Di-organocobalt complexes of macrocyclic ligands

Three new di-metallorganic cobalt complexes of the type trans-(Bz)₂Co(chel), where Bz is a benzyl group σ-bonded to cobalt atom and chel is an equatorial chelating system constituted by an amino-oximic ligand and its conjugated base, were synthesised. The protonated and the unprotonated ligands interact through an O-H ? O bridge stabilising the entire structure. The complexes differ in the equatorial moiety which is derived from the following ligands: HLN-py=3-[(2-pyridyl)ethylimino]-butan-2-one oxime), HLN-Ph=3-[(2-phenyl)ethylimino]-butan-2-one oxime and the analogous HLN-PhCl=3-[(2-chlorophenyl)ethylimino]-butan-2-one oxime. Two of these compounds, namely those derived from HLN-py and HLN-PhCl were structurally characterised by means X-ray diffractometry. Data reveal that each complex is characterised by the presence of two unusually long cobalt-carbon bonds which are 2.120(4) Å (mean value) in complex with HLN-py ligand and 2.119(4) Å (mean value) in complex with HLN-PhCl. These data are consistent with a strong mutual trans-influence exerted by one ligand on the other.     

Examining the influence of specificity ligands and ATP-competitive ligands on the overall effectiveness of bivalent kinase inhibitors

Background

Identifying selective kinase inhibitors remains a major challenge. The design of bivalent inhibitors provides a rational strategy for accessing potent and selective inhibitors. While bivalent kinase inhibitors have been successfully designed, no comprehensive assessment of affinity and selectivity for a series of bivalent inhibitors has been performed. Here, we present an evaluation of the structure activity relationship for bivalent kinase inhibitors targeting ABL1.

Methods

Various SNAPtag constructs bearing different specificity ligands were expressed in vitro. Bivalent inhibitor formation was accomplished by synthesizing individual ATP-competitive kinase inhibitors containing a SNAPtag targeting moiety, enabling the spontaneous self-assembly of the bivalent inhibitor. Assembled bivalent inhibitors were incubated with K562 lysates, and then subjected to affinity enrichment using various ATP-competitive inhibitors immobilized to sepharose beads. Resulting eluents were analyzed using Tandem Mass Tag (TMT) labeling and two-dimensional liquid chromatography-tandem mass spectrometry (2D–LC-MS/MS). Relative binding affinity of the bivalent inhibitor was determined by calculating the concentration at which 50% of a given kinase remained bound to the affinity matrix.

Results

The profiling of three parental ATP-competitive inhibitors and nine SNAPtag conjugates led to the identification of 349 kinase proteins. In all cases, the bivalent inhibitors exhibited enhanced binding affinity and selectivity for ABL1 when compared to the parental compound conjugated to SNAPtag alone. While the rank order of binding affinity could be predicted by considering the binding affinities of the individual specificity ligands, the resulting affinity of the assembled bivalent inhibitor was not predictable. The results from this study suggest that as the potency of the ATP-competitive ligand increases, the contribution of the specificity ligand towards the overall binding affinity of the bivalent inhibitor decreases. However, the affinity of the specificity components in its interaction with the target is essential for achieving selectivity.

Conclusion

Through comprehensive chemical proteomic profiling, this work provides the first insight into the influence of ATP-competitive and specificity ligands binding to their intended target on a proteome-wide scale. The resulting data suggest a subtle interplay between the ATP-competitive and specificity ligands that cannot be accounted for by considering the specificity or affinity of the individual components alone.

