Mixture Of Ligands Research Articles

457P - A First-In-Human Study Evaluating the Safety and Pharmacology of Mm-151, a Novel Oligoclonal Anti-Egfr Antibody Combination in Patients with Refractory Solid Tumors

ABSTRACT Aim: MM-151 is an oligoclonal combination of three IgG1, anti-EGFR antibodies designed to bind distinct non-overlapping EGFR epitopes and inhibit ligand-mediated signal amplification. MM-151's molecular composition enables antagonism of clinically relevant EGFR ligand mixtures, EGFR down-regulation and immune effector function (ADCC, CDC). A Phase 1 study was initiated to assess the safety, tolerability, PK, immunogenicity and preliminary clinical activity of MM-151. Methods: 69 patients were enrolled on 3 schedules (QW, Q2W, and Q3W) at escalating doses using standard 3 + 3 design. Response was assessed per RECIST criteria every 8 weeks. Patients continued on study until disease progression or unacceptable toxicity. Results: Results presented are based on preliminary data as of Apr. 25, 2014. 69 patients (median age 63 years; 33 male, 36 female) have been enrolled across 3 dosing schedules. 69 patients were evaluable for safety and 46 evaluable for efficacy. The most common tumor types were CRC (28 [41%]), NSCLC (9 [13%]), SCCHN (5 [7%]), and pancreatic (5 [7%]). An MTD has not been reached and dose escalation continues. Most adverse events were CTCAE grades 1 and 2. Infusion related reaction (IRR) was the most common AE (47 [68.1%]); however, this was managed with premedication and an optimized infusion schedule. The most common non-IRR AEs were comprised of EGFR-pathway toxicities, including rash (54 [78%]), hypomagnesemia (17 [25%]), mucositis (8 [12%]) and diarrhea (15 [22%]). Initial biomarker data in a subset of patients suggest that IRR relates to engagement of the innate immune system, shown in pre- and post - dose cytokine and peripheral blood flow cytometry data. Partial responses were observed in 2 CRC patients and a total of 8 (29% of mCRC) patients had SD for > 4 months (2 of the 8 had SD for 20.1 and 19.8 months). At doses > 9 mg/kg QW, trough total antibody levels at steady state were in expected therapeutic range. Conclusions: Results to date show that MM-151 has an acceptable safety profile and objective clinical activity in CRC. Updated safety, efficacy and preliminary biomarker data will be presented. Disclosure: C. Lieu: Consultant for Sanofi Aventis; L. Power, C. Sloss, J. Kearns, R. Nering, V. Moyo and B. Wolf: employee of Merrimack Pharmaceuticals, stock ownership. All other authors have declared no conflicts of interest.

Elusive transmetalation intermediate in copper-catalyzed conjugate additions: direct NMR detection of an ethyl group attached to a binuclear phosphoramidite copper complex.

Copper-catalyzed asymmetric conjugate addition reactions are a very powerful and widely applied method for enantioselective carbon-carbon bond formation. However, structural and mechanistic insight into these famous reactions has been very limited so far. In this article, the first direct experimental detection of transmetalation intermediates in copper-catalyzed reactions is presented. Special combinations of (1)H,(31)P HMBC spectra allow for the identification of complexes with chemical bonds between the alkyl groups and the copper complexes. For the structural characterization of these transmetalation intermediates, a special approach is applied, in which samples using enantiopure ligands are compared with samples using enantiomeric mixtures of ligands. It is experimentally proven, for the first time, that the dimeric copper complex structure is retained upon transmetalation, providing an intermediate with mixed trigonal/tetrahedral coordination on the copper atoms. In addition, monomeric intermediates with one ligand, but no intermediates with two ligands, are detected. These experimental results, in combination with the well-known optimal ligand-to-copper ratio of 2:1 in synthetic applications, allow us to propose that a binuclear transmetalation intermediate is the reactive species in copper-catalyzed asymmetric conjugate addition reactions. This first direct experimental insight into the structure of the transmetalation intermediate is expected to support the mechanistic and theoretical understanding of this important class of reactions and to enable their further synthetic development. In addition, the special NMR approach presented here for the identification and characterization of intermediates below the detection limit of (1)H NMR spectra can be applied also to other classes of catalyses.

Multivalent interactions regulate signal transduction in a self-assembled Hg2+ sensor.

