Peter P. Wells

Designer titania-supported Au-Pd nanoparticles for efficient photocatalytic hydrogen production

Photocatalytic hydrogen evolution may provide one of the solutions to the shift to a sustainable energy society, but the quantum efficiency of the process still needs to be improved. Precise control of the composition and structure of the metal nanoparticle cocatalysts is essential, and we show that fine-tuning the Au-Pd nanoparticle structure modifies the electronic properties of the cocatalyst significantly. Specifically, Pd(shell)-Au(core) nanoparticles immobilized on TiO2 exhibit extremely high quantum efficiencies for H2 production using a wide range of alcohols, implying that chemical byproducts from the biorefinery industry can be used as feedstocks. In addition, the excellent recyclability of our photocatalyst material indicates a high potential in industrial applications. We demonstrate that this particular elemental segregation provides optimal positioning of the unoccupied d-orbital states, which results in an enhanced utilization of the photoexcited electrons in redox reactions. We consider that the enhanced activity observed on TiO2 is generic in nature and can be transferred to other narrow band gap semiconductor supports for visible light photocatalysis.

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30–50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR–ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR–ABL1-driven leukaemia. Axitinib potently inhibited BCR–ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

Water-splitting electrocatalysis in acid conditions using ruthenate-iridate pyrochlores

The pyrochlore solid solution (Na0.33Ce0.67)2(Ir1−xRux)2O7 (0≤x≤1), containing B-site RuIV and IrIV is prepared by hydrothermal synthesis and used as a catalyst layer for electrochemical oxygen evolution from water at pH<7. The materials have atomically mixed Ru and Ir and their nanocrystalline form allows effective fabrication of electrode coatings with improved charge densities over a typical (Ru,Ir)O2 catalyst. An in situ study of the catalyst layers using XANES spectroscopy at the Ir LIII and Ru K edges shows that both Ru and Ir participate in redox chemistry at oxygen evolution conditions and that Ru is more active than Ir, being oxidized by almost one oxidation state at maximum applied potential, with no evidence for ruthenate or iridate in +6 or higher oxidation states.

Identification of single-site gold catalysis in acetylene hydrochlorination

Gold-on-carbon catalysts are analogs of homogeneous gold catalysts that use a redox couple of Au(I) and Au(III) species. Supported gold ions The mercuric chloride catalyst for acetylene hydrochlorination creates vinyl chloride, an important polymer feedstock. However, a more environmentally friendly catalyst of gold supported on carbon can now replace mercuric chloride. Malta et al. used x-ray spectroscopic studies of the working catalysts and computational modeling to show that the active species are coexisting single-site Au+ and Au3+ cations. These species are analogs of soluble catalysts with single metal atoms that react via a similar redox couple. Science, this issue p. 1399 There remains considerable debate over the active form of gold under operating conditions of a recently validated gold catalyst for acetylene hydrochlorination. We have performed an in situ x-ray absorption fine structure study of gold/carbon (Au/C) catalysts under acetylene hydrochlorination reaction conditions and show that highly active catalysts comprise single-site cationic Au entities whose activity correlates with the ratio of Au(I):Au(III) present. We demonstrate that these Au/C catalysts are supported analogs of single-site homogeneous Au catalysts and propose a mechanism, supported by computational modeling, based on a redox couple of Au(I)-Au(III) species.

Stable amorphous georgeite as a precursor to a high-activity catalyst

Copper and zinc form an important group of hydroxycarbonate minerals that include zincian malachite, aurichalcite, rosasite and the exceptionally rare and unstable—and hence little known and largely ignored—georgeite. The first three of these minerals are widely used as catalyst precursors for the industrially important methanol-synthesis and low-temperature water–gas shift (LTS) reactions, with the choice of precursor phase strongly influencing the activity of the final catalyst. The preferred phase is usually zincian malachite. This is prepared by a co-precipitation method that involves the transient formation of georgeite; with few exceptions it uses sodium carbonate as the carbonate source, but this also introduces sodium ions—a potential catalyst poison. Here we show that supercritical antisolvent (SAS) precipitation using carbon dioxide (refs 13, 14), a process that exploits the high diffusion rates and solvation power of supercritical carbon dioxide to rapidly expand and supersaturate solutions, can be used to prepare copper/zinc hydroxycarbonate precursors with low sodium content. These include stable georgeite, which we find to be a precursor to highly active methanol-synthesis and superior LTS catalysts. Our findings highlight the value of advanced synthesis methods in accessing unusual mineral phases, and show that there is room for exploring improvements to established industrial catalysts.