     

Dimolybdenum complexes with mixed formamidinate ligands

A series of dimolybdenum complexes containing mixed formamidinate ligand are discussed. The reactions of trans-Mo₂(O₂CCH₃)₂(o-DMophF)₂ [o-HDMophF=N,N^′-di(2-methoxyphenyl)formamidine] with N,N^′-di(2-pyridyl)formamidine (HDpyF), N,N^′-di(2-pyrimidyl)formamidine (HDpmF) and N,N^′-di(6-methyl-2-pyridyl)formamidine (HDMepyF), in refluxing CH₂Cl₂ afforded the complexes, trans-Mo₂(O₂CCH₃)(DpyF)(o-DMophF)₂ (1), trans-Mo₂(O₂CCH₃)(DpmF)(o-DMophF)₂ (2), and trans-Mo₂(O₂CCH₃)(DMepyF)(o-DMophF)₂ (3), respectively. The o-DMophF⁻ and DMepyF⁻ ligands in these complexes adopt the s-cis, s-trans conformation, resulting in Mo-O short distances [2.889 (3) and 2.861(2) Å for 1; 2.880(3) and 3.024(4) Å for 2], while the DpyF⁻ ligand adopts the s-cis, s-trans conformation, resulting in a Mo-N [3.208(4) Å] and a Mo-H [2.90 (3) Å] short distances. The reactions of trans-Mo₂(O₂CCH₃)₂(o-DMophF)₂ with HDMepyF in CH₃CN gave complexes 3, trans-Mo₂(O₂CCH₃)(DMepyF)₂(o-DMophF) (4), and trans-Mo₂(DMepyF)₂(o-DMophF)₂ (5). The o-DMophF⁻ ligands in 4 and 5 adopt the s-cis, s-cis conformation while DMepyF⁻ assumes an s-cis, s-trans conformation. Complexes 1-5 are the first dimolybdenum complexes containing mixed formamidinate ligands.     

A growing family of Notch ligands

Signaling through Notch-like receptors is an evolutionarily well-conserved mechanism for cell-cell communication. Transmembrane ligands of the DSL (Delta, Serrate, LAG-2) family signal to Notch receptors on a neighboring cell, which results in an intracellular signaling cascade, influencing cellular differentiation. Recently published data shed new light on the repertoire of ligands and on processing of Notch receptors. One report provides evidence for a novel, more distantly related ligand of the Delta-type in mouse, Dll3 (Delta-like 3)¹. Ectopic expression of Dll3 perturbs primary neurogenesis in frog embryos in a manner expected for a bona fide Notch ligand. Two reports provide new information about processing of Notch receptors. A novel protease, Kuzbanian, is identified, which cleaves the Notch receptor at the extracellular side². Biochemical experiments show that the cleavage probably occurs during intracellular trafficking, and that only processed Notch receptors appear at the cell surface³. Taken together, these reports extend our knowledge about an important event in cell-cell communication—how Notch ligands and receptors meet and interact. BioEssays 20:103–107, 1998. © 1998 John Wiley & Sons, Inc.     

Diplatinum(III) complexes with bridging 1-methylcytosinate ligands and variable axial ligands, including guanine nucleobases

A series of diplatinum(III) complexes derived from cis-(NH₃)₂Pt^II and the model nucleobase 1-methylcytosine (1-MeC) has been prepared and X-ray structurally characterized, all of which contain two anionic base ligands (1-MeC⁻) in a head–tail (ht) arrangement: ht-cis-[(ONO₂)(NH₃)₂Pt(1-MeC⁻-N3,N4)₂Pt(NH₃)₂(ONO₂)](NO₃)₂·HNO₃·3H₂O (2b), ht-cis-[(NO₂) (NH₃)₂ Pt(1-MeC⁻-N3,N4)₂Pt(NH₃)₂(OH₂)](ClO₄)₃·3.5H₂O (3), ht-cis-[(OH₂)(NH₃)₂Pt(1-MeC⁻-N3,N4)₂Pt(NH₃)₂(OH₂)](ClO₄)₄·H₂O (4b), and ht-cis-[(9-EtGH-N7)(NH₃)₂Pt(1-MeC⁻-N3,N4)₂Pt (NH₃)₂(9-EtGH-N7)](NO₃)₄·9H₂O (7b) (9-EtGH=9-ethylguanine). Several other compounds, differing in the nature of the axial ligands, have been isolated and or observed in solution by ¹H and ¹⁹⁵Pt NMR spectroscopy. The chemistry of these diplatinum(III) compounds is dominated by facile substitution reactions of the axial ligands. Of particular interest in this context is the ready reaction of 2b or 3 with guanine nucleobases. Since similar compounds are not obtained with any of the other common nucleobases, 2b and 3 can be considered guanine-specific chemical probes.     

