Ligand Fragments Research Articles

Design of enhanced agonists through the use of a new virtual screening method: Application to peptides that bind class I major histocompatibility complex (MHC) molecules

A new screening procedure is described that uses docking calculations to design enhanced agonist peptides that bind to major histocompatibility complex (MHC) class I receptors. The screening process proceeds via single mutations of one amino acid at the positions that directly interact with the MHC receptor. The energetic and structural effects of these mutations have been studied using fragments of the original ligand that vary in length. The results of these docking studies indicate that the mutant affinity ranking of long peptides can be practically reproduced with a screening approach performed using fragments of six residues. Fragments of four and five residues could mimic, in some cases, the structural arrangement of the side chains of the full-length peptide. We have compared the structural and energetic results of the docking calculations with experimental data using three unrelated ligand peptides that differ greatly in their affinity for the MHC complex. Analysis of the affinity of the fragments led to the identification of three important parameters in the construction of fragments that mimic the structural and energetic properties of the full-length ligand: the length of the fragment; its intermolecular energy; and the number and localization, internal or terminal, of the anchor residues. The results of this new peptide-design methodology have been applied to suggest new peptides derived from the MUC1-8 peptide that could be used as murine vaccines that trigger the immune response through the MHC class I protein H-2K(b).

Anti-adhesion therapies

Cell adhesion molecules are key mediators of inflammatory processes and are attractive targets for discovery of novel therapeutics. There have been significant positive advances in both basic research and clinical development in this area. Basic research has yielded detailed insight into the structural basis of cell adhesion molecule function, especially the interaction of integrins with their ligands. Co-crystals of several integrin-ligand complexes have been published, including alpha v beta3 with ligand fragments, alpha IIb beta3 with multiple therapeutic ligands and alpha L beta2 (leukocyte function-associated antigen-1 [LFA-1]) with its cell-based ligand intercellular adhesion molecule-1. This has stimulated development of models of integrin function and also the mode of action of small-molecule inhibitors. The most exciting recent advances in the field of clinical development have come with the successful approval of two new anti-adhesion therapeutics: efalizumab (Raptiva) targeting LFA-1 for the treatment of chronic plaque psoriasis, and natalizumab (Tysabri/Antegren) targeting very late antigen-4 for the treatment of relapsing-remitting multiple sclerosis. However, the latter therapeutic ran into a surprising safety issue earlier this year and was withdrawn from the market, casting a shadow over what had seemed a promising new drug.

Reaction of Ruthenium Ethyne‐1,2‐diyl Compounds with Bis(trimethylsilyl)acetylene Complexes of Titanocene and Zirconocene: Remarkable Transfer of a C2 Ligand

Carbon ligand transfer: Compound 1 is formed with reactive metal–ligand fragments generated from Group 4 metallocene compounds. Dropwise addition of ethanolic HCl to a solution of complex 1 in toluene affords complex 2 in a carbon–carbon bond-forming transformation that is thought to be unprecedented.

Comparison of Thermal and Mass-Transport Properties of Bi(tmhd)3, Bi(p-tol)3, and Bi(o-tol)3 MOCVD Precursors

Metal-organic (MO)CVD processes using three different precursors (Bi(tmhd)3, Bi(p-tol)3, and Bi(o-tol)3) have been investigated. Combined, thermal, and mass spectroscopic investigations have provided information on their thermal robustness during sublimation processes. In-situ Fourier-transform infrared (FTIR) measurements have allowed the monitoring of mass-transported precursors during MOCVD experiments. Temperature windows of 190–277 °C, 170–270 °C, and 150–220 °C have proved suitable for the efficient vaporization of Bi(tmhd)3, Bi(p-tol)3, and Bi(o-tol)3, respectively, even though aryl precursors have proved to be more stable than β-diketonate during the sublimation and transport processes.Above 350 °C, decomposition during the MOCVD processes has been observed for all the precursors. In the case of Bi(tmhd)3 and Bi(o-tol)3 it involves the ligand fragmentation, while for Bi(p-tol)3, dissociation of the intact aryl ring seems to occur.