Identification of Active and Spectator Sn Sites in Sn-β Following Solid-State Stannation, and Consequences for Lewis Acid Catalysis

Lewis acidic zeolites are rapidly emerging liquid‐phase Lewis acid catalysts. Nevertheless, their inefficient synthesis procedure currently prohibits greater utilization and exploitation of these promising materials. Herein, we demonstrate that SnIV‐containing zeolite beta can readily be prepared both selectively and extremely rapidly by solid‐state incorporation (SSI) method. Through a combination of spectroscopic (XRD, UV/Vis, X‐ray absorption, magic‐angle spinning NMR, and diffuse reflectance infrared Fourier transform spectroscopy) studies, we unambiguously demonstrate that site‐isolated, isomorphously substituted SnIV sites dominate the Sn population up to a loading of 5 wt % Sn. These sites are identical to those found in conventionally prepared Sn‐beta, and result in our SSI material exhibiting identical levels of intrinsic activity (that is, turnover frequency) despite the threefold increase in Sn loading, and the extremely rapid and benign nature of our preparation methodology. We also identify the presence of spectator sites, in the form of SnIV oligomers, at higher levels of Sn loading. The consequences of this mixed population with regards to catalysis (Meerwein–Pondorf–Verley reaction and glucose isomerization) are also identified.

Effects of composition on structure and activity of PtRu/C catalysts

A series of carbon supported PtRu bimetallic catalysts with varying Pt:Ru ratio were prepared and characterised using ex situ and in situ XRD, in situ EXAFS at 0 V vs. RHE, ex situ XPS and monolayer CO stripping voltammetry. Although the catalysts were found to be well mixed/alloyed, with no evidence of unalloyed Ru (oxides) present, the surfaces of the electrocatalyst nanoparticles were found to be enriched with Pt compared to the nominal bulk composition. The methanol oxidation activities of the catalysts were determined in 1.0 mol dm(-3) H2SO4. In agreement with published studies of polycrystalline bulk PtRu alloys the catalyst with a 0.6 surface fraction of Pt was found to give the best methanol oxidation activity at 30 degrees C. However, at 80 degrees C a greater surface fraction of Ru could be tolerated, with some activity at low current densities found for a Pt surface fraction as low as 0.2. The results support the conclusion that a limited amount of methanol dehydrogenation occurs at Ru sites or Ru dominated surface ensembles at 80 degrees C.

Preparation, structure, and stability of Pt and Pd monolayer modified Pd and Pt electrocatalysts

A controlled surface reaction technique has been successfully employed to prepare a series of Pt modified Pd/C (Pt/Pd/C) and Pd modified Pt/C (Pd/Pt/C) catalysts. The resulting catalyst materials were characterised by TEM, XRD, electrochemistry, and EXAFS techniques. In the case of the Pd/Pt/C carbon catalysts, core-shell structural arrangements were found, with a 0.04 A contraction of the Pd-Pd bond distance for the 1 Pd/Pt/C being observed. A greater degree of alloying was found for the Pt/Pd/C catalysts where the surface had a mixed composition with a large proportion of the Pt in the interior of the nanoparticle. However, strong Pt characteristics were exhibited in the voltammetry of Pt/Pd/C catalysts, most notably a large increase in the stability with respect to the electrochemical environment compared to Pd alone.

Light alkane oxidation using catalysts prepared by chemical vapour impregnation: tuning alcohol selectivity through catalyst pre-treatment

Fe/ZSM-5(30) catalysts have been prepared by chemical vapour impregnation (CVI) using iron(III) acetylacetonate as the precursor. These materials have been used for the oxidation of methane and ethane using aqueous hydrogen peroxide as oxidant. Heating in air leads to materials that exhibit high catalytic activity and give formic and acetic acid with high selectivity from methane and ethane respectively. Heat treatment of the uncalcined materials under a reducing atmosphere results in partial reduction of iron from the FeIII to FeII oxidation state with the majority of the iron being present as isolated octahedral extra-framework species having oxygen neighbours and showing no evidence of a coordination shell containing Al or Fe, as evidenced from studies using X-ray absorption and UV-Vis spectroscopies. These hydrogen treated catalysts show the same catalytic activity as their analogues formed by heating in air, but in contrast exhibit higher alcohol selectivities for both methane and ethane conversion to oxygenates and are reusable. Our findings for both the oxidation of methane and ethane indicate that the selectivity to the oxidation products, i.e. acids or alcohols, can be controlled by tuning the active site structure and/or oxidation state of the Fe species in Fe/ZSM-5.

Chemogenetic Evaluation of the Mitotic Kinesin CENP-E Reveals a Critical Role in Triple-Negative Breast Cancer

Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, and HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using more than a thousand breast cancer samples were conducted, which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basal-like breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E–dependent molecular events (e.g., phosphorylation of histone H3 Ser-10; phospho-HH3-Ser10) to functional outcomes (e.g., chromosomal congression defects). Across a diverse panel of breast cell lines, CENP-E inhibition by PF-2771 selectively inhibits proliferation of basal breast cancer cell lines relative to premalignant ones and its response correlates with the degree of chromosomal instability. Pharmacokinetic–pharmacodynamic efficacy analysis in a basal-a xenograft tumor model shows that PF-2771 exposure is well correlated with increased phospho-HH3-Ser10 levels and tumor growth regression. Complete tumor regression is observed in a patient-derived, basal-a breast cancer xenograft tumor model treated with PF-2771. Tumor regression is also observed with PF-2771 in a taxane-resistant basal-a model. Taken together, CENP-E may be an effective therapeutic target for patients with triple-negative/basal-a breast cancer. Mol Cancer Ther; 13(8); 2104–15. ©2014 AACR.