Polyoxovanadates with organic ligands

Polyoxovanadates are inhibitors to various phosphate-metabolizing enzymes. The question arises of how the cluster is bound to the protein matrix. This paper describes oxovanadates with carboxylate and hydroxide ligands in the periphery of the cluster, which may be considered to model oxovanadate binding to carboxylic and alcoholic side-chain functions of the protein. Examples for complexes carrying alkoxo ligands dealt with in this article are dinuclear vanadate(V) esters, and hexa-, octa- and decanuclear, mixed-valence (V^V/V^IV) clusters, the latter related to decavanadate. The possible role of dimeric vanadate esters as transition state anologues in enzymatic phosphoester cleavage is addressed. Examples for carboxylate complexes are the mononuclear, seven-coordinate mixed anhydride between orthovanadic acid and pivalic acid, containing the carboxylate in the bidentate mode, tetra-, penta- and hexanuclear V^IV/V^V clusters with bridging carboxylate, and trinuclear V^IV and V^II/V^III clusters, bridged by carboxylates and trebly bridged by O^2–. Special attention is given to a comparison of the bowls containing a V₄(-O)₃(-OH)(O₂CR)₄ and V₄(-O₄(O₂CR)₄ core, respectively, which can accomodate a K⁺ or a NO ₃ ^– .⁵¹V NMR spectroscopy is shown to be a useful tool, in many cases, for the vanadium speciation of complex systems.     

Transition metal complexes with pyrazole derivatives as ligands

Degradation reactions of scorpionates were observed in the presence of transition metal salts MX₂ to give complexes of transition metal and pyrazole derivatives. Otherwise, pyrazolato complexes of transition metals and weakly coordinating anions such as nitrates have been synthesized from transition metal nitrates and 3-phenyl- and 4-phenyldiazo-pyrazole. A number of complexes with pyrazole derivatives as ligands, [Zn(3-tBupzH)₂Cl₂], [Fe₂(3-Phpz)₆Cl₄], [Cu(pzH)₄Br₂], [Ni(py)₂(pzH)₂Cl₂], [Li(THF)₄][Ti₂(μ-pz)₃Cl₄(NMe₂)₂], [Zn₂(μ-3-Phpz)₂(3-PhpzH)₂][(NO₃)₂], [M(3-PhpzH)₄(NO₃)₂] (M = Co, Ni, Cu, Zn, Cd), [Zn(3-PhpzH)₂(NO₃)₂], [Zn(4-PhNNpzH)₂(NO₃)₂](H₂O), and [Cd(4-PhNNpzH)₂(NO₃)₂(H₂O)₂], have been crystallized and characterized by single-crystal X-ray diffraction.     

Dinuclear ruthenium complexes containing tripodal dithiophosphonate ligands

Treatment of [(η⁶-p-cymene)RuCl(μ-Cl)]₂ with Lawesson’s reagent [ArP(S)(μ-S)]₂ (Ar = p-C₆H₄OMe) in the presence of ammonium hydroxide afforded the dinuclear complex [(η⁶-p-cymene)Ru{μ-η¹(S),η²(S,S′)-ArP(O)S₂}]₂ (1) in which the tripodal [ArP(O)S₂]²⁻ ligands bind to the ruthenium atom in both bridging and chelating modes with two non-coordinating PO groups. Interaction of [RuHCl(CO)(PPh₃)₃] with [ArP(S)(μ-S)]₂ and bis(diphenylphosphino)methane (dppm) in the presence of ammonium hydroxide gave the dinuclear complex [Ru(CO){μ₃-η¹(O),η²(S,S′)-ArP(O)S₂}(dppm)]₂ (2) in which the tripodal [ArPOS₂]²⁻ ligands bind the two Ru atoms via both sulfur and oxygen atoms. Treatment of [Ru(PPh₃)₃Cl₂] with [ArP(S)(μ-S)]₂ at reflux in the presence of ammonium hydroxide led to the formation of the dinuclear mixed valence complex [Ru₂Cl₂(μ-S){μ₃-η¹(O),η¹(S),-η²(S,S′)-ArP(O)S₂}(PPh₃)₃] (3), which contains a [Ru^II(PPh₃)₂Cl]⁺ and [Ru^IV(PPh₃)Cl]³⁺ moieties by the tripodal [ArPOS₂]²⁻ ligand in a μ₃-η¹(O),η¹(S),η²(S,S′) coordination mode and the μ-S²⁻ anion. The crystal structures of 1, 2, and 3·CH₂Cl₂ along with their spectroscopic and electrochemical properties are reported.     

