Entrapping Digestive Enzymes with Engineered Mesoporous Silica Particles Reduces Metabolic Risk Factors in Humans.

Engineered mesoporous silica particles (MSP) are thermally and chemically stable porous materials composed of pure silica and have attracted attention for their potential biomedical applications. Oral intake of engineered MSP is shown to reduce body weight and adipose tissue in mice. Here, clinical data from a first-in-humans study in ten healthy individuals with obesity are reported, demonstrating a reduction in glycated hemoglobin (HbA1c) and low-density lipoprotein cholesterol, which are well-established metabolic and cardiovascular risk factors. In vitro investigations demonstrate sequestration of pancreatic  α-amylase and lipase in an MSP pore-size dependent manner. Subsequent ex vivo experiments in conditions mimicking intestinal conditions and in vivo experiments in mice show a decrease in enzyme activity upon exposure to the engineered MSP, presumably by the same mechanism. Therefore, it is suggested that tailored MSP act by lowering the digestive enzyme availability in the small intestine, resulting in decreased digestion of macronutrient and leading to reduced caloric uptake. This novel MSP based mechanism-of-action, combined with its excellent safety in man, makes it a promising future agent for prevention and treatment of metabolic diseases.

Mesoporous silica with precisely controlled pores reduces food efficiency and suppresses weight gain in mice.

Aim: Obesity is a risk factor for cardiovascular disease and diabetes. We aimed to elucidate the effects of distinct mesoporous silica particles (MSPs) supplemented in food on metabolic parameters in obesity. Materials & methods: MSPs with precisely controlled pore size were synthesized, characterized and compared with a control in a C57Bl/6 mouse diet-induced obesity model, studying weight, adiposity, metabolic regulation and food efficiency. Results: The most effective MSPs reduced adipose tissue formation to 6.5 ± 0.5 g compared with 9.4 ± 1.2 g, leptin levels nearly halved from 32.8 ± 7.4 to 16.9 ± 1.9 ng/ml and a 33% reduction of food efficiency. Control MSP showed no effects. Conclusion: Results demonstrate potential of distinct MSPs to improve metabolic risk factors. Further studies investigating mechanism of action and confirming human safety are needed.

Electrochemically Driven Water Oxidation by a Highly Active Ruthenium-Based Catalyst.

The highly active ruthenium-based water oxidation catalyst [RuX (mcbp)(OHn )(py)2 ] [mcbp2- =2,6-bis(1-methyl-4-(carboxylate)benzimidazol-2-yl)pyridine; n=2, 1, and 0 for X=II, III, and IV, respectively], can be generated in a mixture of RuIII and RuIV states from either [RuII (mcbp)(py)2 ] or [RuIII (Hmcbp)(py)2 ]2+ precursors. The precursor complexes are isolated and characterized by single-crystal X-ray analysis, NMR, UV/Vis, EPR, and FTIR spectroscopy, ESI-HRMS, and elemental analysis, and their redox properties are studied in detail by electrochemical and spectroscopic methods. Unlike the parent catalyst [Ru(tda) (py)2 ] (tda2- =[2,2':6',2''-terpyridine]-6,6''-dicarboxylate), for which full transformation into the catalytically active species [RuIV (tda)(O)(py)2 ] could not be carried out, stoichiometric generation of the catalytically active Ru-aqua complex [RuX (mcbp)(OHn )(py)2 ] from the RuII precursor was achieved under mild conditions (pH 7.0) and short reaction times. The redox properties of the catalyst were studied and its activity for electrocatalytic water oxidation was evaluated, reaching a maximum turnover frequency (TOFmax ) of around 40 000 s-1 at pH 9.0 (from foot-of-the-wave analysis), which is comparable to the activity of the state-of-the-art catalyst [RuIV (tda)(O)(py)2 ].

Total Chemical Synthesis of Human Thyroid-Stimulating Hormone (hTSH) ß-Subunit: Application of Arginine-tagged Acetamidomethyl (AcmR) Protecting Groups.

The ß-subunit of human thyroid stimulating hormone (hTSH) has been synthesized as a single glycoform bearing a chitobiose disaccharide at the native glycosylation site. Key to the successful completion of this synthesis was the introduction of an arginine-tagged acetamidomethyl group, which served to greatly facilitate handling of a glycopeptide fragment with poor aqueous solubility. This general solution to the challenge of working with intractable peptides is expected to find wide use in protein synthesis.

Chemical and Photochemical Water Oxidation Mediated by an Efficient Single-Site Ruthenium Catalyst.