A self-assembled sensing system able to detect Hg(2+) at low nanomolar concentrations is reported that operates through a signal transduction pathway involving multivalent interactions. The analyte causes dimerization of low-affinity ligands, resulting in a complex with a high affinity for a multivalent monolayer-protected gold nanoparticle (AuNP). This complex displaces a quenched fluorescent reporter from the AuNP, resulting in a turn ON of fluorescence. It is shown that the strength of the output signal can be regulated by tuning the multivalent interactions between the complex and the NP. Finally, it is shown that multivalent interactions drive the self-selection of a high-affinity complex from a mixture of low-affinity ligands.

Polynuclear Heterometallic Complexes from Metal Powders: The “Direct Synthesis” Approach

AbstractThe synthesis of polynuclear coordination compounds, particularly heterometallic coordination compounds, remains a challenge for modern chemistry. Spontaneous self‐assembly (SSA) is a primary approach that proceeds by broad screening, typically with simple, flexible ligands and available metal salts. The “direct synthesis” is a class of SSA, but prescribes the use of zero‐valent metal(s) as a starting material, typically oxidized by air oxygen, which results in a deficiency of anions in the reaction mixture and forces deprotonation of the protic ligand(s) with the formation of unexpected products. The “direct synthesis” approach has been successfully applied to the preparation of heterometallic complexes, which has allowed the isolation of numerous complexes, many with uncommon structures. In this review we summarize our experience in the field of the “direct synthesis” of polynuclear heterometallic complexes, covering preparative and structural aspects as well as applications of the compounds obtained.

Synthesis, structural characterization and radiochemistry of “2 + 1” fac-[99mTc/Re(CO)3(L)(2-mercaptopyridine)] complexes, where L is phosphine or isocyanide

This work focuses on the development of “2+1” technetium and rhenium carbonyl complexes of the formula fac-[99mTc/Re(CO)3(L)(Spy)], where HSpy is 2-mercaptopyridine and acts as (NS) bidentate ligand and L is either triphenylphosphine (PPh3) or benzyl isocyanide (BnNC). Reaction of 2-mercaptopyridine with the precursors fac-(NEt4)2[Re(CO)3Br3] or [Re(CO)5Br] yields the dimeric complex fac-[Re(CO)3(Spy)]2, Re1. Re1 readily reacts with the monodentate ligand to yield the respective “2+1” fac-[Re(CO)3(PPh3/BnNC)(Spy)] complexes Re2/Re4. Re2 was also obtained in a single step reaction of the precursor fac-(NEt4)2[Re(CO)3Br3] with the mixture of ligands in equimolar amounts. Furthermore, the rhenium dicarbonyl complex cis, trans-[Re(CO)2(PPh3)2(Spy)] complex Re3 was synthesized by reaction of HSpy with the precursor mer, trans-[Re(CO)3(PPh3)2Cl]. All rhenium complexes were characterized by IR, NMR, elemental analysis and furthermore the structure of Re1, Re2, Re3 was solved by X-ray crystallography. At the 99mTc tracer level, the “2+1” complex fac-[99mTc(CO)3(PPh3)(Spy)], 99mTc2, was obtained in high radiochemical yield and low ligand concentrations and the complex was very stable in histidine and cysteine in challenge experiments.

Cobalt-catalyzed hydrogenation of β-enamino esters using an internal mixture of bidentate and monodentate ligands

Different β-amino esters have been obtained in good yields by means of octacarbonyldicobalt-catalyzed hydrogenation of β-enamine esters in the presence of mixture of a bidentate phosphine chiral (R-BINAP) and a monodentate phosphine achiral (PPh3). Likewise, a non-symmetric Co/BINAP/PPh3 complex was isolated. This new compound was used in the hydrogenation reaction under different conditions and the results suggest that this heterocombination could be responsible for improving enantiomeric excess in the reduction products.

Effect of steric congestion and non-covalent interaction on the self-organization of two isostructural 1D chiral coordination polymers

Two isostructural 1D chiral coordination polymers namely, [M(L)(N(CN)2)]n have been synthesized using a racemic mixture of chiral tridentate Schiff base ligand, LH (LH=2-((phenyl(2-pyridyl)methylimino)methyl)phenol), M(II) ions (M=Cu (1), Zn (2)) and dicyanamide ion. Structural characterization reveals that dicyanamide ion links two mononuclear units having same enantiomer of ligand L (either R or S) though it’s end-on-end bridging mode and extends further towards the formation of 1D homochiral self-assembly in a chiral self-recognition manner. The effects of different non-covalent interactions on the arrangement of 1D chiral coordination polymers into 2D sheet have been studied. The results demonstrate the effect of dicyanamide ion, steric congestion and non-covalent interactions on the homochiral self-assembly of the synthesized complexes.