Substituted pyridylmethylamide ligands and their zinc complexes

Mononuclear zinc complexes of a family of pyridylmethylamide ligands abbreviated as HL, HL^Ph, HL^Me3, HL^Ph3, and MeL^SMe [HL = N-(2-pyridylmethyl)acetamide; HL^Ph = 2-phenyl-N-(2-pyridylmethyl)acetamide; HL^Me3 = 2,2-dimethyl-N-(2-pyridylmethyl)propionamide; HL^Ph3 = 2,2,2-triphenyl-N-(2-pyridylmethyl)acetamide; MeL^SMe = N-methyl-2-methylsulfanyl-N-pyridin-2-ylmethyl-acetamide] were synthesized and characterized spectroscopically and by single crystal X-ray structural analysis. The reaction of zinc(II) salts with the HL ligands yielded complexes [Zn(HL)₂(OTf)₂] (1), [Zn(HL)₂(H₂O)](ClO₄)₂ (2), [Zn(HL^Ph3)₂(H₂O)](ClO₄)₂ (3), [Zn(HL^Ph)Cl₂] (4), [Zn(HL^Me3)Cl₂] (5), and [Zn(MeL^SMe)Cl₂] (6). The complexes are either four-, five- or six-coordinate, encompassing a variety of geometries including tetrahedral, square-pyramidal, trigonal-bipyramidal, and octahedral.     

Studies of rheniumtricarbonyl complexes of tripodal pyridyl-based ligands

The reaction of N-benzoyl and N-acetyl tris(pyridin-2-yl)methylamine 1b and 1c (LH = tpmbaH and tpmaaH) with [Re(CO)₅Br] has been investigated and shown to proceed via the initial formation of a cationic rheniumtricarbonyl complex [(LH)Re(CO)₃]Br in which coordination of the ligand occurs via the three pyridine rings. For tpmbaH 1b, but not tpmaaH 1c, this initial complex 2b readily undergoes the loss of HBr to give a neutral octahedral complex 4b [(L)Re(CO)₃] where coordination occurs via two of the pyridine rings and the deprotonated amide nitrogen. The ¹H NMR spectrum of the latter complex 4b is very unusual in that at room temperature the signals for the 3-H protons on the coordinated pyridine rings are not visible due to extreme broadening of these resonances. Comparison with the analogous complex 7 from N-benzoyl bis(pyridin-2-yl)methylamine 6b (bpmbaH) confirms that this is due to rotation of the uncoordinated pyridine ring. The structure of the cationic complex 3d [(LH)Re(CO)₃]Br formed from N-benzyl tris(pyridin-2-yl)methylamine 1d (bz-tpmaH) is also discussed. The crystal structures of complexes [(tpmba)Re(CO)₃] 4b, [(bz-tpmaH)Re(CO)₃]Br 3d and [(bpmba)Re(CO)₃] 7 have been determined. In all complexes the coordination geometry around Re is distorted octahedral with a fac-{Re(CO)₃}⁺ core.     