Complexes derived from hydrolytically ‘unstable’ hydrazone ligands – Some unexpected products

Polyfunctional ligands derived from condensation reactions in which small molecules, e.g., water, an alcohol, etc., are eliminated can suffer the ravages of hydrolytic attack on reaction with transition metal ions in aqueous based solvents, or solvents containing small amounts of water. A series of such reactions is described involving hydrazone based ligands, in which hydrolyzed ligand fragments, and their resulting coordination complexes, are produced. Structures are reported to identify these products, which reveal some unexpected ligand rearrangements. Variable temperature magnetic data are discussed for some dinuclear complexes, and a DFT study is presented to rationalize an unusual ligand transformation.

Reactions of the Dianion [1,1,1-(CO)3-2-Ph-closo-1,2-MnCB9H9]2- with Transition-Metal Cations: Facile Insertion and Then Extrusion of Cluster Vertexes

The manganacarborane dianion in [N(PPh(3))(2)][NEt(4)][1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(9)] (1b) reacts with cationic transition metal-ligand fragments to give products in which the electrophilic metal groups (M') are exo-polyhedrally attached to the {closo-1,2-MnCB(9)} cage system via three-center two-electron B-H --> M' linkages and generally also by Mn-M' bonds. With {Cu(PPh(3))}(+), the Cu-Mn-Cu trimetallic species [1,6-{Cu(PPh(3))}-1,7-{Cu(PPh(3))}-6,7-(mu-H)(2)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(7)] (3a) is formed, whereas reactions with {M'(dppe)}(2+) (M' = Ni, Pd; dppe = Ph(2)PCH(2)CH(2)PPh(2)) give [1,3-{Ni(dppe)}-3-(mu-H)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(8)] (5a) and [1,3,6-{Pd(dppe)}-3,6-(mu-H)(2)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(7)] (5b), both of which contain M'-Mn bonds. The latter reaction with M' = Pt affords [3,6-{Pt(dppe)}-3,6-(mu-H)(2)-1,1,1-(CO)(3)-2-Ph-closo-1,2-MnCB(9)H(7)] (6), which lacks a Pt-Mn connectivity. Compound 6 itself spontaneously converts to [1-Ph-2,2,2-(CO)(3)-8,8-(dppe)-hypercloso-8,2,1-PtMnCB(9)H(9)] (7b) and thence to [3,6,7-{Mn(CO)(3)}-3,7-(mu-H)(2)-1-Ph-6,6-(dppe)-closo-6,1-PtCB(8)H(6)] (8). This sequence occurs via initial insertion of the {Pt(dppe)} unit and then extrusion of {Mn(CO)(3)} and one {BH} vertex. In the presence of alcohols ROH, compound 6 is transformed to the 7-OR substituted analogues of 7b. X-ray diffraction studies were essential in elucidating the structures encountered in compounds 5-8 and hence in understanding their behavior.

Thermal decomposition of 5-amino-2-thiol-1,3,4-thiadiazole (<Emphasis Type=?Italic?>HATT</Emphasis>) Cu(II) and Zn(II) complexes

The mercury(II) bis(dialkyldithiocarbamate) complexes, Hg(S 2 CN-R 2 ) 2 , in which R =ethyl, n -propyl, n -butyl and iso-butyl were characterized by TG, DSC, FTIR and elemental analysis. The TG curves presented two thermal decomposition stages; the first stage can be attributed to the partial decomposition of ligand and also to mercury sulfide decomposition. The second stage is representative for the decomposition of ligand fragments. The overlaid TG/DSC curves indicated that the decomposition of the complexes takes place the liquid phase. According to the isothermal kinetic data the phase-boundary controlled kinetic models describes the best the decomposition of complexes. The data obtained by the Ozawa method suggest the following stability order for the complexes: i Bu> n Pr> n Bu>Et.

Gas-phase photoionization of tris(2,2,6,6-tetramethyl-3,5-heptanedionato)europium(III)

In this Letter, we report observation of fragments of the metal–organic complex, Eu(2,2,6,6-tetramethyl-3,5-heptanedionato) 3 resulting from multiphoton ionization of the complex entrained in an Ar molecular beam. Photofragmentation was observed at 532, 355, 266 nm, and in the range of 460–466 nm. At each wavelength, the dominant fragments were bare metal ions in multiple oxidation states and ligand fragments. This fragmentation pattern is interpreted as resulting from excitation to ligand-to-metal charge-transfer states in the sequential ligand dissociation steps. Significantly weaker signal from EuO + and EuOH + fragments was also observed with photoionization at 266 nm.