Water oxidation is a fundamental step in artificial photosynthesis for solar fuels production. In this study, we report a single-site Ru-based water oxidation catalyst, housing a dicarboxylate-benzimidazole ligand, that mediates both chemical and light-driven oxidation of water efficiently under neutral conditions. The importance of the incorporation of the negatively charged ligand framework is manifested in the low redox potentials of the developed complex, which allows water oxidation to be driven by the mild one-electron oxidant [Ru(bpy)3 ]3+ (bpy=2,2'-bipyridine). Furthermore, combined experimental and DFT studies provide insight into the mechanistic details of the catalytic cycle.

Catalyst-solvent interactions in a dinuclear Ru-based water oxidation catalyst.

Photocatalytic water oxidation represents a key process in conversion of solar energy into fuels and can be facilitated by the use of molecular transition metal-based catalysts. A novel straightforward approach for covalent linking of the catalytic units to other moieties is demonstrated by preparation of a dinuclear complex containing two [Ru(pdc)(pic)3]-derived units (pdc = 2,6-pyridinedicarboxylate, pic = 4-picoline). The activity of this complex towards chemical and photochemical oxidation of water was evaluated and a detailed insight is given into the interactions between the catalyst and acetonitrile, a common co-solvent employed to increase solubility of water oxidation catalysts. The solvent-induced transformations were studied by electrochemical and spectroscopic techniques and the relevant quantitative parameters were extracted.

Water oxidation catalyzed by molecular di- and nonanuclear Fe complexes: importance of a proper ligand framework.

The synthesis of two molecular iron complexes, a dinuclear iron(iii,iii) complex and a nonanuclear iron complex, based on the dinucleating ligand 2,2'-(2-hydroxy-5-methyl-1,3-phenylene)bis(1H-benzo[d]imidazole-4-carboxylic acid) is described. The two iron complexes were found to drive the oxidation of water by the one-electron oxidant [Ru(bpy)3](3+).

Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides.

Human granulocyte colony-stimulating factor (G-CSF) is an endogenous glycoprotein involved in hematopoiesis. Natively glycosylated and nonglycosylated recombinant forms, lenograstim and filgrastim, respectively, are used clinically to manage neutropenia in patients undergoing chemotherapeutic treatment. Despite their comparable therapeutic potential, the purpose of O-linked glycosylation at Thr133 remains a subject of controversy. In light of this, we have developed a synthetic platform to prepare G-CSF aglycone with the goal of enabling access to native and designed glycoforms with site-selectivity and glycan homogeneity. To address the synthesis of a relatively large, aggregation-prone sequence, we advanced an isonitrile-mediated ligation method. The chemoselective activation and coupling of C-terminal peptidyl Gly thioacids with the N-terminus of an unprotected peptide provide ligated peptides directly in a manner complementary to that with conventional native chemical ligation-desulfurization strategies. Herein, we describe the details and application of this method as it enabled the convergent total synthesis of G-CSF aglycone.

Well-defined palladium nanoparticles supported on siliceous mesocellular foam as heterogeneous catalysts for the oxidation of water.

Herein, we describe the use of Pd nanoparticles immobilized on an amino-functionalized siliceous mesocellular foam for the catalytic oxidation of H2O. The Pd nanocatalyst proved to be capable of mediating the four-electron oxidation of H2O to O2, both chemically and photochemically. The Pd nanocatalyst is easy to prepare and shows high chemical stability, low leaching, and recyclability. Together with its promising catalytic activity, these features make the Pd nanocatalyst of potential interest for future sustainable solar-fuel production.

Combined heterogeneous metal/chiral amine: multiple relay catalysis for versatile eco-friendly synthesis.

Herein is described a versatile and broad synergistic strategy for expansion of chemical space and the synthesis of valuable molecules (e.g. carbocycles and heterocycles), with up to three quaternary stereocenters, in a highly enantioselective fashion from simple alcohols (31 examples, 95:5 to >99.5:0.5 e.r.) using integrated heterogeneous metal/chiral amine multiple relay catalysis and air/O2 as the terminal oxidant. A novel highly 1,4-selective heterogeneous metal/amine co-catalyzed hydrogenation of enals was also added to the relay catalysis sequences.

Synthesis of granulocyte-macrophage colony-stimulating factor as homogeneous glycoforms and early comparisons with yeast cell-derived material.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a medicinally important glycoprotein, used as an immunostimulant following bone-marrow transplant. On the basis of reports of its potential utility as an anticancer vaccine adjuvant, we undertook to develop a synthetic route toward single-glycoform GM-CSF. We describe herein a convergent total synthesis of GM-CSF aglycone and two homogeneous glycoforms. Analytical and biological studies confirm the structure and activity of these synthetic congeners.

Cycloisomerization of acetylenic acids to γ-alkylidene lactones using a palladium(II) catalyst supported on amino-functionalized siliceous mesocellular foam.