Endogenous ligands for κ-opiate receptors

The receptor preferences of opioids in the mouse vas deferens was tested by means of tolerance and cross-tolerance studies. The preparations were rendered tolerant in situ by superfusion with the κ-receptor agonist dynorphin and with α-neoendorphin, respectively, and set up in vitro in the presence of the respective peptide to maintain tolerance. The investigations revealed strong κ-agonistic activities both of α-neoendorphin and of dynorphin and its fragments 1–13 and 1–11. As the dynorphin chain shortened, the κ-receptor activity declined and δ-receptor activity became progressively apparent. Interestingly, the octapeptide met-enkephalin[Arg⁶,Gly⁷,Leu⁸], a fragment of the adrenal medulla proenkephalin, also displayed considerable κ-agonistic properties under the experimental conditions employed. Presumably, the decapeptide α-neoendorphin and the octapeptide met-enkephalin[Arg⁶,Gly⁷,Leu⁸] cover in addition to the κ-receptor population in the MVD further opiate receptors, most probably δ-receptors.     

Correcting ligands, metabolites, and pathways

Background  

A wide range of research areas in bioinformatics, molecular biology and medicinal chemistry require precise chemical structure information about molecules and reactions, e.g. drug design, ligand docking, metabolic network reconstruction, and systems biology. Most available databases, however, treat chemical structures more as illustrations than as a datafield in its own right. Lack of chemical accuracy impedes progress in the areas mentioned above. We present a database of metabolites called BioMeta that augments the existing pathway databases by explicitly assessing the validity, correctness, and completeness of chemical structure and reaction information.     

Mononuclear rhodium and iridium compounds with pyridyl-pyrazole ligands

Neutral [MCl(L₂)(Hpzpy)], [M(L₂)(pzpy)] and cationic [M(L₂)(Hpzpy)]CF₃SO₃ rhodium(I) or iridium(I) complexes [M = Rh or Ir; L₂ = diolefin or (CO)₂; pzpy = 3-(2-pyridyl)pyrazolate] have been prepared; the pzpy and Hpzpy ligands coordinate to the metal as bidentate chelate groups through one pyrazole nitrogen and the pyridine nitrogen atom. The reactivity of these complexes towards oxidative addition reactions of halogens, methyl iodide or triflic acid and towards displacement reactions has been studied. The neutral and cationic iridium(I) complexes are modest catalysts for the hydrosilylation of phenylacetylene with triethylsilane at 60 °C. The complexes have been characterised by analytical and spectroscopic data; their configuration has been confirmed by COSY and NOESY experiments and the molecular structure of [Rh(COD)(Mepzpy)(PPh₃)]CF₃SO₃ has been established by an X-ray diffraction study.     

New pentafluorophenyl complexes with phosphine-amide ligands

A series of nickel(II) and palladium(II) complexes containing one or two pentafluorophenyl ligands and the phosphino-amides o-Ph₂PC₆H₄CONHR [R = ⁱPr (a), Ph (b)] displaying different coordination modes have been synthesised. The chelating ability of these ligands and the influence of both coligands and the metal centre in their potential hemilabile behaviour have been explored. The crystal structure of (b) has been determined and reveals N–H⋯O intermolecular hydrogen bonding. Bis-pentafluorophenyl derivatives [M(C₆F₅)₂(o-Ph₂PC₆H₄CO-NHR)] [M = Ni; R = ⁱPr (1a); R = Ph (1b); M = Pd; R = ⁱPr (2a); R = Ph (2b)] in which (a) and (b) act as rigid P, O-chelating ligands were readily prepared from the labile precursors cis-[M(C₆F₅)₂(PhCN)₂]. X-ray structures of (1a), (1b) and (2a) have been established, allowing an interesting comparative structural discussion. Dinuclear [{Pd(C₆F₅)(tht)(μ-Cl)}₂] reacted with (a) and (b) yielding the monopentafluorophenyl complexes [Pd(C₆F₅)Cl{PPh₂(C₆H₄–CONH–R)}] (R = ⁱPr (3a), Ph (3b)) that showed a P, O-chelating behaviour of the ligands, confirmed by the crystal structure determination of (3a). New cationic palladium(II) complexes in which (a) and (b) behave as P-monodentate ligands have been synthesised by reacting them with [{Pd(C₆F₅)(tht)(μ-Cl)}₂], stoichiometric Ag(O₃SCF₃) and external chelating reagents such as cod [Pd(C₆F₅)(cod){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃)(R = ⁱPr (4a), Ph (4b)) and 2,2′-bipy [Pd(C₆F₅)(bipy){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃) (R = ⁱPr (5a), Ph (5b)). When chloride abstraction in [{Pd(C₆F₅)(tht)(μ-Cl)}₂] is promoted by means of a dithioanionic salt as dimethyl dithiophospate in the presence of (a) or (b), the corresponding neutral complexes [Pd(C₆F₅){S(S)P(OMe)₂}{PPh₂(C₆H₄-CONH-R)}] (R = ⁱPr (6a), Ph (6b)) were obtained.     