Asymmetric ring opening of epoxides with cyanides catalysed by chiral binuclear titanium complexes

A series of Schiff bases obtained from salicylaldehydes and 3,3′-diformyl-BINOL were synthesized. The complexes of these Schiff bases with Ti(IV) were active for the asymmetric ring opening of epoxides with TMSCN. A mixture of unpurified ligands was found to be as effective as the best one. The influence of temperature, solvent polarity and structural modification of the pre-catalysts on the enantioselectivity of the process has also been investigated.

Synthesis, Water Adsorption, and Proton Conductivity of Solid‐Solution‐Type Metal–Organic Frameworks Al(OH)(bdc‐OH)x(bdc‐NH2)1−x

Mixed-ligand metal-organic frameworks Al(bdc-OH)(x)(bdc-NH2)(1-x) (H2bdc-NH2 = aminoterepthalic acid, H2bdc-OH = hydroxyterephthalic acid) were synthesized and their water adsorption behavior and proton conductivity were investigated. All obtained compounds were isostructural to MIL-53 (MIL = Materials of Institut Lavoisier) according to XRD measurements under ambient humidity conditions, and were also found to be single phase across the whole mixing ratio from the XRD measurements under humidified conditions. This result clearly shows that all compounds are a solid-solution-type mixture of ligands. MIL-53-NH2 adsorbs one water molecule per formula with humidification whereas MIL-53-OH adsorbs five water molecules. The mixing ratio of the ligands in Al(OH)(bdc-OH)(x)(bdc-NH2)(1-x) affected the gate-opening pressure for water adsorption and total water uptake. Proton conductivity of these compounds largely depends on the adsorbed amount of water, which indicates that the proton conductivity of these compounds depends strongly on the hydrogen-bond network of the conducting media.

Narcissistic self-sorting vs. statistic ligand shuffling within a series of phenothiazine-based coordination cages

Previously, we introduced a series of anion-binding interpenetrated double-cages based on phenothiazine and its mono- and di-S-oxygenated derivatives. Here, we complete the structural comparison of the three related assemblies by an X-ray single crystal analysis of the sulfone derivative. We further show that the three palladium cages coexist in solution upon post-assembly mixing due to the very slow ligand exchange whereas treatment of binary mixtures of the corresponding ligands with Pd(II) leads to the formation of mixed cages comprising a statistical ligand distribution. In contrast, mixtures of one of these ligands with a shorter ligand derivative lead to narcissistic self-assembly into a double-cage and a coexisting small monomeric cage, regardless of the order of mixing and Pd(II) addition.

Novel Supramolecular Thixotropic Metallohydrogels Consisting of Rare Metal–Organic Nanoparticles: Synthesis, Characterization, and Mechanism of Aggregation

Even without obvious sticky sites, novel supramolecular thixotropic metallohydrogels consisting of rare metal–organic nanoparticles (MNPs) have been readily accessible from simple structured pincer-type terpyridine Cu(II) complexes at the gelator concentration as low as 0.25 wt %. The obtained soft materials have been fully characterized by using a combination of experimental techniques including scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), X-ray diffraction (XRD), high-resolution mass spectrometry (HR-MS), and rheology measurements. Based on these studies, hypothesized molecular assembly mechanisms for distinctly different morphologies observed in different solvents were proposed. Besides general heating–cooling gel preparation procedures, surprisingly, the metallohydrogel was formed by simply stirring the mixture of pincer ligand and Cu salts in water directly, further indicating thixotropic property and self-h...

A Hair Growth-Promoting Effect of Chinese Black Tea Extract in Mice

Chinese black tea extract (CBTE) fermented with Aspergillus sp. significantly promoted hair growth after 2 weeks of topical application in shaved 6 week-old male C3H/He mice. The hair growth-promoting effect of CBTE was potentiated synergistically by capsaicin, which has no effect on hair growth by itself. CBTE displayed an affinity for estrogen receptor (ER)α, with an IC50 value of 74.8 µg/mL. This effect of CBTE might be mediated by the ERs, since a similar effect induced by orally administered soy isoflavone, a mixture of ERs ligands, has been reported to be synergistically potentiated by capsaicin.