Pathways of directed synthesis of iron(II) clathrochelates and polyclathrochelates with non-equivalent capping groups starting from antimony- and germanium-containing precursors

Alternative methods for directed syntheses of clathrochelates and polyclathrochelates with two non-equivalent capping fragments using semiclathrochelate precursors and capping group reactions are described. The lability of antimony-capped iron(II) clathrochelates in remetallation (a capping group exchange) reactions allowed to obtain of mono- and bis-clathrochelates of a general formula FeNx3X1X2 and (FeNx3X1)2X2 (where Nx2− is cyclohexanedione-1,2-dioxime dianion; X1, X2 are different capping groups). The first and unique dioximate [Fe(HNx)3(Sb(C6H5)3)](ClO4) semiclathrochelate was isolated and characterized. The reaction of this complex with differing mono- and bifunctional cross-linking agents (Lewis acids) led to the formation of clathrochelates molecules with non-equivalent capping groups. The clathrochelates with a labile triethylantimony capping group underwent remetallation in the presence of silicon dioxide as a catalyst. The first stage led to the formation of a surface-immobilized mixed SbSi-capped clathrochelate, which under the action of another capping agent desorbed from the surface gives a mono- or bis-clathrochelate depending on the nature of this agent. An alternative pathway using the bis-capping agents has been implemented for synthesis of bis-clathrochelates when reactive fragments of an initial azomethine ligand demonstrate essentially different chemical properties. The oximehydrazonate germanium-capped iron(II) bis-clathrochelate was synthesized starting from a bis-semiclathrochelate, which was initially isolated with bis-capping germanium(IV) tetraethoxide. A further H+-catalyzed macrocyclization with triethyl orthoformate produced germanium-capped bis-clathrochelate. The obtained mono- and bis-clathrochelates have been characterized using elemental analysis, PD mass, IR, UV–Vis and 1H and 13C NMR spectra, and X-ray crystallography (for FeNx3(Sb(C2H5)3)2 complex), as well as by cyclic voltammograms. The distortion angle ϕ values and the main distances in the clathrochelate frameworks have been deduced using 57Fe Mössbauer parameters, and EXAFS data and molecular mechanics calculations, respectively.

Fluorenyl based syndiotactic specific metallocene catalysts structural features, origin of syndiospecificity

AbstractThe stereochemistry of propylene insertion/propagation reactions with a variety of Cs symmetric fluorenyl‐ containing single site catalysts is discussed. Our recent results indicate that independent of the chemical composition of the ancillary ligand fragments, or nature of the transition metal, active sites with local Cs symmetry and enantiotopic coordination positions behave syndioselectively in the general context of chain migratory insertion mechanism. Perfect bilateral symmetry neither exists nor is required in these processes. In this context the mechanism of syndiospecific polymerization is revisited by taking into account the structural characteristics and catalytic behavior of the original metallocene based (η5‐C5H4‐CMe2‐η5‐C13H8) MCl2/ MAO; M = Zr (1), Hf (2) catalyst systems and new syndiotactic specific systems including (η5‐C5H4‐CPh2‐η5‐3,6‐di‐tBut‐C13H6)ZrCl2 (3), η1,η5‐(μMe2Si)(3,6‐di‐tBut‐Flu)(t‐ButN)MCl2/ MAO; M =Ti (4), Zr (5) and η1,η5‐(μMe2Si)(2,7‐di‐tBut‐Flu)(t‐ButN)MCl2/ MAO; M = Ti (6), Zr (7).

Transition Metal Complexes Containing All‐Carbon Ligands

AbstractFor Abstract see ChemInform Abstract in Full Text.

Bis(imino)phenoxide complexes of aluminium.