Monocyclopentadienyl titanium complexes supported by functionalized carboxylate ligands

The reaction of [TiCp*Cl₃] with [Fe(η⁵-C₅H₅)(η⁵-C₅H₄COOH)] in the presence of NEt₃ yields [TiCp*{(OOC-C₅H₄)FeCp}₃] (1), (Cp = η⁵-C₅H₅). The alkyl complex [TiCp*Me₃] reacts with [FeCp(η⁵-C₅H₄-CH₂COOH)] or anthranilic acid rendering the tris-carboxylate titanium complexes [TiCp*{(OOCCH₂-C₅H₄)FeCp}₃] (2) and [TiCp*{(OOCC₆H₄NH₂)₃] (3), respectively. Complex 3 can be protonated with triflic acid to render [TiCp*{(OOCC₆H₄NH₂)₃].HOTf (4). The reaction of [TiCp*Me₃] with anthranilic acid in a 1:2 M ratio yields the alkyl carboxylate derivative [TiCp*Me{(OOCC₆H₄NH₂)₂] (5). Complex 5 reacts with ^tBuNC to render the iminoacyl complex [TiCp*(η²-MeCN^tBu){(OOCC₆H₄NH₂)₂] (6). The reaction of [TiCp*Cl₃] with the ferroceneacetic acid, gives [TiCp*Cl₂{(OOCCH₂-C₅H₄)FeCp}] (7). The [TiCp*Cl]₂(μ-O)[(ΟΟC-C₅H₄)₂Fe] (8) can be obtained by reaction of [TiCp*Cl₃] with [Fe(η⁵-C₅H₄-COOH)₂] in the presence of a base. The molecular structures of 1 and 8 have been established by X-ray diffraction methods.     

Organo-Group 15 derivatives of triosmium clusters containing naphthyl ligands

Reactions of the clusters Os₃(μ-H)₂(μ₃-1-OC₁₀H₆)(CO)₉, 1, and Os₃(μ-H)(μ-2-OC₁₀H₇)(CO)₁₀, 2, with the group 15 ligands EPh₃ (E=P, As, Sb) generally afforded the mono- and, or disubstituted derivatives. These derivatives tend to decompose during chromatographic separations on silica gel; thus one of the decomposition products from the reaction of 1 with PPh₃ has been identified as Os(H)₂(CO)₂(PPh₃)₂, 3. The molecular structures of 3, as well as the derivatives Os₃(μ-H)₂(μ₃-1-OC₁₀H₆)(CO)₈(AsPh₃), 4, Os₃(μ-H)₂(μ₃-1-OC₁₀H₆)(CO)₇(SbPh₃)₂, 5c, Os₃(μ-H)(μ-2-OC₁₀H₇)(CO)₈(AsPh₃)₂, 7b, and Os₃(μ-H)(μ-2-OC₁₀H₇)(CO)₈(SbPh₃)₂, 7c, have been determined by single crystal X-ray diffraction studies.     