Bivalent Ligands That Target μ Opioid (MOP) and Cannabinoid1 (CB1) Receptors Are Potent Analgesics Devoid of Tolerance

Given that μ opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.

Nanoporous Bicontinuous Structures via Addition of Thermally-Stable Amphiphilic Nanoparticles within Block Copolymer Templates

Herein, we fabricated the bicontinuous structures from nanocomposites of poly(styrene-b-methyl methacrylate) (PS-b-PMMA) block copolymer and the shell-cross-linked, thermally stable gold nanoparticles (Au NPs). The surface property of Au NPs was controlled with ligands containing various compositions of PS and PMMA so that the resulting Au NPs were selective to PS or PMMA block or nonselective (i.e., neutral) to both blocks. The amphiphilic Au NPs were also prepared by coating the surface of Au NPs with equimolar mixtures of PS and PMMA selective ligands. Consequently, it was found that the morphological behaviors of thermally annealed nanocomposites containing amphiphilic Au NPs and PS-b-PMMA were dramatically different from the case of neutral Au NPs that were coated with nonselective ligands. With increasing the amount of amphiphilic Au NPs, a transition from lamellar to bicontinuous structures was observed, whereas the neutral Au NPs were aggregated within the PS-b-PMMA lamellae. Furthermore, the nanoporous bicontinuous thin films were fabricated on the silicon substrates and the morphological behaviors were quantitatively investigated by grazing-incidence small-angle X-ray scattering (GISAXS) analysis.

ChemInform Abstract: Asymmetric Hydrogenation Using Rhodium Complexes Generated from Mixtures of Monodentate Neutral and Anionic Phosphorus Ligands.

AbstractThis is a study concerning ligand effects and catalyst formation in the asymmetric hydrogenation of olefins.

Determining the affinity and stoichiometry of interactions between unmodified proteins in solution using Biacore

We describe a general Biacore method for measuring equilibrium binding affinities and stoichiometries for interactions between unmodified proteins and their unmodified ligands free in solution. Mixtures of protein and ligand are preequilibrated at different ratios in solution and then analyzed by Biacore using a sensor chip surface that detects only unbound analyte. Performing the Biacore analysis under mass transport limited conditions allows the concentration of unbound analyte to be determined from the initial velocity of binding. Plots of initial velocity versus the concentration of the varied binding partner are fitted to a quadratic binding equation to give the affinity and stoichiometry of binding. We demonstrate the method using soluble Her2 extracellular domain binding to monovalent, bivalent, and trivalent forms of an anti-Her2 antibody. The affinity we measured agrees with that obtained from conventional Biacore kinetic analysis, and the stoichiometries for the resulting 1:1, 1:2, and 1:3 complexes were confirmed by gel filtration with in-line light scattering. The method is applicable over an affinity range of approximately 100pM to 1μM and is particularly useful when there is concern that covalently modifying one or the other binding partner might affect its binding properties or where multivalency might otherwise complicate a quantitative analysis of binding.

Synergistic extraction of uranium(VI) and thorium(IV) with mixtures of Cyanex272 and other organophosphorus ligands

The extraction of thorium(IV) and uranium(VI) from nitric acid solutions has been studied using mixtures of bis(2,4,4-trimethylpentyl)phosphinic acid (Cyanex272 or HA), and synergistic extractants (S) such as tri-butylphosphate (TBP), tri-octylphosphine oxide (TOPO) or bis(2,4,4-trimethylpentyl)thiophosphinic acid (Cyanex301). The results showed that these metallic ions are extracted into kerosene as Th(OH)2(NO3)A·HA and UO2(NO3)A·HA with Cyanex272 alone. In the presence of neutral organophosphorus ligands TBP and TOPO, they are found to be extracted as Th(OH)2(NO3)A·HA·S and UO2(NO3)A·HA·S. On the other hand, Th(IV), U(VI) are extracted as Th(OH)2(NO3)A·HA·2S and UO2(NO3)A·HA·S in the presence of Cyanex301. The addition of neutral extractants such as TOPO and TBP to the extraction system enhanced the extraction efficiency of both elements while Cyanex301 as an acidic extractant has improved the selectivity between uranium and thorium. The effect of TOPO on the extraction was higher than other extractants. The equilibrium constants of above species have been estimated by non-linear regression method. The extraction amounts were determined and the results were compared with those of TBP. Also, it was found that the binding to the neutral ligands by the thorium–Cyanex272 complexes follows the neutral ligand basicity sequence.