Reaction of Me(3)Al (one equivalent) with the bis(imino)phenol, [2,6-(ArNCH)(2)-4-MeC(6)H(2)OH] (I)(Ar = 2,6-Pr(i)(2)C(6)H(3)) in toluene at ambient temperature yields the yellow complex [Me(2)Al[2,6-(ArNCH)(2)-4-MeC(6)H(2)O]](1). Interaction of two equivalents of Me(3)Al in refluxing toluene affords the red complex [(Me(2)Al)(2)[2-ArNCH(Me)-6-(ArNCH)-4-MeC(6)H(2)O]](2). Similar interaction (two equivalents, refluxing toluene) of MeAlCl(2) or (i)Bu(3)Al with [2,6-(ArNCH)(2)-4-MeC(6)H(2)OH] affords [ClAl[2,6-(ArNCH)(2)-4-MeC(6)H(2)O](2)](3) or [(i)Bu(2)Al[2,6-(ArNCH)(2)-4-MeC(6)H(2)O]](4), respectively. Hydrolysis of 2 readily affords the iminoaminophenol ligand [2-(ArN=CH)-6-ArNHCH(Me)-4-MeC(6)H(2)OH](II), which reacts further with Me(3)Al to afford [Me(2)Al[2-ArNCH(Me)-6-(ArNCH)-4-MeC(6)H(2)O]](5). An X-ray study on reveals bidentate imino-alkoxide ligation about the distorted aluminium centre, whereas is a binuclear structure with tetrahedral aluminiums ligated by imino-alkoxide and amido-alkoxide ligand fragments, respectively. For and bidentate imino-alkoxide ligation is observed.

Hydrothermal synthesis and magnetic properties of novel Mn(II) and Zn(II) materials with thiolato-carboxylate donor ligand frameworks.

The hydrothermal reaction of thiosalicylic acid, (C(6)H(4)(CO(2)H)(SH)-1,2) with manganese(III) acetate leads to formation of the coordination solid [Mn(5)((C(6)H(4)(CO(2))(S)-1,2)(2))(4)(mu3-OH)2] (1) via a redox reaction, where resulting manganese(II) centres are coordinated by oxygen donor atoms and S-S disulfide bridge formation is simultaneously observed. Reaction of the same ligand under similar conditions with zinc(II) chloride yields the layered coordination solid [Zn(C(6)H(4)(CO(2))(S)-1,2)] (2). Hydrothermal treatment of manganese(III) acetate with 2-mercaptonicotinic acid, (NC(5)H(3)(SH)(CO(2)H)-2,3) was found to produce the 1-dimensional chain structure [Mn(2)((NC(5)H(3)(S)(CO(2))-2,3)(2))(2)(OH(2))(4)].4H(2)O (3) which also exhibits disulfide bridge formation and oxygen-only metal interactions. Compound 3 has been studied by thermogravimetric analysis and indicates sequential loss of lattice and coordinated water, prior to more comprehensive ligand fragmentation at elevated temperatures. The magnetic behaviour of 1 and 3 has been investigated and both exhibit antiferromagnetic interactions. The magnetic behaviour of 1 has been modelled as two corner-sharing isosceles triangles whilst 3 has been modelled as a 1-dimensional chain.

Wavelength-dependent photofragmentation and photoionization of gaseous (eta4-cycloocta-1,5-diene)(eta5-cyclopentadienyl)cobalt.

Gas-phase photoreactions and photoproducts of the mixed-ligand compound (eta(4)-cycloocta-1,5-diene)(eta(5)-cyclopentadienyl)cobalt are reported. Significant amounts of the monoligated complexes CoCOD and CoCp are produced, and the relative amounts are wavelength dependent. The COD ligand (with the weakest metal-ligand bonds) is always preferentially labilized as expected, but the relative amounts of the CoCOD and CoCp fragments change by 1 order of magnitude as the excitation wavelength is changed. The gas-phase photoreactions exhibit other surprising features that are uncommon in the photoreactions of organometallic compounds in the gas phase. Significant amounts of the intact cation are formed, in contrast to most reported reactions where fragmentation of the weak metal-ligand bonds precedes ionization. Most surprisingly, fragmentation of the ligands occurs while the ligands are still coordinated. The resulting metal complexes contain ligand fragments that remain coordinated to the metal. Breaking several carbon-carbon bonds with retention of weaker metal-ligand bonds is unexpected. For example, C(5)H(5) undergoes fragmentation while still coordinated to the cobalt, yielding smaller compounds such as Co(CH)(+), Co(C(2)H(2))(+), Co(C(3)H(3))(+), and Co(C(4)H(6))(+). Correspondingly, coordinated COD yields Co(C(6)H(6))(+), Co(C(5)H(5))(+), Co(C(4)H(6))(+), Co(C(3)H(3))(+), Co(C(2)H(2))(+), and Co(CH)(+). The wavelength dependence of the ligand labilization is examined by utilizing mass-selected resonance enhanced multiphoton ionization spectroscopy. Both broad bands and sharp lines are observed in the mass-selected excitation spectra. The action spectra obtained in the gas phase while monitoring the cobalt ion follow the absorption onset found in solution. The changes in fragmentation pathways are interpreted in terms of the initially accessed excited state.

