82 research outputs found
Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design
The main task of the medicinal chemist is to design molecules that interact
specifically with derailed or degenerating processes in a diseased organism,
translating the available knowledge of pathobiochemical and physiological data into
chemically useful information and structures. Current knowledge of the biological
and chemical processes underlying diseases is vast and rapidly expanding. In
particular the unraveling of the genome in combination with, for instance, the rapid
development of structural biology has led to an explosion in available information and
identification of new targets for chemotherapy. The task of translating this wealth of
data into active and selective new drugs is an enormous, but realistic, challenge. It
requires knowledge from many different fields, including molecular biology,
chemistry, pharmacology, physiology, and medicine and as such requires a truly
interdisciplinary approach.
Ultimately, the goal is to design molecules that satisfy all the requirements for a
candidate drug to function therapeutically. Therapeutic activity can then be achieved
by an understanding of and control over structure and reactivity of the candidate drug
through molecular manipulation
ΠΡΠ΅ΡΠΎΡΠΊΠ»Π΅ΡΠΎΠ·: ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΌΠ΅Ρ Π°Π½ΠΈΠ·ΠΌΡ ΠΈ ΠΏΡΠΈΠ½ΡΠΈΠΏΡ Π»Π΅ΡΠ΅Π½ΠΈΡ
ΠΡΠΎΠ²Π΅Π΄Π΅Π½ Π°Π½Π°Π»ΠΈΠ· ΡΠ°ΠΊΡΠΎΡΠΎΠ² ΡΠΈΡΠΊΠ° ΡΠ°Π·Π²ΠΈΡΠΈΡ Π°ΡΠ΅ΡΠΎΡΠΊΠ»Π΅ΡΠΎΠ·Π°, Π΄Π°Π½Π° ΠΎΡΠ΅Π½ΠΊΠ° ΡΡΠ΄Π° ΡΠ΅ΠΎΡΠΈΠΉ, ΠΎΠ±ΡΡΡΠ½ΡΡΡΠΈΡ
ΠΏΠΎΡΠ²Π»Π΅Π½ΠΈΠ΅ Π°ΡΠ΅ΡΠΎΡΠΊΠ»Π΅ΡΠΎΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΠΉ ΠΊΠΎΡΠΎΠ½Π°ΡΠ½ΡΡ
Π°ΡΡΠ΅ΡΠΈΠΉ. ΠΠΎΠ΄ΡΠ΅ΡΠΊΠΈΠ²Π°Π΅ΡΡΡ ΡΠΎΠ»Ρ ΡΠ½Π΄ΠΎΡΠ΅Π»ΠΈΠ°Π»ΡΠ½ΠΎΠΉ Π΄ΠΈΡΡΡΠ½ΠΊΡΠΈΠΈ Π² ΠΏΡΠΎΠ³ΡΠ΅ΡΡΠΈΡΠΎΠ²Π°Π½ΠΈΠΈ ΠΈ ΠΎΠ±ΠΎΡΡΡΠ΅Π½ΠΈΠΈ ΡΠ΅ΡΠ΄Π΅ΡΠ½ΠΎβΡΠΎΡΡΠ΄ΠΈΡΡΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. ΠΡΠΎΠ°Π½Π°Π»ΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Ρ ΡΠΎΠ²ΡΠ΅ΠΌΠ΅Π½Π½ΡΠ΅ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄Ρ ΠΊ Π»Π΅ΡΠ΅Π½ΠΈΡ Π°ΡΠ΅ΡΠΎΡΠΊΠ»Π΅ΡΠΎΠ·Π°.Risk factors of atherosclerosis development are described, a number of theories explaining atherosclerotic changes appearance in the coronary arteries are analyzed critically. The role of endothelial dysfunction in progress and exacerbation of cardiovascular diseases is emphasized. Contemporary approaches to atherosclerosis treatment are discussed
High-Yield 5-Hydroxymethylfurfural Synthesis from Crude Sugar Beet Juice in a Biphasic Microreactor
5-Hydroxymethylfurfural (HMF) is an important biobased platform chemical obtainable in high selectivity by the hydrolysis of fructose (FRC). However, FRC is expensive, making the production of HMF at a competitive market price highly challenging. Here, it is shown that sugar beet thick juice, a crude, sucrose-rich intermediate in sugar refining, is an excellent feedstock for HMF synthesis. Unprecedented high selectivities and yields of '90 % for HMF were achieved in a biphasic reactor setup at 150 Β°C using salted diluted thick juice with H2SO4 as catalyst and 2-methyltetrahydrofuran as a bioderived extraction solvent. The conversion of glucose, obtained by sucrose inversion, could be limited to '10 mol %, allowing its recovery for further use. Interestingly, purified sucrose led to significantly lower HMF selectivity and yields, showing advantages from both an economic and chemical selectivity perspective. This opens new avenues for more cost-effective HMF production
Vanillic acid and methoxyhydroquinone production from guaiacyl units and related aromatic compounds using Aspergillus niger cell factories
Background The aromatic compounds vanillin and vanillic acid are important fragrances used in the food, beverage, cosmetic and pharmaceutical industries. Currently, most aromatic compounds used in products are chemically synthesized, while only a small percentage is extracted from natural sources. The metabolism of vanillin and vanillic acid has been studied for decades in microorganisms and many studies have been conducted that showed that both can be produced from ferulic acid using bacteria. In contrast, the degradation of vanillin and vanillic acid by fungi is poorly studied and no genes involved in this metabolic pathway have been identified. In this study, we aimed to clarify this metabolic pathway in Aspergillus niger and identify the genes involved. Results Using whole-genome transcriptome data, four genes involved in vanillin and vanillic acid metabolism were identified. These include vanillin dehydrogenase (vdhA), vanillic acid hydroxylase (vhyA), and two genes encoding novel enzymes, which function as methoxyhydroquinone 1,2-dioxygenase (mhdA) and 4-oxo-monomethyl adipate esterase (omeA). Deletion of these genes in A. niger confirmed their role in aromatic metabolism and the enzymatic activities of these enzymes were verified. In addition, we demonstrated that mhdA and vhyA deletion mutants can be used as fungal cell factories for the accumulation of vanillic acid and methoxyhydroquinone from guaiacyl lignin units and related aromatic compounds. Conclusions This study provides new insights into the fungal aromatic metabolic pathways involved in the degradation of guaiacyl units and related aromatic compounds. The identification of the involved genes unlocks new potential for engineering aromatic compound-producing fungal cell factories.Peer reviewe
