximato (deprotonated) forms were obtained and were readily interconverted by pH manipulation; for bha only the hydroximato complex was obtained as a stable species. Electrochemical analysis was used to probe the redox chemistry of the complexes and assess their ease of reduction. All of the complexes displayed irreversible reduction and had low cathodic peak potentials. This suggests that the Co-tpa carrier system would provide a suitably inert framework to deliver the drugs to target sites intact yet would release the ligands upon reduction to the more labile Co(II) oxidation state.     

A DFT study of the mechanism of polymerization of epsilon-caprolactone initiated by organolanthanide borohydride complexes

The mechanisms of polymerization of epsilon-caprolactone (CL) initiated by either the rare-earth hydride [Cp2Eu(H)] or the borohydrides [Cp2Eu(BH4)] or [(N2NN')Eu(BH4)] were studied at the DFT level (Cp=eta5-C5H5; N2NN'=(2-C5H4N)CH2(CH2CH2NMe)2). For all compounds the reaction proceeds in two steps: a hydride transfer from the rare earth initiator to the carbonyl carbon of the lactone, followed by ring-opening of the monomer. In the last step a difference is observed between the hydride and borohydride complexes, because for the latter the ring-opening is induced by an additional B-H bond cleavage leading to a terminal--CH2OBH2 group. This corresponds to the reduction by BH3 of the carbonyl group of CL. Upon reaction of [Cp2Eu(H)] with CL, the alkoxy-aldehyde complex produced, [Cp2Eu(O(CH2)5C(O)H)], is the first-formed initiating species. In contrast, for the reaction of CL with the borohydride complexes [(Lx)Eu(BH4)] (Lx=Cp2 or N2NN'), an aliphatic alkoxide with a terminal--CH2OBH2 group, [(Lx)Eu(O(CH2)6OBH2)] is formed and subsequently propagates the polymerization. The present DFT investigations are fully compatible with previously reported mechanistic studies of experimental systems.     

Inhibition of urease activity by dipeptidyl hydroxamic acids.

A series of dipeptidyl hydroxamic acids (H-X-Gly-NHOH: X = amino acid residues) was synthesized, and the inhibitory activity against Jack bean and Proteus mirabilis ureases [EC 3.5.1.5] was examined. A number of H-X-Gly-NHOH inhibited Jack bean urease with an I50 of the order of 10(-6) M and inhibited Proteus mirabilis urease with an I50 of the order of 10(-5) M. The inhibition against Jack bean urease was more potent than that with the corresponding aminoacyl hydroxamic acids (H-X-NHOH).     

Chromium(V) complexes of hydroxamic acids: formation, structures, and reactivities

A new family of relatively stable Cr(V) complexes, [Cr(V)O(L)(2)](-) (LH(2) = RC(O)NHOH, R = Me, Ph, 2-HO-Ph, or HONHC(O)(CH(2))(6)), has been obtained by the reactions of hydroxamic acids with Cr(VI) in polar aprotic solvents. Similar reactions in aqueous solutions led to the formation of transient Cr(V) species. All complexes have been characterized by electron paramagnetic resonance spectroscopy and electrospray mass spectrometry. A Cr(V) complex of benzohydroxamic acid (1, R = Ph) was isolated in a pure form (as a K(+) salt) and was characterized by X-ray absorption spectroscopy and analytical techniques. Multiple-scattering analysis of X-ray absorption fine structure spectroscopic data for 1 (solid, 10 K) point to a distorted trigonal-bipyramidal structure with trans-oriented Ph groups and Cr-ligand bond lengths of 1.58 A (Cr-O), 1.88 A (Cr-O(C)), and 1.98 A (Cr-O(N)). Under ambient conditions, 1 is stable for days in aprotic solvents but decomposes within minutes in aqueous solutions (maximal stability at pH approximately 7), which leads predominantly to the formation of Cr(III) complexes. Complex 1 readily undergoes ligand-exchange reactions with biological 1,2-diols, including D-glucose and mucin, in neutral aqueous solutions. It differs from most other types of Cr(V) complexes in its biological activity, since no oxidative cleavage of plasmid DNA in vitro and no significant bacterial mutagenicity (in the TA 102 strain of Salmonella typhimurium) was observed for 1. In natural systems, stabilization of Cr(V) by hydroxamato ligands from bacterial-derived siderophores (followed by ligand-exchange reactions with more abundant carbohydrate ligands) may occur during the biological reduction of Cr(VI) in contaminated soils.     

A DFT study on NLO response of push-pull hybrid porphyrin-polyoxometalate complexes

Density functional theory (DFT) calculations were carried out to investigate the second-order nonlinear optical (NLO) properties of a series of proposed porphyrin-polyoxometalate-based complexes related to [5-(3,5-dimethyl-4-hexamolybdate amino-phenyl-ethynyl)-15-(4-nitrophenyl-ethynyl)porphinato]zinc(II) which have donor-π conjugated bridge-acceptor (D-π-A) configurations. Our calculations show that these species possess considerably large molecular total second-order polarizability (β₀), ～2000 × 10^?30 esu. Furthermore, it can be seen that {W₆O₁₈} exhibits stronger electron-donating ability than {Mo₆O₁₈}. And two-dimensional (2D) system with A-π-D-π-A structure might be a promising candidate for NLO materials based on the large β₀ (4583.5 × 10^?30 esu) and in-plane nonlinear anisotropy.     

Magnetic couplings in vanadium aromatic sandwich complexes and their crystals by using DFT methods

Using density functional theory, we have theoretically studied the origin of ferromagnetic coupling of spins in the long multiple deckers of vanadium sandwich complexes with benzene (Bz). This is done by calculating the band structure of their infinite one-dimensional (1D) crystals along the periodic (=Z) direction. We find that the magnetic coupling can be ascribed to spin polarization in the band (= those derived from d(z2)) whose k states are not involved in the formation of partial covalent bonds between vanadium atoms and benzene rings. We have also studied magnetic and electronic properties of multiple deckers of a naphthalene (Np)-vanadium complex. We find that there is a stronger covalent interaction as well as a stronger electrostatic interaction between V and Np rings than between V and Bz rings. This suggests that there is a possibility of longer multiple deckers of a Np-V complex. In addition, ferrimagnetic coupling of spins is expected, resulting in a magnetic moment 45% larger than that of the Bz-V complex at the same length. For their 1D crystals, band structure analysis also shows that the origin of magnetic coupling in long multiple deckers should be similar to that of Bz-V multiple deckers.