Synthesis and Structure of the Novel 11-Vertex Rhenacarborane Dianion [1,1,1-(CO)3-2-Ph-closo-1,2-ReCB9H9]2-and Its Reactivity toward Cationic Transition Metal Fragments

Treatment of [NEt4][6-Ph-nido-6-CB9H11] in tetrahydrofuran (THF) with BunLi (2 equiv) followed by [ReBr(THF)2(CO)3] gives the title rhenacarborane dianion isolated, by addition of [N(PPh3)2]Cl, as a mixed salt [N(PPh3)2][NEt4][1,1,1-(CO)3-2-Ph-closo-1,2-ReCB9H9], whose structure was confirmed by X-ray diffraction. The closo 11-vertex dianion reacts readily with several cationic transition metal−ligand fragments, affording products with novel structures in which the electrophilic metal groups are attached exo-polyhedrally to the {closo-1,2-ReCB9} cage system by rhenium−metal bonds supported by three-center two-electron B−H⇀M linkages. Species prepared include [1,3-{M(dppe)}-3-μ-H-1,1,1-(CO)3-2-Ph-closo-1,2-ReCB9H8] (M = Ni, Pd, or Pt; dppe = Ph2PCH2CH2PPh2), [N(PPh3)2][1,3,6-{M(CO)3}-3,6-(μ-H)2-1,1,1-(CO)3-2-Ph-closo-1,2-ReCB9H7] (M = Mn or Re), and [1,6-{M(PPh3)}-1,7-{M(PPh3)}-6,7-(μ-H)2-1,1,1-(CO)3-2-Ph-closo-1,2-ReCB9H7] (M = Cu or Au). Of these, the structures of the platinum−rhenium and dicopper−rheni...

Unexpected coupling between an eta5-indenyl ligand and alkenyl-vinylidene fragments: synthesis of unprecedented (eta6-indene)ruthenium(II) metallacycles.

Vinylidene complexes [Ru[=C=C(H)CR1R2CH2C(Me)=CH2](eta5-C9H7)(PPh3)2][BF4] undergo an intramolecular coupling between the alkenyl-vinylidene fragment and the eta5-indenyl ligand to afford indene-metallacyclic compounds (6a,b) in which the resulting functionalised indene group is eta6-coordinated to the metal.

Cadmium-containing pyridyl–thiazole complexes: crystal structures and solution behaviour of mononuclear, dinuclear double helicate and dinuclear triple helicate complexes

Reaction of Cd(ClO 4) 2 with the potentially tetra- (L 1), penta- (L 2) and hexadentate (L 3) pyridine–thiazole-containing ligands gives [Cd 2(L 1) 3(H 2O)][ClO 4] 4 (a dinuclear triple helicate), mononuclear [Cd(L 2)(ClO 4) 2], and [Cd 2(L 3) 2(ClO 4)(CH 3CN)][ClO 4] 3 (a dinuclear double helicate), respectively. In [Cd 2(L 1) 3(H 2O)][ClO 4] 4 two of the ligands L 1 partition into two bidentate pyridyl–thiazole domains whereas the remaining ligand partitions into a bidentate (pyridyl–thiazole) and monodentate (coordinating pyridyl unit with a pendant thiazole) unit; one Cd(II) centre is coordinated by three bidentate ligand fragments, whereas the other is coordinated by two bidentate and one monodentate ligand fragments as well as a water molecule. This low-symmetry arrangement is retained in solution. In [Cd(L 2)(ClO 4) 2], L 2 acts as a planar pentadentate equatorial ligand with perchlorate anions coordinated at the axial sites; the ligand has a shallow helical twist to minimise steric interactions between the terminal pyridyl H 6 protons, which are directed towards each other. In [Cd 2(L 3) 2(ClO 4)(CH 3CN)][ClO 4] 3, the potentially hexadentate ligand L 3 is partitioned into terdentate (pyridyl–thiazole–pyridyl) and bidentate (pyridyl–thiazole) coordination domains with a non-coordinated terminal pyridyl unit; each Cd(II) centre is coordinated by one terdentate and one bidentate ligand fragment, with the sixth site being occupied by MeCN at one Cd(II) site and a perchlorate anion at the other. Again, the low symmetry coordination mode of the ligands is retained in solution although the two metal centres become equivalent.