Robust Bayes-Like Estimation: Rho-Bayes estimation
We consider the problem of estimating the joint distribution of
independent random variables within the Bayes paradigm from a non-asymptotic
point of view. Assuming that admits some density with respect to a
given reference measure, we consider a density model for that
we endow with a prior distribution (with support ) and we
build a robust alternative to the classical Bayes posterior distribution which
possesses similar concentration properties around whenever it belongs to
the model . Furthermore, in density estimation, the Hellinger
distance between the classical and the robust posterior distributions tends to
0, as the number of observations tends to infinity, under suitable assumptions
on the model and the prior, provided that the model contains the
true density . However, unlike what happens with the classical Bayes
posterior distribution, we show that the concentration properties of this new
posterior distribution are still preserved in the case of a misspecification of
the model, that is when does not belong to but is close
enough to it with respect to the Hellinger distance.Comment: 68 page
Electronic and bite angle effects in catalytic C-O bond cleavage of a lignin model compound using ruthenium xantphos complexes
The authors would like to thank the EPSRC (Global Engagement grant EP/K00445X/1 and critical mass grant EP/J018139/1) and the European Union (Marie Curie ITN βSuBiCatβ PITN-GA-2013-607044) for financial support. NMSF-Swansea and Mr. Stephen Boyer are kindly acknowledged for mass spectrometry and elemental analysis, respectively.Bite angle and electronic effects on the ruthenium-diphosphine catalysed ether bond cleavage of the lignin Ξ²-O-4 model compound 2-phenoxy-1-phenethanol were tested. Enhanced conversion of the substrate was observed with increasing Ο-donor capacity of the ligands. Kinetic and thermodynamic data suggest oxidative addition of the dehydrogenated model compound to the diphosphine Ru(0) complex to be rate-limiting.PostprintPeer reviewe
Catalytic fast pyrolysis of biomass : catalyst characterization reveals the feed-dependent deactivation of a technical ZSM-5-based catalyst
Catalyst deactivation due to coking is a major challenge in the catalytic fast pyrolysis (CFP) of biomass. Here, a multitechnique investigation of a technical Al2O3-bound ZSM-5-based extrudate catalyst, used for the CFP of pine wood and cellulose (at a reactor temperature of 500 Β°C), provided insight into the effects of extrusion, the catalytic pyrolysis process, and catalyst regeneration on the catalyst structure. As a result of a reduction in acidity and surface area due to the coking catalyst, the activity dropped drastically with increasing time-on-stream (TOS), as evidenced by a decrease in aromatics yield. Strikingly, confocal fluorescence microscopy at the single-particle level revealed that vapor components derived from whole biomass or just the cellulose component coke differently. While pine-wood-derived species mainly blocked the external area of the catalyst particle, larger carbon deposits were formed inside the catalystβs micropores with cellulose-derived species. Pyridine FT-IR and solid-state NMR spectroscopy demonstrated irreversible changes after regeneration, likely due to partial dealumination. Taken together with <30 g kgβ1 aromatics yield on a feed basis, the results show a mismatch between biomass pyrolysis vapors and the technical catalyst used due to a complex interplay of mass transfer limitations and CFP chemistry
Supported bimetallic nano-alloys as highly active catalysts for the one-pot tandem synthesis of imines and secondary amines from nitrobenzene and alcohols