Matrix Assisted Ionization Vacuum (MAIV), a New Ionization Method for Biological Materials Analysis Using Mass Spectrometry

The introduction of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) for the mass spectrometric analysis of peptides and proteins had a dramatic impact on biological science. We now report that a wide variety of compounds, including peptides, proteins, and protein complexes, are transported directly from a solid-state small molecule matrix to gas-phase ions when placed into the vacuum of a mass spectrometer without the use of high voltage, a laser, or added heat. This ionization process produces ions having charge states similar to ESI, making the method applicable for high performance mass spectrometers designed for atmospheric pressure ionization. We demonstrate highly sensitive ionization using intermediate pressure MALDI and modified ESI sources. This matrix and vacuum assisted soft ionization method is suitable for the direct surface analysis of biological materials, including tissue, via mass spectrometry.

Liquid chromatographic approach to investigation of dissolved organic matter adsorptive fractionation and competitive displacement on minerals

Although physicochemical processes at liquid/solid boundaries are critical in several increasingly important areas of environmental science and engineering, research methods used to contact solutes and adsorbents have changed little in recent decades. We describe an emerging liquid chromatographic (LC) experimental approach which can be used to investigate various phenomena at liquid/solid boundaries, and we report its application in studies of Suwannee River Humic Acid (SRHA) adsorptive fractionation and phosphate competitive displacement on aluminum oxide coated quartz (AlQ). This LC-based approach is similar to continuous-flow column (i.e., breakthrough) methods. However, using the LC auto-injection system, `pulsed' (i.e., non-continuous) additions of adsorbate (or displacement agent) are made onto adsorbent-packed columns, and non-adsorbed (or displaced) ligands are monitored in multiple optical chromatographic detection channels. We applied the LC-based method in this area of research because (i) this method promises to be more efficient (in materials and analytical/experimental time) than conventional (batch and continuous-flow column) methods, and (ii) it generates unique data that reveal changes in of solution-phase adsorbate mixture compositions due to preferential adsorption or displacement effects. In an SRHA-AlQ adsorption study, detector signal ratios suggested preferential adsorption of high molecular weight (MW) SRHA constituents. When phosphate ions reacted with SRHA-saturated AlQ surfaces, these ratios indicated preferential displacement of low MW SRHA constituents. Adsorption and displacement results agreed, indicating relatively high MW SRHA constituents bound with greatest affinity. Results agree with previous studies of similar adsorbate–adsorbent systems conducted using conventional methods, which validates this method. Each of these experiments, which provided data on both adsorptive fractionation and competitive displacement, was completed in the timeframe of a typical chromatographic experiment and consumed <1mg adsorbate and < 2g adsorbent. Based on its temporal and materials efficiencies and its ability to yield unique forms of data pertaining to the interactions of complex organic ligand mixtures with adsorbent surfaces, this LC-based method will be an important alternative and/or complementary technique that will provide new insights into the interplay of processes that ultimately govern humic substances adsorption.

Mixed-ligand terbium terephthalates: Synthesis, photophysical and thermal properties and use for luminescent terbium terephthalate thin film deposition

Abstract Addition of potassium terephthalate K 2 tph to an aqueous solution of a mixture of terbium nitrate and ancillary ligands L resulted in the formation of mixed-ligand terbium terephthalates Tb 2 tph 3 (TPPO) 8 (H 2 O) 4 (II), Tb 2 tph 3 (TOPO) 2 (H 2 O) 4 (III), Tb 2 tph 3 (diglyme) 2 (H 2 O) (IV), Tb 2 tph 3 (tetraglyme) 4 (H 2 O) 3 (V), Tb 2 tph 3 (Phen) 2 (H 2 O) 2 (VI). The composition of the mixed-ligand complexes (MLCs) was confirmed by elemental analysis, Raman spectroscopy, thermal analysis, and luminescent spectroscopy. According to the thermal analysis data, II–V exhibit lower thermal stability in comparison with the terephthalate hydrate Tb 2 tph 3 (H 2 O) 4 (I). MLCs II, IV, and V are able to eliminate ancillary ligands, followed by formation of anhydrous Tb 2 tph 3 , while in case of III and IV ligand elimination is accompanied by partial thermal decomposition of Tb 2 tph 3 . Solubility tests showed that MLC II exhibits sufficient solubility in acetonitrile for thin film deposition. Thus thin films of II were deposited by spin-coating, and luminescent thin films of Tb 2 tph 3 were obtained for the first time by thermal treatment of II films.