Reactions of the bis(iminophosphoranyl)methane ligand CH 2(Ph 2PNSiMe 3) 2 with nickel(II) halides and the structural characterization of ligand fragmentation products

While anhydrous nickel(II) chloride reacts with CH 2(Ph 2PNSiMe 3) 2 to afford the pseudotetrahedral complex NiCl 2[CH 2(Ph 2PNSiMe 3) 2] ( 2), the analogous reaction with anhydrous nickel(II) iodide gives the structurally related complex NiI 2[CH 2(PPh 2NSiMe 3)(PPh 2NH)] ( 3) in which one of the trimethylsilyl groups of 1 has been replaced by hydrogen. Another reaction in which the fragmentation of 1 occurs is that with the hydrate NiCl 2·6H 2O; in this case a square-planar nickel(II) complex of composition [Ni{Ph 2PCH 2PPh 2(NH)} 2]Cl 1.25(NO 3) 0.75 ( 4) was identified as one of the products. The phosphonium salt [Ph 2P(NH 2)NPPh 2(CH 3)]I ( 5) is found to be a major product of the reaction between 3 and CO. The structures of 2– 5 have been established by X-ray crystallography.

Low valent chromium complexes bearing N,O-chelating pyridyl-enolate ligands [OC(But)(2-CHN5H3Me-x)]− (x = 3–6)

Treatment of [CrCl2(THF)] (THF = tetrahydrofuran) with the sodium salt of HOC(But)(2-CH2NC5H3Me-x)2 (x = 6) in refluxing THF results in fragmentation of the L2X (L = neutral donor, X = anionic donor) ligand to afford the square planar bis(pyridyl-enolate) chromium(II) complex [Cr{OC(But)(2-CHNC5H3Me-6)}2] (1) and the by-product trans-[CrCl2(2,6-dimethylpyridine)2] (2). On prolonged heating in refluxing toluene, oxidation of 1 occurs yielding the octahedral tris(pyridyl-enolate) chromium(III) complex [Cr{OC(But)(2-CHNC5H3Me-6)}3] (3). Similar use of the sodium salts of HOC(But)(2-CH2NC5H3Me-x)2 (x = 3–5) also results in ligand fragmentation but gives solely the chromium(III) tris-chelated complexes [Cr{OC(But)(2-CHNC5H3Me-x)}3] [x = 3 (4), 4 (5), 5 (6)]. Surprisingly, prolonged heating in a sealed tube of a mixture of [CrCl2(THF)] and the sodium salt of HOC(But)(2-CH2NC5H3Me-x)2 (x = 6) in the presence of diphenylacetylene furnishes the bimetallic chromium(II) complex [ClCr{(μ-OC(But)(2-CH2NC5H3Me-6)2}CrCl] (7), in which the two intact L2X ligands bridge the Cr–Cr vector (2.92 A), one acting as a bidentate ligand and the other as a tridentate ligand. Single crystal X-ray diffraction studies have been performed on 1, 2, 3, 6 and 7.

Ligand Fragmentation Promoted by a Transient Low-Valent Thulium

Dipyrrolide dianions were formed by a transient divalent Tm complex via fragmentation of the (Et8-calix[4]tetrapyrrole)[K(DME)]4 ligand during the reaction with TmI2(DME)3.