The synthesis and functionalization of imines and amines are key steps in the preparation of many fine chemicals and for pharmaceuticals in particular. Traditionally, metal complexes are used as homogeneous catalysts for these organic transformations. Here we report gold-palladium and ruthenium-palladium nano-alloys supported on TiO2 acting as highly efficient heterogeneous catalysts for the one-pot synthesis of the imine N-benzylideneaniline and the secondary amine N-benzylaniline directly from the easily available and stable nitrobenzene and benzyl alcohol precursors using a hydrogen auto-transfer strategy. These reactions were carried out without any added external hydrogen, sacrificial hydrogen donor or a homogeneous base. The bimetallic catalysts were prepared by the recently developed modified impregnation strategy, giving efficient control of size and nano-alloy composition. Both bimetallic catalysts were found to be far more active than their monometallic analogues due to a synergistic effect. Based on the turnover numbers the catalytic activities follow the order Ru < Pd < Au << Au-Pd < Ru-Pd. Aberration corrected scanning transmission electron microscopy (AC-STEM) and X-ray absorption spectroscopy (XAFS) studies of these catalysts revealed that the reason for the observed synergistic effect is the electronic modification of the metal sites in the case of the Au-Pd system and a size stabilisation effect in the case of the Ru-Pd catalyst
Identification of a diagnostic structural motif reveals a new reaction intermediate and condensation pathway in kraft lignin formation
The authors gratefully acknowledge financial support of NWO, the Smart Mix Program of the Netherlands Ministry of Economic Affairs and the Netherlands Ministry of Education, Culture and Science. The NWO Large grant 175.107.301.10 is also gratefully acknowledged.Kraft lignin, the main by-product of the pulping industry, is an abundant, yet highly underutilized renewable aromatic polymer. During kraft pulping, the lignin undergoes extensive structural modification, with many labile native bonds being replaced by new, more recalcitrant ones. Currently little is known about the nature of those bonds and linkages in kraft lignin, information that is essential for its efficient valorization to renewable fuels, materials or chemicals. Here, we provide detailed new insights into the structure of softwood kraft lignin, identifying and quantifying the major native as well as kraft pulping-derived units as a function of molecular weight. De novo synthetic kraft lignins, generated from (isotope labelled) dimeric and advanced polymeric models, provided key mechanistic understanding of kraft lignin formation, revealing different process dependent reaction pathways to be operating. The discovery of a novel kraft-derived lactone condensation product proved diagnostic for the identification of a previously unknown homovanillin based condensation pathway. The lactone marker is found in various different soft- and hardwood kraft lignins, suggesting the general pertinence of this new condensation mechanism for kraft pulping. These novel structural and mechanistic insights will aid the development of future biomass and lignin valorization technologies.Publisher PDFPeer reviewe
Improved catalytic activity of rutheniumβarene complexes in the reduction of NAD+
A series of neutral Ru-II half-sandwich complexes of the type [(eta(6)-arene)Ru(N,N')Cl] where the arene is para-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), or benzene (bn) and N,N' is N-(2-aminoethyl) -4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-4-toluenesulfonamide (TsEn), or N-(2-aminoethyl)-methylenesulfonamide (MsEn) were synthesized and characterized. X-ray crystal structures of [(p-cym)Ru(MsEn)Cl] (1), [(hmb)Ru(TsEn)Cl] (5), [(hmb)Ru(TfEn)Cl] (6), [(bip)Ru(MsEn)Cl] (7), and [(bip)Ru(TsEn)Cl] (8) have been determined. The complexes can regioselectively catalyze the transfer hydrogenation of NAD(+) to give 1,4-NADH in the presence of formate. The turnover frequencies (TOF) when the arene is varied decrease in the order bn > bip > p-cym > hmb for complexes with the same N,N' chelating ligand. The TOF decreased with variation in the N,N' chelating ligand in the order TfEn > TsEn > MsEn for a given arene. [(bn)Ru(TfEn)Cl] (12) was the most active, with a TOP of 10.4 h(-1). The effects of NAD(+) and formate concentration on the reaction rates were determined for [(p-cym)Ru(TsEn)Cl] (2). Isotope studies implicated the formation of [(arene)Ru(N,N')(H)] as the rate-limiting step. The coordination of formate and subsequent CO2 elimination to generate the hydride were modeled computationally by density functional theory (DFT). CO2 elimination occurs via a two-step process with the coordinated formate first twisting to present its hydrogen toward the metal center. The computed barriers for CO2 release for arene = benzene follow the order MsEn > TsEn > TfEn, and for the Ms En system the barrier followed bn < hmb, both consistent with the observed rates. The effect of methanol on transfer hydrogenation rates in aqueous solution was investigated. A study of pH dependence of the reaction in D2O gave the optimum pH* as 7.2 with a TOF of 1.58 h(-1) for 2. The series of compounds reported here show an improvement in the catalytic activity by an order of magnitude compared to the ethylenediamine analogues
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