Cycloisomerization of various γ-acetylenic acids to their corresponding γ-alkylidene lactones by the use of a heterogeneous Pd(II) catalyst supported on amino-functionalized siliceous mesocellular foam is described. Substrates containing terminal as well as internal alkynes were cyclized in high to excellent yields within 2­24 h under mild reaction conditions. The protocol exhibited high regio- and stereoselectivity, favoring the exo-dig product with high Z selectivity. Moreover, the catalyst displayed excellent stability under the employed reaction conditions, as demonstrated by its good recyclability and low leaching.

Artificial photosynthesis: from nanosecond electron transfer to catalytic water oxidation.

Human society faces a fundamental challenge as energy consumption is projected to increase due to population and economic growth as fossil fuel resources decrease. Therefore the transition to alternative and sustainable energy sources is of the utmost importance. The conversion of solar energy into chemical energy, by splitting H2O to generate molecular O2 and H2, could contribute to solving the global energy problem. Developing such a system will require the combination of several complicated processes, such as light-harvesting, charge separation, electron transfer, H2O oxidation, and reduction of the generated protons. The primary processes of charge separation and catalysis, which occur in the natural photosynthetic machinery, provide us with an excellent blueprint for the design of such systems. This Account describes our efforts to construct supramolecular assemblies capable of carrying out photoinduced electron transfer and to develop artificial water oxidation catalysts (WOCs). Early work in our group focused on linking a ruthenium chromophore to a manganese-based oxidation catalyst. When we incorporated a tyrosine unit into these supramolecular assemblies, we could observe fast intramolecular electron transfer from the manganese centers, via the tyrosine moiety, to the photooxidized ruthenium center, which clearly resembles the processes occurring in the natural system. Although we demonstrated multi-electron transfer in our artificial systems, the bottleneck proved to be the stability of the WOCs. Researchers have developed a number of WOCs, but the majority can only catalyze H2O oxidation in the presence of strong oxidants such as Ce(IV), which is difficult to generate photochemically. By contrast, illumination of ruthenium(II) photosensitizers in the presence of a sacrificial acceptor generates [Ru(bpy)3](3+)-type oxidants. Their oxidation potentials are significantly lower than that of Ce(IV), but our group recently showed that incorporating negatively charged groups into the ligand backbone could decrease the oxidation potential of the catalysts and, at the same time, decrease the potential for H2O oxidation. This permitted us to develop both ruthenium- and manganese-based WOCs that can operate under neutral conditions, driven by the mild oxidant [Ru(bpy)3](3+). Many hurdles to the development of viable systems for the production of solar fuels remain. However, the combination of important features from the natural photosynthetic machinery and novel artificial components adds insights into the complicated catalytic processes that are involved in splitting H2O.

Application and mechanistic studies of a water-oxidation catalyst in alcohol oxidation by employing oxygen-transfer reagents.

By using a dimeric ruthenium complex in combination with tert-butyl hydrogen peroxide (TBHP) as stoichiometric oxidant, a mild and efficient protocol for the oxidation of secondary benzylic alcohols was obtained, thereby giving the corresponding ketones in high yields within 4 h. However, in the oxidation of aliphatic alcohols, the TBHP protocol suffered from low conversions owing to a competing Ru-catalyzed disproportionation of the oxidant. Gratifyingly, by switching to Oxone (2 KHSO(5)⋅KHSO(4)⋅K(2)SO(4) triple salt) as stoichiometric oxidant, a more efficient and robust system was obtained that allowed for the oxidation of a wide range of aliphatic and benzylic secondary alcohols, giving the corresponding ketones in excellent yields. The mechanism for these reactions is believed to involve a high-valent Ru(V)-oxo species. We provide support for such an intermediate by means of mechanistic studies.

Highly enantioselective cascade transformations by merging heterogeneous transition metal catalysis with asymmetric aminocatalysis.

The concept of combining heterogeneous transition metal and amine catalysis for enantioselective cascade reactions has not yet been realized. This is of great advantage since it would allow for the recycling of expensive and non-environmentally friendly transition metals. We disclose that the use of a heterogeneous Pd-catalyst in combination with a simple chiral amine co-catalyst allows for highly enantioselective cascade transformations. The preparative power of this process has been demonstrated in the context of asymmetric cascade Michael/carbocyclization transformations that delivers cyclopentenes bearing an all carbon quaternary stereocenters in high yields with up to 30:1 dr and 99% ee. Moreover, a variety of highly enantioselective cascade hetero-Michael/carbocyclizations were developed for the one-pot synthesis of valuable dihydrofurans and pyrrolidines (up to 98% ee) by using bench-stable heterogeneous Pd and chiral amines as co-catalysts.