Iridium and rhodium complexes containing dichalcogenoimidodiphosphinato ligands

Treatment of [MCl(CO)(PPh₃)₂] with K[N(R₂PQ)₂] afforded [M{N(Ph₂PQ)₂}(CO)(PPh₃)] (M = Ir, Rh; Q = S, Se). The IR C=O stretching frequencies for [M(CO)(PPh₃){N(Ph₂PQ)₂}] were found to decrease in the order S > Se. Treatment of [M(COD)Cl]₂ with K[N(Ph₂PQ)₂] afforded [M(COD){N(Ph₂PQ)₂}] (COD = 1,5-cyclooctadiene; M = Ir, Rh; Q = S, Se). Treatment of [Ir(ol)₂Cl] with afforded (ol = cyclooctene COE, C₂H₄; Q = S, Se). Oxidative addition of [Ir(CO)(PPh₃){N(Ph₂PS)₂}] and [Ir(COD){N(Ph₂PS)₂}] with HCl afforded [Ir(H)(Cl)(CO)(PPh₃){N(Ph₂PS)₂}] and trans-[Ir(H)(Cl)(COD){N(Ph₂PS)₂}], respectively. Oxidative addition of [Ir(CO)(PPh₃){N(Ph₂PS)₂}] with MeI afforded [Ir(Me)(I)(CO)(PPh₃){N(Ph₂PS)₂}]. Treatment of [Ir(COE)₂Cl]₂ with K[N(R₂PO)₂] afforded [Ir(COE)₂{N(Ph₂PO)₂}] that reacted with MeOTf (OTf = triflate) to give [Ir{N(Ph₂PO)₂}(COE)₂(Me)(OTf)]. The crystal structures of [Ir(CO)(PPh₃){N(Ph₂PS)₂}], [M(COD){N(Ph₂PS)₂}] (M = Ir, Rh), (ol = COE, C₂H₄), trans-[Ir(H)(Cl)(COD){N(Ph₂PS)₂}], and [Ir(COE)₂{N(Ph₂PO)₂}] have been determined.     

High affinity sugar ligands of C-type lectin receptor langerin

Background

Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti-inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application.

Heterometallic coordination polymers constructed by linear ligands

Eight lanthanide–copper coordination polymers of linear rigid 4-(4-pyridyl)benzoate(L¹) and isonicotinate(L²), [LnCuI(L¹)₂(OAc) (H₂O)]_n (Ln = Pr, 1; Nd, 2; Sm, 3; Eu, 4; Gd, 5), [Ln₂Cu₄I₃(L²)₇ (H₂O)]_n (Ln = La, 6; Pr, 7), and [Nd₂Cu₇I₆(L²)₇ (H₂O)₆]_n·2.5nH₂O (8), were hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction. The three-dimensional frameworks of 1–5 can be described as wave-like layer modules of [Ln(L¹)₂(OAc)(H₂O)]_n linking with each other through dimeric units of Cu₂I₂, whereas that of compounds 6 and 7 are constructed by layer modules of and Cu₄I₃ clusters. As for 8, dimeric units of Nd₂(L²)₇(H₂O)₆ connect layered polymeric forming a 3D framework.     

High affinity sialoside ligands of myelin associated glycoprotein

Myelin associated glycoprotein (Siglec-4) is a myelin adhesion receptor, that is, well established for its role as an inhibitor of axonal outgrowth in nerve injury, mediated by binding to sialic acid containing ligands on the axonal membrane. Because disruption of myelin-ligand interactions promotes axon outgrowth, we have sought to develop potent ligand based inhibitors using natural ligands as scaffolds. Although natural ligands of MAG are glycolipids terminating in the sequence NeuAcα2-3Galβ1-3(±NeuAcα2−6)GalNAcβ-R, we previously established that synthetic O-linked glycoprotein glycans with the same sequence α-linked to Thr exhibited ∼1000-fold increased affinity (∼1 μM). Attempts to increase potency by introducing a benzoylamide substituent at C-9 of the α2-3 sialic acid afforded only a two-fold increase, instead of increases of >100-fold observed for other sialoside ligands of MAG. Surprisingly, however, introduction of a 9-N-fluoro-benzoyl substituent on the α2-6 sialic acid increased affinity 80-fold, resulting in a potent inhibitor with a K_d of 15 nM. Docking this ligand to a model of MAG based on known crystal structures of other siglecs suggests that the Thr positions the glycan such that aryl substitution of the α2-3 sialic acid produces a steric clash with the GalNAc, while attaching an aryl substituent to the other sialic acid positions the substituent near a hydrophobic pocket that accounts to the increase in affinity.